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Last Updated :2024/08/29

研究者情報

マスター

アカウント（マスター）

  • 氏名

    中村　昭伸(ナカムラ　アキノブ), ナカムラ　アキノブ

所属（マスター）

  • 医学研究院　内科系部門　内科学分野

所属（マスター）

  • 医学研究院　内科系部門　内科学分野

独自項目

syllabus

  • 2021, 基本医学研究, Master's Thesis Research in Medical Sciences, 修士課程, 医学院, 免疫、代謝・内分泌、腎 Rheumatology, Endocrinology, Nephrology
  • 2021, 基本医学総論, Basic Principles of Medicine, 修士課程, 医学院, 免疫、代謝・内分泌、腎 Rheumatology, Endocrinology, Nephrology
  • 2021, 応用社会行動科学, Advanced Social and behavioral Sciences, 修士課程, 医学院, 健康増進科学、健康増進活動、栄養、食生活、運動、身体活動 health promotion studies, health promotion activities, nutrition, diet, exercise, physical activity
  • 2021, 医学総論, Principles of Medicine, 博士後期課程, 医学院, 免疫、代謝・内分泌、腎 Rheumatology, Endocrinology, Nephrology
  • 2021, 基盤医学研究, Dissertation Research in Medical Sciences, 博士後期課程, 医学院, 免疫、代謝・内分泌、腎 Rheumatology, Endocrinology, Nephrology
  • 2021, 臨床医学研究, Dissertation Research in Clinical Medicine, 博士後期課程, 医学院, 免疫、代謝・内分泌、腎 Rheumatology, Endocrinology, Nephrology
  • 2021, 統合・内分泌・代謝学, Integrated・Endocrinology and Metabolism, 学士課程, 医学部, 健康増進科学、健康増進活動、栄養、食生活、運動、身体活動 health promotion studies, health promotion activities, nutrition, diet, exercise, physical activity
  • 2021, 成人健康障害論Ⅱ, Surgical Disorders in Nursing Ⅱ, 学士課程, 医学部, 血液疾患、呼吸器疾患、循環器疾患、消化器疾患 代謝・免疫学的疾患、感染症、腎・泌尿器疾患、神経疾患
  • 2021, 保健生理学, Physiology, 学士課程, 医学部, 細胞・組織生理、循環生理、呼吸生理、消化・吸収の生理、代謝・内分泌生理、外部環境からの防御、発生と老化、神経・筋生理

researchmap

プロフィール情報

学位

  • 医学博士（北海道大学）

プロフィール情報

  • 姓

    中村, ナカムラ

  • 名

    昭伸, アキノブ

  • ID各種

    201201057536041317

業績リスト

研究キーワード

  • 糖尿病薬物療法   膵β細胞   インスリン分泌   2型糖尿病   

研究分野

  • ライフサイエンス / 代謝、内分泌学

経歴

  • 2020年03月 - 現在 北海道大学大学院医学研究院
  • 2013年04月 - 2020年02月 北海道大学病院
  • 2009年05月 - 2013年03月 横浜市立大学附属病院

学歴

  • 2005年04月 - 2009年03月   北海道大学大学院

受賞

  • 2024年 日本臨床分子医学会 学会賞
     
    受賞者: 中村昭伸
  • 2024年 日本糖尿病・肥満動物学会 研究賞
     
    受賞者: 中村昭伸
  • 2022年 日本糖尿病協会 ウイリアム・カレン賞
     
    受賞者: 中村昭伸
  • 2021年 日本内分泌学会 研究奨励賞
     
    受賞者: 中村昭伸
  • 2019年 令和元年度 北海道科学技術奨励賞
     
    受賞者: 中村 昭伸
  • 2014年 日本糖尿病協会 国際交流研究奨励賞
     
    受賞者: 中村 昭伸
  • 2013年 横浜市立大学医学研究奨励賞
     
    受賞者: 中村 昭伸
  • 2010年 第47回 日本臨床分子医学会 学術奨励賞
     
    受賞者: 中村 昭伸
  • 2010年 第83回 日本内分泌学会 若手研究奨励賞
     
    受賞者: 中村 昭伸
  • 2009年 第37回 内分泌代謝研究会 優秀演題賞
     
    受賞者: 中村 昭伸
  • 2008年 第22回 日本糖尿病・肥満動物学会 若手研究奨励賞
     
    受賞者: 中村 昭伸

論文

  • Akihiro Takahashi, Hiroshi Nomoto, Kinnosuke Onishi, Satoru Manda, Aika Miya, Hiraku Kameda, Akinobu Nakamura, Tatsuya Atsumi
    Diabetes, obesity & metabolism 26 8 3471 - 3474 2024年08月
  • Maiko Miyamoto, Akinobu Nakamura, Aika Miya, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, Naoya Iwahara, Kiyohiko Hotta, Nobuo Shinohara, Tatsuya Atsumi
    American journal of physiology. Endocrinology and metabolism 327 2 E194-E202  2024年08月01日 
    Our previous study revealed that over 50% of recipients with pretransplant impaired glucose tolerance (IGT) improved to normal glucose tolerance after kidney transplantation. However, the mechanism is unclear. We aimed to investigate whether the changes in glucose tolerance are associated with β-cell function and insulin resistance in Japanese kidney transplant recipients with pretransplant IGT. Of the 265 recipients who received kidney transplantation, 54 with pretransplant IGT were included. We divided the recipients into improvement and nonimprovement groups according to the change in the area under the curve for glucose obtained from the oral glucose tolerance test (OGTT). β-Cell function was estimated by the insulin secretion sensitivity index-2 (ISSI-2) and the disposition index (DI). Insulin resistance was estimated by the Matsuda index (MI) and the homeostasis model assessment of insulin resistance (HOMA-IR). ISSI-2 and DI increased significantly after transplantation in the improved group (P < 0.01, P < 0.05, respectively), but not in the nonimproved group. ΔISSI-2 and ΔDI were significantly and positively associated with pretransplant 60-min OGTT plasma glucose levels (both P < 0.01). There were no differences in MI or HOMA-IR between these two groups after transplantation. In recipients not on pretransplant dialysis, a significant negative association was found between Δblood urea nitrogen (BUN) and ΔDI (correlation coefficient = -0.48, P < 0.05). In pretransplant IGT recipients, improvements in glucose tolerance after kidney transplantation were linked to improvements in β-cell function. The higher the 60-min OGTT plasma glucose level, the greater the improvement in posttransplant β-cell function. Improvements in BUN after transplantation were associated with improvements in β-cell function.NEW & NOTEWORTHY In recipients with pretransplant impaired glucose tolerance, improvements in glucose tolerance after kidney transplantation were associated with improvements in β-cell function. The higher the pretransplant 60-min OGTT plasma glucose level, the greater the improvement in posttransplant β-cell function. Although glucose tolerance is known to be impaired after transplantation, the present study focused on the reason for the improvement in glucose tolerance rather than the development of posttransplantation diabetes mellitus.
  • Yuki Oe, Hiroshi Nomoto, Kyu Yong Cho, Kei Yokozeki, Tsubasa Ono, Aika Miya, Hiraku Kameda, Akinobu Nakamura, Yoshiaki Arimura, Tatsuya Atsumi
    BMC endocrine disorders 24 1 124 - 124 2024年07月24日 
    BACKGROUND: Oral semaglutide in older subjects with type 2 diabetes was as effective as in younger subjects, according to phase 3 clinical trials. However, its efficacy can be limited in very aged population, due to the presence of impaired cognitive function and the complex instructions for its use. Here, we investigated its efficacy and safety by further age bracket in older subjects in real-world. METHODS: We retrospectively studied subjects > 65 years of age with type 2 diabetes who started oral semaglutide treatment. The primary outcome was the change in glycated hemoglobin (HbA1c) over 6 months. Adverse events and cognitive function were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) and the Hasegawa Dementia Rating Scale-revised (HDS-R). The achievement rate of glycemic targets was evaluated based on the age, health status of subjects and their use of anti-diabetic agents which can cause hypoglycemia, with additional analysis between two subgroups; early (65-74) versus late (≥ 75) older. Furthermore, we evaluated the relationships between their improvements in HbA1c and the baseline characteristics of the subjects, including their cognitive function and insulin secretory capacity. RESULTS: We studied the efficacy of the drug in 24 subjects. Their HbA1c and body weight significantly decreased (- 13.1 ± 7.5 mmol/mol and - 3.0 ± 2.4 kg, respectively; P < 0.01). Although cognitive function was lower in the late older group (r = -0.57, P < 0.01), changes in HbA1c showed no difference between the two subgroups (P = 0.66) and it correlated with the insulin secretory capacity rather than cognitive function (r = -0.49, P < 0.05). Glycemic targets were more likely to be achieved (P < 0.01), but HbA1c excessively decreased in late older subjects who were also using insulin or an insulin secretagogue. The frequency of adverse events was similar to that in the clinical trial, whereas discontinuation of medication were more frequent among the late older subjects (Early; n = 2, Late; n = 4). CONCLUSIONS: Oral semaglutide improves the glycemic control of older subjects, but it might be a risk for potential hypoglycemia and discontinuation because of adverse events in subjects of ≥ 75 years. Attention should be paid to insulin secretory capacity and concomitant medications rather than concern about adherence.
  • Sho Furusawa, Hiroshi Nomoto, Chiho Oba-Yamamoto, Jun Takeuchi, Miki Ito, Hiroyoshi Kurihara, Shin Aoki, Aika Miya, Hiraku Kameda, Akinobu Nakamura, Tatsuya Atsumi
    Endocrine journal 71 6 603 - 616 2024年06月18日 
    Oral semaglutide has potent anti-hyperglycemic efficacy in phase III trials. However, the complicated dosing instructions hamper to use this drug; therefore, we evaluated the efficacy and safety of oral semaglutide in subjects with type 2 diabetes in a real-world clinical setting. In this multi-center retrospective observational study, we analyzed subjects with type 2 diabetes newly treated with an oral semaglutide for >6 months at four medical centers located in Sapporo, Japan. The changes in glycated hemoglobin, body weight, and other metabolic parameters were evaluated and any adverse event leading to semaglutide discontinuation were recorded from February 2021 to December 2022. This study was registered with the University Hospital Medical Information Network Center (UMIN000050583). Of 543 subjects who met the inclusion criteria, data for 434 subjects (age 55.5 ± 12.6 years; body mass index 29.6 ± 6.0 kg/m2) were analyzed. After a 6 months of observation period, semaglutide 3 mg, 7 mg, or 14 mg was used by 55 (12.7%), 241 (55.5%), and 138 (31.8%) of subjects, respectively. Both glycated hemoglobin and body weight significantly improved: 7.65 ± 1.11% to 6.88 ± 0.91% (p < 0.001) and 80.2 ± 19.2 kg to 77.6 ± 19.2 kg (p < 0.001), respectively. Efficacy was also confirmed in the subgroup switched from other anti-hyperglycemic agents, including dipeptidyl peptidase-4 inhibitors. In total, 154 subjects had symptomatic gastrointestinal symptoms and 39 (7.2%) were discontinued semaglutide due to the adverse events. None of the participants experienced severe hypoglycemic events. Oral semaglutide in subjects with type 2 diabetes improved glycemic control and body weight in a real-world clinical setting.
  • Hiroshi Nomoto, Sho Furusawa, Hiroki Yokoyama, Yuka Suzuki, Rimi Izumihara, Yuki Oe, Kiyohiko Takahashi, Aika Miya, Hiraku Kameda, Kyu Yong Cho, Jun Takeuchi, Yoshio Kurihara, Akinobu Nakamura, Tatsuya Atsumi
    The Journal of clinical endocrinology and metabolism 2024年05月02日 
    CONTEXT: Whether continuation of dipeptidyl peptidase-4 inhibitors (DPP-4is) or switching to oral semaglutide is more beneficial for β-cell function is unclear. OBJECTIVE: To assess the efficacy of switching from DPP-4is to oral semaglutide for β-cell function compared with DPP-4i continuation. METHODS: Post hoc analysis of SWITCH-SEMA 2, a multicenter prospective randomized controlled trial on the switch to oral semaglutide vs DPP-4i continuation without dose adjustment for 24 weeks in subjects with type 2 diabetes treated with DPP-4is, was conducted. Changes in markers for glucose metabolism, including homeostatic model assessment (HOMA2) scores and disposition index (DI), were compared between the groups. RESULTS: A total of 146 subjects (semaglutide group, 69; DPP-4i group, 77) were analyzed. In the semaglutide group, glycemic control, liver enzyme deviations, and lipid profiles improved after 24 weeks. Regarding indices for β-cell function, changes in HOMA2-β as well as DI, reflecting the ability of β-cells to compensate for insulin resistance, were significantly higher in the semaglutide group compared with the DPP-4i group (mean change, +10.4 vs +0.6 in HOMA2-β [P = .001] and +0.09 vs 0.0 in DI [P < .001]). Improvement in DI in the semaglutide group was correlated significantly to changes in body mass index (BMI), HbA1c, and fatty liver index reflecting liver steatosis. Multiple linear regression analysis revealed that dose of semaglutide (≥ 7 mg/day), reduction in fatty liver index, and metformin nonuse were independently associated with improvement of DI. CONCLUSION: Switching to oral semaglutide ameliorated β-cell function compared with DPP-4is, presumably via tissue-to-tissue crosstalk between liver and β-cells.
  • Sho Furusawa, Hiroshi Nomoto, Hiroki Yokoyama, Yuka Suzuki, Atsushi Tsuzuki, Kiyohiko Takahashi, Aika Miya, Hiraku Kameda, Kyu Yong Cho, Jun Takeuchi, So Nagai, Shinji Taneda, Yoshio Kurihara, Akinobu Nakamura, Tatsuya Atsumi
    Diabetes, obesity & metabolism 26 3 961 - 970 2024年03月 
    AIM: To assess whether oral semaglutide provides better glycaemic control, compared with dipeptidyl peptidase-4 inhibitor (DPP-4i) continuation, in people with type 2 diabetes. MATERIALS AND METHODS: In this multicentre, open-label, prospective, randomized, parallel-group comparison study, participants receiving DPP-4is were either switched to oral semaglutide (3-14 mg/day) or continued on DPP-4is. The primary endpoint was the change in glycated haemoglobin (HbA1c) over 24 weeks. Secondary endpoints included changes in metabolic parameters and biomarkers, along with the occurrence of adverse events. Factors associated with HbA1c improvement were also explored. RESULTS: In total, 174 eligible participants were enrolled; 17 dropped out of the study. Consequently, 82 participants in the DPP-4i group and 75 participants in the semaglutide group completed the study and were included in the analysis. Improvement in HbA1c at week 24 was significantly greater when switching to semaglutide compared with DPP-4i continuation [-0.65 (95% confidence interval: -0.79, -0.51) vs. +0.05 (95% confidence interval: -0.07, 0.16) (p < .001)]. Body weight, lipid profiles and liver enzymes were significantly improved in the semaglutide group than in the DPP-4i continuation group. Multiple linear regression analysis revealed that baseline HbA1c and homeostasis model assessment 2-R were independently associated with HbA1c improvement after switching to semaglutide. Seven participants in the semaglutide group discontinued medication because of gastrointestinal symptoms. CONCLUSIONS: Although the potential for gastrointestinal symptoms should be carefully considered, switching from DPP-4is to oral semaglutide may be beneficial for glycaemic control and metabolic abnormalities in people with higher HbA1c and insulin resistance.
  • Rimi Izumihara, Hiroshi Nomoto, Kenichi Kito, Yuki Yamauchi, Kazuno Omori, Yui Shibayama, Shingo Yanagiya, Aika Miya, Hiraku Kameda, Kyu Yong Cho, So Nagai, Ichiro Sakuma, Akinobu Nakamura, Tatsuya Atsumi
    Diabetes & metabolism journal 2024年02月29日 
    BACKGROUND: Fibrates have renal toxicity limiting their use in subjects with chronic kidney disease (CKD). However, pemafibrate has fewer toxic effects on renal function. In the present analysis, we evaluated the effects of pemafibrate on the renal function of diabetic subjects with or without CKD in a real-world clinical setting. METHODS: We performed a sub-analysis of data collected during a multi-center, prospective, observational study of the effects of pemafibrate on lipid metabolism in subjects with type 2 diabetes mellitus complicated by hypertriglyceridemia (the PARM-T2D study). The participants were allocated to add pemafibrate to their existing regimen (ADD-ON), switch from their existing fibrate to pemafibrate (SWITCH), or continue conventional therapy (CTRL). The changes in estimated glomerular filtration rate (eGFR) over 52 weeks were compared among these groups as well as among subgroups created according to CKD status. RESULTS: Data for 520 participants (ADD-ON, n=166; SWITCH, n=96; CTRL, n=258) were analyzed. Of them, 56.7% had CKD. The eGFR increased only in the SWITCH group, and this trend was also present in the CKD subgroup (P<0.001). On the other hand, eGFR was not affected by switching in participants with severe renal dysfunction (G3b or G4) and/or macroalbuminuria. Multivariate analysis showed that being older and a switch from fenofibrate were associated with elevation in eGFR (both P<0.05). CONCLUSION: A switch to pemafibrate may be associated with an elevation in eGFR, but to a lesser extent in patients with poor renal function.
  • Akinobu Nakamura, Aika Miya, Yuka Suzuki, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, So Nagai, Tatsuya Atsumi
    Endocrine journal 71 2 193 - 197 2024年02月28日 
    The post-hoc study, derived from our previous prospective observational study, investigated the association between fasting serum proinsulin levels and hepatic steatosis in people with type 2 diabetes. The severity of hepatic steatosis was assessed using the fatty liver index. A total of 268 participants were divided into three groups: low (n = 110), moderate (n = 75), and high fatty liver index (n = 83). In both the crude and age/sex-adjusted analysis, logarithm-transformed proinsulin was significantly higher in the high fatty liver index group than in the low or moderate groups (all p < 0.01). The moderate fatty liver index group showed higher logarithm-transformed proinsulin than the low group (both p < 0.01). Positive associations between proinsulin and fatty liver index shown in this study would support an involvement of hepato-pancreatic crosstalk in the pathophysiology of type 2 diabetes.
  • Aika Miya, Akinobu Nakamura, Hiroshi Nomoto, Hiraku Kameda, Tatsuya Atsumi
    Endocrine journal 2024年02月23日 
    The proinsulin-to-C-peptide (PI:C) ratio is an index applied during the early stage of pancreatic β-cell dysfunction. The aim of this study was to identify the characteristics associated with the PI:C ratio to discuss pancreatic β-cell dysfunction progression during the natural course of type 2 diabetes and its relationship with glycemic management. This multicenter, prospective observational study included 272 outpatients with type 2 diabetes. Continuous glucose monitoring was performed and fasting blood samples were collected and analyzed. We identified the clinical factors associated with the PI:C ratio by multiple regression analysis. The mean age of the cohort was 68.0 years, mean hemoglobin A1c 7.1% (54 mmol/mol), and mean body mass index 24.9 kg/m2. Multiple regression analysis showed that a prolonged time above the target glucose range (>180 mg/dL) and high body mass index contributed to a high PI:C ratio. However, no associations were found between the PI:C ratio and glucose variability indices. These findings suggested that the PI:C ratio is positively associated with a prolonged hyperglycemic time in type 2 diabetes, whereas its relationship with glucose variability remains unclear.
  • Hiroshi Iesaka, Hiraku Kameda, Aika Miya, Hiroshi Nomoto, Kyu Yong Cho, Akinobu Nakamura, Takashige Abe, Nobuo Shinohara, Tatsuya Atsumi
    Medicine 102 51 e36664  2023年12月22日 
    RATIONALE: The increasing use of immune checkpoint inhibitors (ICIs) for treating malignant tumors result in the concomitant rise of immune-related adverse events (irAEs). This case report may provide useful insight to understanding the etiology of ICI-induced hypophysitis, a severe irAE leading to potentially fatal secondary adrenal insufficiency. PATIENT CONCERNS: An 81-year-old Japanese man was hospitalized for diabetic ketoacidosis following 4 courses of ICI combination therapy with nivolumab and ipilimumab for metastatic renal cell carcinoma. DIAGNOSIS: Insulin secretion was depleted, leading to diagnosis of fulminant type 1 diabetes. Adrenocorticotropic hormone (ACTH) and cortisol levels were very high (60.8 pmol/L and 1575 nmol/L, respectively) upon admission. ACTH and cortisol returned to normal ranges on the 2nd day. On the 8th day, an ACTH loading test showed intact cortisol response (peak value 519 nmol/L). However, on the 14th day, there was a sharp decrease in ACTH and cortisol levels (10.5 pmol/L and 47 nmol/L, respectively) accompanied by fatigue and a drop in blood pressure to 97/63 mm Hg. As secondary adrenal insufficiency was suspected, hydrocortisone replacement was initiated. An ACTH loading test on the 17th day revealed low cortisol peak (peak value 232 nmol/L), indicating sudden disruption of adrenal function. Magnetic resonance imaging showed no abnormal findings and there was no other pituitary hormone deficiency. These findings, along with the patient clinical course, suggest that secondary adrenal insufficiency was caused by acute ACTH producing cell destruction as an irAE associated with ICI therapy. INTERVENTIONS: The patient hyperglycemia and ketoacidosis were treated using extracellular fluid and insulin therapy. After development of adrenal insufficiency, hydrocortisone 20 mg was started, and the patient symptoms improved. OUTCOMES: He was continued on insulin therapy, hydrocortisone, and reinitiated nivolumab. LESSONS: This case provides a detailed course of the fulminant onset of ACTH deficiency during ICI administration, emphasizing the importance of close monitoring.
  • Hiroshi Nomoto, Kenichi Kito, Hiroshi Iesaka, Takahisa Handa, Shingo Yanagiya, Aika Miya, Hiraku Kameda, Kyu Yong Cho, Jun Takeuchi, So Nagai, Ichiro Sakuma, Akinobu Nakamura, Tatsuya Atsumi
    Diabetology & metabolic syndrome 15 1 214 - 214 2023年10月26日 
    BACKGROUND: Pemafibrate has been reported to ameliorate lipid profiles and liver dysfunction. However, which patients derive benefit from the hepatoprotective effects of pemafibrate is unclear. METHODS: We conducted a sub-analysis of the PARM-T2D study where subjects with type 2 diabetes complicated by hypertriglyceridemia were prospectively treated with pemafibrate or conventional therapies for 52 weeks. From the original cohort, subjects who had metabolic-associated fatty liver disease without changing their treatment regimens for comorbidities were analyzed. Eligible subjects (n = 293) (average age 61.2 ± 11.7 years, 37.5% female) treated with pemafibrate (pemafibrate, n = 152) or controls who did not change their treatment regimens (controls, n = 141) were divided into three groups based on their alanine aminotransferase (ALT) levels: ALT ≤ upper normal limit (UNL) (pemafibrate, n = 65; controls, n = 50), UNL < ALT ≤ 2×UNL (pemafibrate, n = 58; controls, n = 54), and 2×UNL < ALT (pemafibrate, n = 29; controls, n = 27). RESULTS: Pemafibrate treatment significantly ameliorated ALT levels (from 29 to 22 U/L, p < 0.001 by Wilcoxon's signed-rank test) in the total cohort and subjects with high ALT levels (2×ULN < ALT), and improved liver fibrosis as assessed by the Fibrosis-4 index (mean change - 0.05 (95% confidence interval: -0.22 to - 0.02), p < 0.05 versus baseline by the Mann-Whitney U-test and p < 0.05 versus the ALT ≤ UNL group by the Kruskal-Wallis test followed by Dunn's post-hoc analysis). CONCLUSIONS: The hepatoprotective effects of pemafibrate were dominant in subjects with type 2 diabetes complicated with liver dysfunction. TRIAL REGISTRATION: This study was registered with the University Hospital Medical Information Network Center Clinical Trials Registry (UMIN000037385).
  • Tomonori Sekizaki, Hiraku Kameda, Akinobu Nakamura, Saki Kuwabara, Hiroshi Nomoto, Kyu Yong Cho, Yukitomo Ishi, Hiroaki Motegi, Hideaki Miyoshi, Tatsuya Atsumi
    Pituitary 26 5 597 - 610 2023年10月 
    PURPOSE: Cushing's disease (CD) results from autonomous adrenocorticotropic hormone (ACTH) secretion by corticotroph adenomas, leading to excessive cortisol production, ultimately affecting morbidity and mortality. Pasireotide is the only FDA approved tumor directed treatment for CD, but it is effective in only about 25% of patients, and is associated with a high rate of hyperglycemia. Neuromedin B (NMB), a member of the bombesin-like peptide family, regulates endocrine secretion and cell proliferation. Here, we assessed NMB and NMB receptor (NMBR) expression in human corticotroph adenomas and the effects of NMBR antagonist PD168368 on murine and human corticotroph tumors. METHODS: To investigate NMB and NMBR expression, real-time qPCR and immunostaining on human pathological specimens of corticotroph, non-functional and somatotroph adenomas were performed. The effects of PD168368 on hormone secretion and cell proliferation were studied in vitro, in vivo and in seven patient-derived corticotroph adenoma cells. NMB and NMBR were expressed in higher extent in human corticotroph adenomas compared with non-functional or somatotroph adenomas. RESULTS: In murine AtT-20 cells, PD168368 reduced proopiomelanocortin (Pomc) mRNA/protein expression and ACTH secretion as well as cell proliferation. In mice with tumor xenografts, tumor growth, ACTH and corticosterone were downregulated by PD168368. In patient-derived adenoma cells, PD168368 reduced POMC mRNA expression in four out of seven cases and ACTH secretion in two out of five cases. A PD168368-mediated cyclin E suppression was also identified in AtT-20 and patient-derived cells. CONCLUSION: NMBR antagonist represents a potential treatment for CD and its effect may be mediated by cyclin E suppression.
  • Hiroshi Nomoto, Yuka Takahashi, Yoshinari Takano, Hiroki Yokoyama, Kazuhisa Tsuchida, So Nagai, Aika Miya, Hiraku Kameda, Kyu Yong Cho, Akinobu Nakamura, Tatsuya Atsumi
    Pharmaceutics 15 8 2023年08月20日 
    Non-alcoholic fatty liver disease (NAFLD) is an important common comorbidity in individuals with type 2 diabetes (T2DM). Although some glucagon-like peptide-1 receptor agonists (GLP-1RAs) have beneficial effects on NAFLD, the efficacy of once-weekly semaglutide has not been established. This was a subanalysis of the SWITCH-SEMA 1 study, a multicenter, prospective, randomized, parallel-group trial comparing switching from liraglutide or dulaglutide to once-weekly semaglutide in subjects with T2DM (SWITCH) versus continuing current GLP-1RAs (Continue) for 24 weeks. This subanalysis consisted of participants who were suspected to have NAFLD [fatty liver index (FLI) ≥ 30]. In total, 58 participants met the criteria of this subanalysis. There were no statistical differences in baseline characteristics between the SWITCH (n = 31) and Continue groups (n = 27). FLI significantly improved during treatment in the SWITCH group (68.6 to 62.7) but not in the Continue group (71.1 to 72.3) (p < 0.01). The improvement of FLI in the SWITCH group was greater in switching from dulaglutide to semaglutide and significantly correlated with older age (p = 0.016) and lower baseline FLI (p < 0.01). The multiple linear regression analysis revealed that the switch from dulaglutide was associated with an improvement in FLI (p = 0.041). Switching from conventional GLP-1RAs to once-weekly semaglutide might be beneficial for individuals with NAFLD complicated with T2DM.
  • Aika Miya, Akinobu Nakamura, Yuka Suzuki, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, Yoichi M Ito, So Nagai, Hideaki Miyoshi, Tatsuya Atsumi
    Diabetes, obesity & metabolism 25 7 1883 - 1889 2023年07月 
    AIM: To evaluate the contribution of body fat mass and serum adiponectin concentration to glucose variability (GV) stability in people with type 2 diabetes with impaired versus preserved endogenous insulin secretion. MATERIALS AND METHODS: This multicentre prospective observational study included 193 people with type 2 diabetes who underwent ambulatory continuous glucose monitoring, abdominal computed tomography and fasting blood sampling. A fasting C-peptide (FCP) concentration >2 ng/mL was defined as preserved endogenous insulin secretion. The participants were divided into high (FCP > 2 ng/mL) and low FCP subgroups (FCP ≤ 2 ng/mL). Multivariate regression analysis was performed in each subgroup. RESULTS: In the high FCP subgroup, the coefficient of variation (CV) in GV was unrelated to abdominal fat area. In the low FCP subgroup, a high CV was significantly related to small abdominal visceral fat area (β = -0.11, standard error 0.03; P < 0.05) and to small subcutaneous fat area (β = -0.09, standard error 0.04; P < 0.05). No significant relationship between serum adiponectin concentration and continuous glucose monitoring-related variables was found. CONCLUSIONS: The contribution of body fat mass to GV depends on the endogenous insulin secretion residue. A small body fat area has independent adverse effects on GV in people with type 2 diabetes and impaired endogenous insulin secretion.
  • Hiroshi Nomoto, Kenichi Kito, Hiroshi Iesaka, Yuki Oe, Shinichiro Kawata, Kazuhisa Tsuchida, Shingo Yanagiya, Aika Miya, Hiraku Kameda, Kyu Yong Cho, Ichiro Sakuma, Naoki Manda, Akinobu Nakamura, Tatsuya Atsumi
    Pharmaceutics 15 7 2023年06月27日 
    Pemafibrate, a novel selective peroxisome proliferator-activated receptor modulator, has beneficial effects on lipid metabolism. However, its effects on glucose metabolism in individuals with type 2 diabetes (T2DM) remain to be fully clarified. This was a subanalysis of the PARM-T2D study, a multicenter prospective observational study on the use of pemafibrate versus conventional therapy for 52 weeks in subjects with T2DM complicated with hypertriglyceridemia. The subanalysis included participants who did not change their treatment for diabetes and did not receive insulin or insulin secretagogues during the study period. Changes in glucose metabolism markers, including homeostatic model assessment (HOMA2) scores and disposition index, were assessed. A total of 279 participants (141 in the pemafibrate group; 138 in the control group) met the criteria for the subanalysis. There were no significant changes in HbA1c during the 52-week study period in both groups. However, the pemafibrate group showed significant improvements versus the control group for insulin resistance assessed by HOMA2-R (-0.15 versus 0.08; estimated treatment difference -0.23 (95% confidence interval -0.44, -0.02); p = 0.03) and maintenance of β-cell function assessed by disposition index (0.015 versus -0.023; estimated treatment difference 0.037 (95% confidence interval 0.005, 0.069); p = 0.02). Correlation analyses showed that improvements in HOMA2-R and disposition index were significantly associated with improvements in lipid abnormalities and γ-glutamyl transpeptidase. In conclusion, pemafibrate reduced insulin resistance and maintained β-cell function in subjects with T2DM and hypertriglyceridemia, presumably by improving lipid profiles and lipid-related hepatocyte stress.
  • 高橋 明広, 亀田 啓, 古澤 翔, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 岩田 尚子, 藤沢 治樹, 鈴木 敦詞, 椙村 益久, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 99 Suppl.Update 11 - 13 (一社)日本内分泌学会 2023年05月 
    症例は34歳男性で、倦怠感、多尿を主訴に、下垂体前葉機能低下、中枢性尿崩症を認め、汎下垂体機能低下症と診断した。診断後はヒドロコルチゾン、レボチロキシン、デスモプレシン点鼻薬の補充により倦怠感や多尿は改善した。頭部Gd造影MRIで下垂体から下垂体茎、視床下部にかけて腫大を認め、下垂体生検よりリンパ球性汎下垂体炎が考えられた。胚細胞腫の好発年齢であり、鑑別に血清抗rabphilin-3A抗体をウェスタンブロット法で測定したところ陽性で、リンパ球性汎下垂体炎と診断した。上記の補充療法とともにhCG投与を行い、現在も経過観察中である。
  • 第1子妊娠中に一過性の尿崩症を呈し,第2子妊娠中に再び尿崩症が出現した1例
    小野 翼, 亀田 啓, 横関 恵, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 渥美 達也
    日本内分泌学会雑誌 99 1 294 - 294 (一社)日本内分泌学会 2023年05月
  • COVID-19感染症を契機に多彩な電解質異常を呈し尿細管機能障害が疑われた一例
    高橋 明広, 亀田 啓, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 渥美 達也
    日本内分泌学会雑誌 99 1 295 - 295 (一社)日本内分泌学会 2023年05月
  • 腹腔鏡下スリーブ状胃切除術は脂肪肝と膵β細胞機能を改善する 前向きコホート研究
    大江 悠希, 中村 昭伸, 曹 圭龍, 宮 愛香, 野本 博司, 亀田 啓, 渥美 達也, 三好 秀明
    日本内分泌学会雑誌 99 1 296 - 296 (一社)日本内分泌学会 2023年05月
  • GH産生下垂体腺腫でのβ-カテニンの細胞内局在と75g経口ブドウ糖負荷試験におけるGHの奇異性上昇
    桑原 咲, 亀田 啓, 野本 博司, 曹 圭龍, 中村 昭伸, 伊師 雪友, 茂木 洋晃, 藤村 幹, 渥美 達也
    日本内分泌学会雑誌 99 1 332 - 332 (一社)日本内分泌学会 2023年05月
  • db/dbマウス副腎におけるステロイドホルモン合成亢進機序DHCR24阻害薬の効果
    上垣 里紗, 亀田 啓, 柴山 惟, 野本 博司, 曹 圭龍, 中村 昭伸, 神 繁樹, 的場 光太郎, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 99 1 392 - 392 (一社)日本内分泌学会 2023年05月
  • 高橋 明広, 亀田 啓, 古澤 翔, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 岩田 尚子, 藤沢 治樹, 鈴木 敦詞, 椙村 益久, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 99 Suppl.Update 11 - 13 (一社)日本内分泌学会 2023年05月
  • 日本人肥満2型糖尿病における腹腔鏡下スリーブ状胃切除術が脂肪肝と膵β細胞機能に及ぼす効果
    大江 悠希, 中村 昭伸, 曹 圭龍, 高瀬 崇宏, 小川 浩司, 海老原 裕磨, 宮 愛香, 野本 博司, 亀田 啓, 渥美 達也, 三好 秀明
    日本臨床分子医学会学術総会プログラム・抄録集 58回 50 - 50 日本臨床分子医学会 2023年04月
  • 肥満糖尿病病態における膵β細胞の細胞内代謝変化
    千葉 幸輝, 野本 博司, 泉原 里美, 亀田 啓, 中村 昭伸, 三好 秀明, 渥美 達也
    日本臨床分子医学会学術総会プログラム・抄録集 58回 52 - 52 日本臨床分子医学会 2023年04月
  • 日本人2型糖尿病患者の剖検膵を用いた膵β細胞内のエネルギー代謝変化と膵の組織学的所見との関連
    泉原 里美, 野本 博司, 千葉 幸輝, 亀田 啓, 中村 昭伸, 三好 秀明, 水上 浩哉, 渥美 達也
    日本臨床分子医学会学術総会プログラム・抄録集 58回 52 - 52 日本臨床分子医学会 2023年04月
  • 成長ホルモン産生下垂体腺腫におけるβ-カテニンの細胞内局在と腫瘍径および術後寛解率との関連
    桑原 咲, 亀田 啓, 野本 博司, 曹 圭龍, 中村 昭伸, 伊師 雪友, 茂木 洋晃, 藤村 幹, 三好 秀明, 渥美 達也
    日本臨床分子医学会学術総会プログラム・抄録集 58回 58 - 58 日本臨床分子医学会 2023年04月
  • ニューロメジンB受容体拮抗薬のクッシング病に対する効果の検討
    関崎 知紀, 亀田 啓, 宮 愛香, 野本 博司, 茂木 洋晃, 中村 昭伸, 三好 秀明, 渥美 達也
    日本臨床分子医学会学術総会プログラム・抄録集 58回 58 - 58 日本臨床分子医学会 2023年04月
  • db/dbマウスにおける副腎ステロイドホルモン合成亢進に対するDHCR24阻害薬の効果と副腎内代謝変化の検討
    上垣 里紗, 亀田 啓, 柴山 惟, 野本 博司, 曹 圭龍, 中村 昭伸, 神 繁樹, 的場 光太郎, 三好 秀明, 渥美 達也
    日本臨床分子医学会学術総会プログラム・抄録集 58回 59 - 59 日本臨床分子医学会 2023年04月
  • 日本人2型糖尿病患者における膵β細胞の細胞内代謝変化の解明 剖検膵組織を用いた検討
    野本 博司, 泉原 里美, 中村 昭伸, 千葉 幸輝, 亀田 啓, 三好 秀明, 水上 浩哉, 渥美 達也
    糖尿病 66 Suppl.1 S - 137 (一社)日本糖尿病学会 2023年04月
  • 高中性脂肪血症合併2型糖尿病患者におけるペマフィブラート投与による耐糖能への影響 PARM-T2D studyサブ解析
    野本 博司, 鬼頭 健一, 佐久間 一郎, 大江 悠希, 山内 裕貴, 土田 和久, 大森 一乃, 柴山 惟, 曹 圭龍, 竹内 淳, 種田 紳二, 栗原 義夫, 中村 昭伸, 渥美 達也, 三好 秀明
    糖尿病 66 Suppl.1 S - 155 (一社)日本糖尿病学会 2023年04月
  • 経口セマグルチドの有効性と安全性の検討 多施設共同後ろ向き観察研究
    竹内 淳, 三好 秀明, 伊藤 美樹, 古澤 翔, 野本 博司, 中村 昭伸, 大場 知穂, 栗原 弘義, 青木 伸
    糖尿病 66 Suppl.1 S - 161 (一社)日本糖尿病学会 2023年04月
  • 高齢者における既存のGLP-1受容体作動薬からセマグルチド皮下注への切り替えによる代謝因子の改善効果 SWITCH-SEMA1サブ解析
    高橋 由華, 野本 博司, 横山 宏樹, 高野 善成, 永井 聡, 続木 惇, 曹 圭龍, 土田 和久, 宮 愛香, 宮崎 あすか, 亀田 啓, 大場 知穂, 濱谷 柚香, 中田 健人, 泉原 里美, 上垣 里紗, 山下 久美子, 竹内 淳, 木島 弘道, 種田 紳二, 栗原 義夫, 青木 伸, 中村 昭伸, 渥美 達也, 三好 秀明
    糖尿病 66 Suppl.1 S - 162 (一社)日本糖尿病学会 2023年04月
  • 2型糖尿病におけるDPP-4阻害薬から経口セマグルチド切り替えによる血糖マネジメントへの影響 SWITCH SEMA-2 study
    古澤 翔, 野本 博司, 濱谷 柚香, 横関 恵, 宮本 麻唯子, 中田 健人, 大江 悠希, 泉原 里美, 家坂 光, 続木 惇, 宮 愛香, 亀田 啓, 曹 圭龍, 中村 昭伸, 高橋 清彦, 竹内 淳, 安井 彩乃, 関崎 知紀, 高瀬 崇宏, 永井 聡, 種田 紳二, 横山 宏樹, 栗原 義夫, 青木 伸, 渥美 達也, 三好 秀明
    糖尿病 66 Suppl.1 S - 197 (一社)日本糖尿病学会 2023年04月
  • 2型糖尿病における膵β細胞機能指標と血糖変動との関連
    宮 愛香, 中村 昭伸, 野本 博司, 亀田 啓, 渥美 達也
    糖尿病 66 Suppl.1 S - 216 (一社)日本糖尿病学会 2023年04月
  • 肥満糖尿病病態への介入は膵島の細胞内代謝変化を是正する
    千葉 幸輝, 野本 博司, 泉原 里美, 亀田 啓, 中村 昭伸, 三好 秀明, 渥美 達也
    糖尿病 66 Suppl.1 S - 222 (一社)日本糖尿病学会 2023年04月
  • 2型糖尿病患者の高血糖・低血糖に対する認識と実測値とのずれに関する因子の検討
    濱谷 柚香, 宮 愛香, 野本 博司, 亀田 啓, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也
    糖尿病 66 Suppl.1 S - 264 (一社)日本糖尿病学会 2023年04月
  • 食餌誘導性肥満・糖尿病モデルマウスにおけるグルコキナーゼ抑制が膵β細胞機能・量に与える影響
    重沢 郁美, 中村 昭伸, 山内 裕貴, 川田 晋一朗, 宮崎 あすか, 野本 博司, 亀田 啓, 三好 秀明, 寺内 康夫, 渥美 達也
    糖尿病 66 Suppl.1 S - 282 (一社)日本糖尿病学会 2023年04月
  • 日本人2型糖尿病患者の膵β細胞内代謝変化の機序の解明
    泉原 里美, 野本 博司, 千葉 幸輝, 亀田 啓, 中村 昭伸, 三好 秀明, 水上 浩哉, 渥美 達也
    糖尿病 66 Suppl.1 S - 283 (一社)日本糖尿病学会 2023年04月
  • 耐糖能異常症例における腎移植後の耐糖能,インスリン分泌,インスリン抵抗性の変化
    宮本 麻唯子, 中村 昭伸, 宮 愛香, 野本 博司, 亀田 啓, 曹 圭龍, 堀田 記世彦, 篠原 信雄, 三好 秀明, 渥美 達也
    糖尿病 66 Suppl.1 S - 309 (一社)日本糖尿病学会 2023年04月
  • DPP-4阻害薬とメトホルミン併用療法へのイメグリミン追加によるHbA1c低下効果 研究プロトコル(MEGMI study)
    高橋 明広, 野本 博司, 中村 昭伸, 宮 愛香, 亀田 啓, 曹 圭龍, 川田 晋一郎, 栗原 弘義, 竹内 淳, 永井 聡, 和田 典男, 横山 宏樹, 種田 紳二, 三好 秀明, 渥美 達也
    糖尿病 66 Suppl.1 S - 318 (一社)日本糖尿病学会 2023年04月
  • 低炭水化物食スコアと糖代謝指標との関連
    八重樫 昭徳, 木村 尚史, 岡田 恵美子, 中村 幸志, 鵜川 重和, 中村 昭伸, 玉腰 暁子
    日本栄養・食糧学会大会講演要旨集 77回 328 - 328 (公社)日本栄養・食糧学会 2023年03月
  • 大江 悠希, 亀田 啓, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 渥美 達也, 三好 秀明
    日本内分泌学会雑誌 98 5 1293 - 1293 (一社)日本内分泌学会 2023年03月
  • 桑原 咲, 亀田 啓, 野本 博司, 曹 圭龍, 中村 昭伸, 伊師 雪友, 茂木 洋晃, 藤村 幹, 渥美 達也
    日本内分泌学会雑誌 98 5 1394 - 1394 (一社)日本内分泌学会 2023年03月
  • 上垣 里紗, 亀田 啓, 柴山 惟, 野本 博司, 曹 圭龍, 中村 昭伸, 神 繁樹, 的場 光太郎, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 98 5 1443 - 1443 (一社)日本内分泌学会 2023年03月
  • 低炭水化物食スコアと糖代謝指標との関連
    八重樫 昭徳, 木村 尚史, 岡田 恵美子, 中村 幸志, 鵜川 重和, 中村 昭伸, 玉腰 暁子
    日本栄養・食糧学会大会講演要旨集 77回 328 - 328 (公社)日本栄養・食糧学会 2023年03月
  • 小野 翼, 亀田 啓, 横関 恵, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 98 4 716 - 716 (一社)日本内分泌学会 2023年02月
  • 古澤 翔, 亀田 啓, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 98 4 717 - 717 (一社)日本内分泌学会 2023年02月
  • 澁佐 知歩, 亀田 啓, 濱谷 柚香, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 茂木 洋晃, 松野 吉宏, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 98 4 717 - 717 (一社)日本内分泌学会 2023年02月
  • 関 萌花, 亀田 啓, 宮本 麻唯子, 小野 翼, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 山口 秀, 田中 伸哉, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 98 4 718 - 718 (一社)日本内分泌学会 2023年02月
  • 横関 恵, 亀田 啓, 濱谷 柚香, 泉原 里美, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 鈴木 崇祥, 稲村 直哉, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 98 4 719 - 719 (一社)日本内分泌学会 2023年02月
  • DPP-4阻害薬からSGLT2阻害薬への切替による脈拍日内変動の改善
    亀田 玲奈, 曹 圭龍, 野本 博司, 宮 愛香, 亀田 啓, 中村 昭伸, 竹内 淳, 永井 聡, 栗原 義夫, 渥美 達也, 三好 秀明
    糖尿病 66 2 171 - 171 (一社)日本糖尿病学会 2023年02月
  • SGLT2阻害薬投与による尿中L-FABPの変化
    曹 圭龍, 家坂 光, 大場 知穂, 野本 博司, 亀田 啓, 中村 昭伸, 竹内 淳, 渥美 達也
    糖尿病 66 2 171 - 171 (一社)日本糖尿病学会 2023年02月
  • イメグリミン追加またはメトホルミン増量による糖代謝の比較研究
    高橋 明広, 野本 博司, 中村 昭伸, 栗原 弘義, 竹内 淳, 永井 聡, 種田 紳二, 三好 秀明, 渥美 達也
    糖尿病 66 2 171 - 171 (一社)日本糖尿病学会 2023年02月
  • 経口セマグルチドの有効性と安全性の検討 多施設共同後向き観察研究
    三好 秀明, 古澤 翔, 野本 博司, 中村 昭伸, 山下 久美子, 竹内 淳, 栗原 義夫
    糖尿病 66 2 172 - 172 (一社)日本糖尿病学会 2023年02月
  • 認知機能低下を伴う高齢2型糖尿病患者における経口セマグルチドの有効性
    大江 悠希, 野本 博司, 曹 圭龍, 小野 翼, 横関 恵, 宮 愛香, 亀田 啓, 中村 昭伸, 三好 秀明, 渥美 達也
    糖尿病 66 2 172 - 172 (一社)日本糖尿病学会 2023年02月
  • 2型糖尿病患者の高血糖に対する認識と実際の高血糖時間との不一致に関連する背景因子
    濱谷 柚香, 宮 愛香, 野本 博司, 亀田 啓, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也
    糖尿病 66 2 173 - 173 (一社)日本糖尿病学会 2023年02月
  • 腎移植後の耐糖能改善は移植前の維持透析療法の有無に影響されない
    宮本 麻唯子, 中村 昭伸, 宮 愛香, 野本 博司, 亀田 啓, 曹 圭龍, 堀田 記世彦, 篠原 信雄, 三好 秀明, 渥美 達也
    糖尿病 66 2 173 - 173 (一社)日本糖尿病学会 2023年02月
  • 腹腔鏡下スリーブ状胃切除術が肥満2型糖尿病の脂肪肝と膵β細胞機能に及ぼす効果
    大江 悠希, 曹 圭龍, 中村 昭伸, 小川 浩司, 海老原 裕磨, 宮 愛香, 野本 博司, 亀田 啓, 渥美 達也, 三好 秀明
    糖尿病 66 2 174 - 174 (一社)日本糖尿病学会 2023年02月
  • 高度肥満症患者における減量・代謝改善手術後の栄養アセスメント蛋白と微量元素の変化
    横関 恵, 曹 圭龍, 大江 悠希, 宮 愛香, 野本 博司, 亀田 啓, 中村 昭伸, 渥美 達也, 三好 秀明
    糖尿病 66 2 174 - 174 (一社)日本糖尿病学会 2023年02月
  • 高中性脂肪血症合併2型糖尿病におけるペマフィブラートの脂質改善効果
    鬼頭 健一, 野本 博司, 佐久間 一郎, 曹 圭龍, 山下 久美子, 半田 喬久, 永井 聡, 中村 昭伸, 渥美 達也, 三好 秀明
    糖尿病 66 2 174 - 174 (一社)日本糖尿病学会 2023年02月
  • ペマフィブラートは高中性脂肪血症合併2型糖尿病のインスリン抵抗性を改善させる
    家坂 光, 野本 博司, 鬼頭 健一, 佐久間 一郎, 萬田 直紀, 川田 晋一朗, 亀田 啓, 曹 圭龍, 中村 昭伸, 渥美 達也, 三好 秀明
    糖尿病 66 2 175 - 175 (一社)日本糖尿病学会 2023年02月
  • Kyu Yong Cho, Hideaki Miyoshi, Akinobu Nakamura, Andrew S Greenberg, Tatsuya Atsumi
    Journal of atherosclerosis and thrombosis 30 2 170 - 181 2023年02月01日 
    AIM: Perilipins (PLINs), peripheral lipid droplet (LD) proteins, play important roles in lipid accumulation and maturation in adipocytes. The relationship between PLIN family proteins and macrophage polarization in atherosclerosis has not been elucidated. METHODS: The experiments used tissues from human arteries of 65 patients who had undergone a carotid endarterectomy, and cultured macrophages generated from healthy human peripheral blood mononuclear cells. RESULTS: Plaque immunohistochemistry demonstrated co-expression of PLIN1 and PLIN2 in both symptomatic (n=31) and asymptomatic patients (n=34). PLIN2 mRNA expression increased 3.38-fold in the symptomatic group compared with those from asymptomatic. PLIN1 was not expressed on small LDs at a shorter incubation but was on large LDs at longer incubation with oxidized LDL and VLDL, while PLIN2 was observed after 24 h and increased with a longer incubation in cultured M1 macrophage. In M2 macrophages, PLIN1 was seen as early as 24 h following incubation with VLDL, and LD size increased with longer incubation. PLIN1 overexpression increased the size of LDs in M1 macrophages, even after a short incubation, and reduced the RNA expression of TNFA, MMP2, ABCA1, and ABCG1 versus the M1 control. Conversely, silencing of PLIN1 in M2 macrophages had the opposite effects on LD size and RNA expression. CONCLUSION: There was a relationship between macrophage polarity, cytosolic LD size, and PLIN1/PLIN2 expression levels. PLIN2 was mainly expressed in arterial plaques in symptomatic stroke patients, and associated with the inflammatory phenotype of human macrophages, while PLIN1 expression is closely associated with plaque stability and the anti-inflammatory phenotype.
  • Yuka Takahashi, Hiroshi Nomoto, Hiroki Yokoyama, Yoshinari Takano, So Nagai, Atsushi Tsuzuki, Kyu Yong Cho, Aika Miya, Hiraku Kameda, Jun Takeuchi, Shinji Taneda, Yoshio Kurihara, Tatsuya Atsumi, Akinobu Nakamura, Hideaki Miyoshi
    Diabetes, obesity & metabolism 25 6 1503 - 1511 2023年02月01日 
    OBJECTIVE: To investigate the effects of switching from liraglutide or dulaglutide to once-weekly semaglutide on glycemic control and treatment satisfaction in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: In this multicenter, open-labeled, prospective, randomized, parallel-group comparison study, patients treated with liraglutide 0.9-1.8 mg/day (plan A) or dulaglutide 0.75 mg/week (plan B) were either switched to semaglutide or continued on current therapy. The primary endpoint was the mean change in glycated hemoglobin (HbA1c) over 24 weeks. The secondary endpoints included the changes of Diabetes Treatment Satisfaction Questionnaire (DTSQ) scores, body weight, and metabolic indices. RESULTS: In total, 110 patients were enrolled, and 10 were excluded; therefore, 37 patients in plan A and 63 patients in plan B completed the study. HbA1c levels were significantly reduced in the semaglutide group in both plans (plan A, 7.8 ± 1.0% to 7.8 ± 0.7% [liraglutide] vs. 7.9 ± 0.7% to 7.3 ± 0.7% [semaglutide], P < 0.01; plan B, 7.8 ± 1.0% to 7.9 ± 1.2% [dulaglutide] vs. 7.8 ± 0.8% to 7.1 ± 0.6% [semaglutide], P < 0.01). Semaglutide also improved DTSQ scores in both groups (plan A, + 0.1 vs. +8.3, P < 0.01; plan B, -1.2 vs. + 3.5, P < 0.01). Switching from dulaglutide yielded greater reductions in body weight and improved metabolic parameters. CONCLUSIONS: Once-weekly semaglutide administration improved glycemic control and treatment satisfaction after switching from liraglutide or dulaglutide. These results highlighted a useful treatment option for patients with metabolic abnormalities despite GLP-1 receptor agonist treatment. This article is protected by copyright. All rights reserved.
  • Yuki Oe, Hiroshi Nomoto, Aika Miya, Hiraku Kameda, Kyu Yong Cho, Akinobu Nakamura, Hideaki Miyoshi, Tatsuya Atsumi
    Advances in therapy 40 1 383 - 386 2023年01月
  • Yuki Yamauchi, Akinobu Nakamura, Takashi Yokota, Kiyohiko Takahashi, Shinichiro Kawata, Kazuhisa Tsuchida, Kazuno Omori, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, Toshihisa Anzai, Shinya Tanaka, Yasuo Terauchi, Hideaki Miyoshi, Tatsuya Atsumi
    Scientific Reports 12 1 2022年12月 
    Abstract We aimed to determine the mechanism by which the sodium glucose co-transporter 2 inhibitor, luseogliflozin, preserves pancreatic beta-cell mass and function in db/db mice. Six-week-old db/db mice were fed to standard chow or standard chow containing 0.01% luseogliflozin. After 4 weeks, DNA microarray analysis, real-time PCR analysis, and measurement of mitochondrial respiratory capacity and reactive oxygen species (ROS) generation were performed using isolated islets. Immunohistochemistry and electron microscopic analysis were performed using pancreatic tissues. Metabolites extracted from the islets were measured by capillary electrophoresis mass spectrometry. The expression of genes involved in the tricarboxylic acid (TCA) cycle and electron transport chain was upregulated by luseogliflozin. Luseogliflozin improved the mitochondrial complex II-linked oxidative phosphorylation capacity and reduced ROS generation. Mitochondrial morphology was normally maintained by luseogliflozin. Luseogliflozin increased NK6 homeobox 1 (NKX6.1) expression and TCA cycle metabolites. Relief of glucotoxicity by luseogliflozin may involve lower mitochondrial ROS generation and an improvement in complex II-linked mitochondrial respiration. Reducing ROS generation through preventing complex II damage likely increases NKX6.1 expression and ameliorate glucose metabolism in the TCA cycle, contributing to the protection of pancreatic beta-cells. Protection of complex II in pancreatic beta-cells represents a novel therapeutic target for type 2 diabetes.
  • Hiroshi Nomoto, Akihiro Takahashi, Akinobu Nakamura, Hiroyoshi Kurihara, Jun Takeuchi, So Nagai, Shinji Taneda, Aika Miya, Hiraku Kameda, Kyu Yong Cho, Hideaki Miyoshi, Tatsuya Atsumi
    BMJ open diabetes research & care 10 6 2022年11月 
    INTRODUCTION: Imeglimin is a novel anti-hyperglycemic drug that improves both insulin resistance and insulin secretion. The effects of imeglimin on glycemic control were confirmed in phase III clinical trials, but little is known about its effectiveness in daily clinical practice settings, especially compared with metformin. Therefore, we aim to clarify the efficacy of imeglimin in patients with type 2 diabetes (T2D) being treated with a dipeptidyl peptidase-4 (DPP-4) inhibitor plus low-dose metformin. RESEARCH DESIGN AND METHODS: This is a multicenter, randomized, prospective, open-label, parallel-group trial. Seventy participants with T2D treated with a DPP-4 inhibitor plus metformin (500-1000 mg/day) for more than 12 weeks and a glycated hemoglobin (HbA1c) level of 52-85 mmol/mol (7.0%-9.9%) will be randomized to receive add-on imeglimin 1000 mg two times per day or metformin dose escalation for 24 weeks. Biochemical analyses and physical assessments will be performed at baseline and at the end of the study, and adverse events will be recorded. The primary endpoint is the change in HbA1c after 24 weeks. The secondary endpoints comprise the changes in blood pressure, pulse rate, body weight, abdominal circumference, and other laboratory parameters; the relationship between improvements of biological parameters including glycemic control and patient background characteristics; and side effects. RESULTS: This study will reveal new insights into the incorporation of imeglimin into the diabetes treatment strategy. CONCLUSIONS: This will be the first randomized controlled trial to compare the efficacy of adding imeglimin versus metformin dose escalation on glycemic control in patients with T2D. TRIAL REGISTRATION NUMBER: jRCT1011220005.
  • 高橋 明広, 古澤 翔, 亀田 啓, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也, 岩田 尚子, 藤沢 治樹, 鈴木 敦詞, 椙村 益久
    日本内分泌学会雑誌 98 2 564 - 564 (一社)日本内分泌学会 2022年10月
  • 濱谷 柚香, 亀田 啓, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 鈴木 崇祥, 清水 亜衣, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 98 2 589 - 589 (一社)日本内分泌学会 2022年10月
  • 澁佐 知歩, 亀田 啓, 横関 恵, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 98 2 590 - 590 (一社)日本内分泌学会 2022年10月
  • 宮本 麻唯子, 亀田 啓, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 中久保 祥, 佐藤 琢真, 松本 隆児, 大塚 拓也, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 98 2 597 - 597 (一社)日本内分泌学会 2022年10月
  • 高橋 由華, 野本 博司, 横山 宏樹, 宮 愛香, 亀田 啓, 曹 圭龍, 竹内 淳, 永井 聡, 種田 紳二, 木島 弘道, 栗原 義夫, 青木 伸, 中村 昭伸, 渥美 達也, 三好 秀明
    日本内分泌学会雑誌 98 2 617 - 617 (一社)日本内分泌学会 2022年10月
  • 大江 悠希, 亀田 啓, 高瀬 崇宏, 小川 浩司, 海老原 裕磨, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 坂本 直哉, 平野 聡, 渥美 達也, 三好 秀明
    日本内分泌学会雑誌 98 2 629 - 629 (一社)日本内分泌学会 2022年10月
  • 糖尿病性ケトアシドーシスに高度脂肪肝を合併した2例
    横関 恵, 野本 博司, 濱谷 柚香, 宮 愛香, 亀田 啓, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也
    糖尿病 65 10 552 - 552 (一社)日本糖尿病学会 2022年10月
  • 神経性やせ症の治療経過中に1型糖尿病を発症し治療に難渋した1例
    宮崎 あすか, 野本 博司, 桑原 咲, 山内 裕貴, 宮 愛香, 亀田 啓, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也
    糖尿病 65 10 554 - 554 (一社)日本糖尿病学会 2022年10月
  • 週3回デグルデク投与の効果を持続血糖モニターにて評価した高齢者2型糖尿病の1例
    中田 健人, 野本 博司, 宮 愛香, 亀田 啓, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也
    糖尿病 65 10 555 - 555 (一社)日本糖尿病学会 2022年10月
  • 1型糖尿病患者に対するSGLT2阻害薬投与の安全性と体重・代謝指標への影響
    高橋 由華, 鴨嶋 ひかる, 野本 博司, 中村 昭伸, 山下 久美子, 土田 和久, 桑原 咲, 種田 紳二, 青木 伸, 小野 百合, 三好 秀明
    糖尿病 65 10 556 - 556 (一社)日本糖尿病学会 2022年10月
  • デグルデク/リラグルチド配合注は血糖変動を改善しQOLを向上させ得る
    大江 悠希, 野本 博司, 中村 昭伸, 桑原 咲, 高橋 由華, 安井 彩乃, 宮 愛香, 亀田 啓, 曹 圭龍, 渥美 達也, 三好 秀明
    糖尿病 65 10 557 - 557 (一社)日本糖尿病学会 2022年10月
  • 2型糖尿病における減量・代謝改善手術はインスリン抵抗性と分泌能を改善させる
    久住 麻唯子, 曹 圭龍, 大江 悠希, 高瀬 崇宏, 宮 愛香, 野本 博司, 亀田 啓, 中村 昭伸, 渥美 達也, 三好 秀明
    糖尿病 65 10 558 - 558 (一社)日本糖尿病学会 2022年10月
  • 減量・代謝改善手術1年後総体重減少率が18.2%を超えると糖尿病治療薬を中止し得る
    大藤 悠理, 曹 圭龍, 大江 悠希, 高瀬 崇宏, 宮 愛香, 野本 博司, 亀田 啓, 中村 昭伸, 渥美 達也, 三好 秀明
    糖尿病 65 10 558 - 558 (一社)日本糖尿病学会 2022年10月
  • 糖尿病合併肥満患者に対する腹腔鏡下スリーブ状胃切除術後の骨密度への影響
    濱谷 柚香, 曹 圭龍, 大江 悠希, 高瀬 崇宏, 宮 愛香, 野本 博司, 亀田 啓, 中村 昭伸, 渥美 達也, 三好 秀明
    糖尿病 65 10 558 - 558 (一社)日本糖尿病学会 2022年10月
  • 高中性脂肪血症合併2型糖尿病におけるペマフィブラートの効果 前向きコホート研究
    鬼頭 健一, 野本 博司, 佐久間 一郎, 山下 久美子, 曹 圭龍, 中村 昭伸, 柳谷 真悟, 半田 喬久, 渥美 達也, 三好 秀明
    糖尿病 65 10 559 - 559 (一社)日本糖尿病学会 2022年10月
  • ペマフィブラートは高中性脂肪血症合併2型糖尿病患者の肝機能・肝脂肪化を改善する
    古澤 翔, 鬼頭 健一, 野本 博司, 佐久間 一郎, 山下 久美子, 柳谷 真悟, 曹 圭龍, 中村 昭伸, 渥美 達也, 三好 秀明
    糖尿病 65 10 559 - 559 (一社)日本糖尿病学会 2022年10月
  • COVID-19肺炎治療中に冠攣縮性狭心症を発症した褐色細胞腫の一例
    宮本 麻唯子, 亀田 啓, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 中久保 祥, 佐藤 琢真, 松本 隆児, 大塚 拓也, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 98 2 597 - 597 (一社)日本内分泌学会 2022年10月
  • Yuri Ofuji, Hiroshi Nomoto, Aika Miya, Hiraku Kameda, Kyu Yong Cho, Akinobu Nakamura, Hideaki Miyoshi, Tatsuya Atsumi
    Geriatrics & Gerontology International 22 10 894 - 895 2022年10月
  • Kenichi Kito, Hiroshi Nomoto, Ichiro Sakuma, Akinobu Nakamura, Kyu Yong Cho, Hiraku Kameda, Aika Miya, Kazuno Omori, Shingo Yanagiya, Takahisa Handa, Shinji Taneda, Jun Takeuchi, So Nagai, Kumiko Yamashita, Yoshio Kurihara, Tatsuya Atsumi, Hideaki Miyoshi
    Diabetes Research and Clinical Practice 192 110091 - 110091 2022年10月
  • 日本人肥満2型糖尿病における腹腔鏡下スリーブ状胃切除術が脂肪肝と膵β細胞機能に及ぼす効果 前向きコホート研究
    大江 悠希, 中村 昭伸, 曹 圭龍, 高瀬 崇宏, 小川 浩司, 海老原 裕磨, 吉川 仁人, 西田 睦, 宮 愛香, 野本 博司, 亀田 啓, 荘 拓也, 須田 剛生, 倉島 庸, 阿保 大介, 工藤 與亮, 坂本 直哉, 平野 聡, 渥美 達也, 三好 秀明
    糖尿病合併症 36 Suppl.1 172 - 172 (一社)日本糖尿病合併症学会 2022年09月
  • 内因性インスリン分泌が低下した2型糖尿病の血糖変動における内臓脂肪の関与
    宮 愛香, 中村 昭伸, 濱谷 柚香, 野本 博司, 亀田 啓, 曹 圭龍, 三好 秀明, 渥美 達也
    糖尿病合併症 36 Suppl.1 194 - 194 (一社)日本糖尿病合併症学会 2022年09月
  • 耐糖能異常症例における腎移植後の耐糖能変化はインスリン分泌能の変化と関連する
    中村 昭伸, 宮本 麻唯子, 宮 愛香, 野本 博司, 亀田 啓, 曹 圭龍, 堀田 記世彦, 篠原 信雄, 三好 秀明, 渥美 達也
    糖尿病合併症 36 Suppl.1 195 - 195 (一社)日本糖尿病合併症学会 2022年09月
  • 持効型インスリンからデグルデク/リラグルチド配合注への切替えによる血糖変動の改善効果には内因性インスリン分泌能が影響する
    野本 博司, 大江 悠希, 中村 昭伸, 桑原 咲, 高橋 由華, 安井 彩乃, 宮 愛香, 亀田 啓, 曹 圭龍, 三好 秀明, 渥美 達也
    糖尿病合併症 36 Suppl.1 211 - 211 (一社)日本糖尿病合併症学会 2022年09月
  • リラグルチドおよびデュラグルチドからセマグルチド切り替えによる血糖コントロール及びQOLへの影響 SWITCH-SEMA1 study
    高橋 由華, 野本 博司, 横山 宏樹, 続木 惇, 宮 愛香, 亀田 啓, 曹 圭龍, 大場 知穂, 竹内 淳, 永井 聡, 土田 和久, 種田 紳二, 高野 善成, 木島 弘道, 山下 久美子, 栗原 義夫, 青木 伸, 中村 昭伸, 渥美 達也, 三好 秀明
    糖尿病合併症 36 Suppl.1 211 - 211 (一社)日本糖尿病合併症学会 2022年09月
  • 2型糖尿病経過中に劇症1型糖尿病が発症した1例
    大西 錦之介, 野田 学, 増田 創, 高橋 由華, 川田 晋一朗, 野本 博司, 亀田 啓, 曹 圭龍, 中村 昭伸, 三好 秀明
    糖尿病 65 8 468 - 468 (一社)日本糖尿病学会 2022年08月
  • 免疫チェックポイント阻害薬投与中に早期に発見・治療し得た劇症1型糖尿病の1例
    桑原 咲, 野本 博司, 高橋 由華, 安井 彩乃, 泉原 里美, 大江 悠希, 亀田 啓, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也
    糖尿病 65 8 469 - 469 (一社)日本糖尿病学会 2022年08月
  • 酸塩基平衡異常が遷延したSGLT2阻害薬服用下の糖尿病性ケトアシドーシスの2例
    上垣 里紗, 野本 博司, 亀田 啓, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也
    糖尿病 65 8 470 - 470 (一社)日本糖尿病学会 2022年08月
  • canagliflozinとteneligliptinの併用はTime Rangeと食後高血糖を改善する
    曹 圭龍, 野本 博司, 中村 昭伸, 川田 晋一朗, 亀田 啓, 渥美 達也, 三好 秀明
    糖尿病 65 8 472 - 472 (一社)日本糖尿病学会 2022年08月
  • 持効型インスリン/GLP-1アナログ配合注の導入により血糖変動が改善した3例
    泉原 里美, 野本 博司, 桑原 咲, 高橋 由華, 安井 彩乃, 大江 悠希, 亀田 啓, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也
    糖尿病 65 8 473 - 473 (一社)日本糖尿病学会 2022年08月
  • 腹腔鏡下スリーブ状胃切除術は肥満2型糖尿病患者の治療薬剤を減量し得る
    高橋 由華, 曹 圭龍, 大江 悠希, 高瀬 崇宏, 野本 博司, 亀田 啓, 中村 昭伸, 海老原 裕磨, 平野 聡, 渥美 達也, 三好 秀明
    糖尿病 65 8 473 - 473 (一社)日本糖尿病学会 2022年08月
  • 肥満合併2型糖尿病患者において、術前骨格筋量が肥満手術の減量効果を予測する
    大江 悠希, 高瀬 崇宏, 野本 博司, 亀田 啓, 曹 圭龍, 中村 昭伸, 海老原 裕磨, 平野 聡, 渥美 達也, 三好 秀明
    糖尿病 65 8 474 - 474 (一社)日本糖尿病学会 2022年08月
  • 腹腔鏡下スリーブ状胃切除術は脂質代謝および脂肪肝を改善させる
    安井 彩乃, 高瀬 崇宏, 野本 博司, 亀田 啓, 曹 圭龍, 中村 昭伸, 海老原 裕磨, 平野 聡, 渥美 達也, 三好 秀明
    糖尿病 65 8 474 - 474 (一社)日本糖尿病学会 2022年08月
  • 高中性脂肪血症合併2型糖尿病におけるペマフィブラートの肝機能改善効果
    鬼頭 健一, 野本 博司, 佐久間 一郎, 山下 久美子, 柳谷 真吾, 曹 圭龍, 亀田 啓, 中村 昭伸, 渥美 達也, 三好 秀明
    糖尿病 65 8 474 - 474 (一社)日本糖尿病学会 2022年08月
  • 本邦における腹腔鏡下スリーブ状胃切除術後の骨密度変化と関連因子 前向きコホート研究
    大江 悠希, 曹 圭龍, 小川 浩司, 海老原 裕磨, 宮 愛香, 野本 博司, 亀田 啓, 中村 昭伸, 坂本 直哉, 平野 聡, 渥美 達也, 三好 秀明
    日本骨粗鬆症学会雑誌 8 Suppl.1 158 - 158 (一社)日本骨粗鬆症学会 2022年08月
  • 腹腔鏡下スリーブ状胃切除術は肥満2型糖尿病患者の治療薬剤を減量し得る
    高橋 由華, 曹 圭龍, 大江 悠希, 高瀬 崇宏, 野本 博司, 亀田 啓, 中村 昭伸, 海老原 裕磨, 平野 聡, 渥美 達也, 三好 秀明
    糖尿病 65 8 473 - 473 (一社)日本糖尿病学会 2022年08月
  • 肥満合併2型糖尿病患者において、術前骨格筋量が肥満手術の減量効果を予測する
    大江 悠希, 高瀬 崇宏, 野本 博司, 亀田 啓, 曹 圭龍, 中村 昭伸, 海老原 裕磨, 平野 聡, 渥美 達也, 三好 秀明
    糖尿病 65 8 474 - 474 (一社)日本糖尿病学会 2022年08月
  • 腹腔鏡下スリーブ状胃切除術は脂質代謝および脂肪肝を改善させる
    安井 彩乃, 高瀬 崇宏, 野本 博司, 亀田 啓, 曹 圭龍, 中村 昭伸, 海老原 裕磨, 平野 聡, 渥美 達也, 三好 秀明
    糖尿病 65 8 474 - 474 (一社)日本糖尿病学会 2022年08月
  • Aika Miya, Akinobu Nakamura, Isao Yokota, Kyu Yong Cho, Hiraku Kameda, Hiroshi Nomoto, Takahiro Takase, Kazuno Omori, Mayuko Ono, So Nagai, Shinji Taneda, Hideaki Miyoshi, Tatsuya Atsumi
    Geriatrics & gerontology international 22 8 560 - 567 2022年06月30日 
    AIM: To investigate the achievement of individualized target HbA1c based on the Japanese guideline after geriatric assessment with the Dementia Assessment Sheet for Community-based Integrated Care System 8-items (DASC-8) and to evaluate patient characteristics acting as barriers to achieving the target HbA1c in elderly outpatients with diabetes. METHODS: This cross-sectional study enrolled 303 Japanese outpatients aged ≥65 years with diabetes. Their health status was measured using the DASC-8. The target HbA1c was optimized for each patient by the guideline based on the DASC-8 score and use of drugs potentially associated with severe hypoglycemia. Patient characteristics related to the agreement between measured HbA1c and target HbA1c were extracted by multivariate logistic regression analysis. RESULTS: The mean age was 73.0 years and the mean body mass index (BMI) was 24.2 kg/m2 . The agreement between measured HbA1c and target HbA1c was 43.9% (95% confidence interval: 38.4%-50.0%). In multivariate logistic regression analysis, the agreement in patients with drugs potentially associated with severe hypoglycemia was significantly lower than in those without these drugs (37.8% vs. 60.5%, P = 0.0004). In patients with these drugs, higher BMI (P = 0.0271) and higher fasting plasma glucose (P = 0.0034) were independent related factors for measured HbA1c being higher than target HbA1c. Vulnerable elderly patients (P = 0.0116) and not taking sodium glucose co-transporter-2 (SGLT2) inhibitor (P = 0.0186) were independent related factors for inappropriately lower HbA1c. CONCLUSIONS: The agreement between measured HbA1c and target HbA1c was low in elderly patients with diabetes. Geriatr Gerontol Int 2022; ••: ••-••.
  • Houman Goudarzi, Hirokazu Kimura, Hiroki Kimura, Hironi Makita, Munehiro Matsumoto, Nozomu Takei, Kaoruko Shimizu, Masaru Suzuki, Taku Watanabe, Eiki Kikuchi, Hiroshi Ohira, Ichizo Tsujino, Jun Sakakibara-Konishi, Naofumi Shinagawa, Noriharu Shijubo, Hirokazu Sato, Katsunori Shigehara, Kichizo Kaga, Yasuhiro Hida, Soichi Murakami, Yuma Ebihara, Akinobu Nakamura, Hideaki Miyoshi, Satoshi Hirano, Nobuyuki Hizawa, Tatsuya Atsumi, Shau-Ku Huang, Yoichi M Ito, Masaharu Nishimura, Satoshi Konno
    Respiratory research 23 1 174 - 174 2022年06月29日 
    INTRODUCTION: Club cell secretory protein-16 (CC16) is a major anti-inflammatory protein expressed in the airway; however, the potential role of CC16 on overweight/obese asthma has not been assessed. In this study, we examined whether obesity reduces airway/circulatory CC16 levels using experimental and epidemiological studies. Then, we explored the mediatory role of CC16 in the relationship of overweight/obesity with clinical asthma measures. METHODS: Circulating CC16 levels were assessed by ELISA in three independent human populations, including two groups of healthy and general populations and asthma patients. The percentage of cells expressing club markers in obese vs. non-obese mice and human airways was determined by immunohistochemistry. A causal mediation analysis was conducted to determine whether circulatory CC16 acted as a mediator between overweight/obesity and clinical asthma measures. RESULTS: BMI was significantly and monotonously associated with reduced circulating CC16 levels in all populations. The percentage of CC16-expressing cells was reduced in the small airways of both mice and humans with obesity. Finally, mediation analysis revealed significant contributions of circulatory CC16 in the association between BMI and clinical asthma measures; 21.8% of its total effect in BMI's association with airway hyperresponsiveness of healthy subjects (p = 0.09), 26.4% with asthma severity (p = 0.030), and 23% with the required dose of inhaled corticosteroid (p = 0.042). In logistic regression analysis, 1-SD decrease in serum CC16 levels of asthma patients was associated with 87% increased odds for high dose ICS requirement (p < 0.001). CONCLUSIONS: We demonstrate that airway/circulating CC16, which is inversely associated with BMI, may mediate development and severity in overweight/obese asthma.
  • Hiroshi Nomoto, Sho Furusawa, Akinobu Nakamura, Jun Takeuchi, So Nagai, Hiroki Yokoyama, Ichiro Sakuma, Shinji Taneda, Yoshio Kurihara, Shin Aoki, Aika Miya, Hiraku Kameda, Kyu Yong Cho, Tatsuya Atsumi, Hideaki Miyoshi
    BMJ open 12 5 e056885  2022年05月18日 
    INTRODUCTION: Incretin-based therapies exert antihyperglycaemic effects in patients with type 2 diabetes (T2D) in a blood glucose concentration-dependent fashion. The first-in-class oral glucagon-like peptide-1 receptor agonist semaglutide has potent effects on glycaemic and weight control, but little evidence has been published for the superiority of semaglutide for glycaemic control in patients after switching from a dipeptidyl peptidase-4 (DPP-4) inhibitor. Therefore, we aim to verify the efficacy of oral semaglutide in patients with T2D being treated with a DPP-4 inhibitor. METHODS AND ANALYSIS: This study is a multicentre, prospective, randomised, open-label, parallel-group trial. In total, 172 participants with T2D who have been treated with a DPP-4 inhibitor for more than 12 weeks and who have a glycated haemoglobin (HbA1c) level of 7.0%-9.9% will be randomised to continue using their existing DPP-4 inhibitor or switch to oral semaglutide for 24 weeks. Biochemical analyses and physical assessment will be performed, and adverse events will be recorded at baseline and at the end of the study. The primary endpoint will be the effect of oral semaglutide on the change in HbA1c. The secondary endpoints will be the mean changes in body weight, abdominal circumference, systolic and diastolic blood pressure (BP), pulse rate, the relationship between improvement of metabolic parameters including HbA1c and patient background characteristics, side effects and other laboratory parameters. ETHICS AND DISSEMINATION: This will be the first study to compare the effects of switching from a DPP-4 inhibitor to oral semaglutide on glycaemic control in patients with T2D. The results will be disseminated in peer-reviewed journals and at scientific conferences. Hokkaido University Certified Review Board (CRB no.1180001) has approved the protocol (no. 020-013). TRIAL REGISTRATION NUMBER: UMIN000045270 in the University Hospital Medical Information Network; jRCT1011210032 in the Japan Registry of Clinical Trials.
  • Atsushi Tsuzuki, Yoichiro Fujioka, Aiko Yoshida, Sayaka Kashiwagi, Maho Amano, Tohru Hira, Akinobu Nakamura, Hideaki Miyoshi, Tatsuya Atsumi, Yusuke Ohba
    Journal of diabetes investigation 13 7 1134 - 1139 2022年04月04日 
    Live-cell imaging with fluorescent proteins (FPs) is a powerful tool for investigating the exocytosis processes of hormones. However, the secretion process of glucagon-like peptide-1 (GLP-1) has not been visualized by FPs, which might be because tagging FPs inhibits GLP-1 synthesis through the post-translational processing from proglucagon. Here, we have developed FP-tagged GLP-1 by inserting FPs into the middle of GLP-1 and adding the proglucagon signal peptide. Confocal imaging confirmed that GLP-1 fused to FPs with high folding efficiency showed granular structure, in which secretory vesicle markers colocalized. The fluorescence intensity of FP in the culture supernatant from cells treated with KCl or forskolin was significantly increased compared with those from untreated cells. Furthermore, FP-tagged GLP-1 enables direct visualization of stimulation-dependent exocytosis of GLP-1 at a single granule resolution with total internal reflection fluorescence microscopy. FP-tagged GLP-1 might facilitate the screening of GLP-1 secretagogues and the discovery of new antidiabetic drugs.
  • 濱谷 柚香, 亀田 啓, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 穴田 麻眞子, 矢部 一郎, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 98 1 254 - 254 (一社)日本内分泌学会 2022年04月
  • 中田 健人, 亀田 啓, 桑原 咲, 安井 彩乃, 高橋 由華, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 岡田 絵里, 野津 寛大, 渥美 達也
    日本内分泌学会雑誌 98 1 256 - 256 (一社)日本内分泌学会 2022年04月
  • 関崎 知紀, 亀田 啓, 宮 愛香, 野本 博司, 曹 圭龍, 茂木 洋晃, 中村 昭伸, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 98 1 297 - 297 (一社)日本内分泌学会 2022年04月
  • 桑原 咲, 亀田 啓, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 小梁川 直秀, 竹内 淳, 永井 聡, 三次 有奈, 和田 典男, 種田 紳二, 栗原 義夫, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 98 1 300 - 300 (一社)日本内分泌学会 2022年04月
  • 大江 悠希, 高瀬 崇宏, 曹 圭龍, 海老原 裕磨, 宮 愛香, 野本 博司, 亀田 啓, 中村 昭伸, 平野 聡, 渥美 達也, 三好 秀明
    日本内分泌学会雑誌 98 1 308 - 308 (一社)日本内分泌学会 2022年04月
  • 濱谷 柚香, 亀田 啓, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 穴田 麻眞子, 矢部 一郎, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 98 1 346 - 346 (一社)日本内分泌学会 2022年04月
  • 山内 裕貴, 中村 昭伸, 横田 卓, 高橋 清彦, 川田 晋一朗, 土田 和久, 大森 一乃, 野本 博司, 亀田 啓, 曹 圭龍, 安斉 俊久, 田中 伸哉, 寺内 康夫, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 98 1 361 - 361 (一社)日本内分泌学会 2022年04月
  • 川田 晋一朗, 中村 昭伸, 三好 秀明, 山内 裕貴, 土田 和久, 大森 一乃, 高橋 清彦, 野本 博司, 亀田 啓, 曹 圭龍, 寺内 康夫, 渥美 達也
    日本内分泌学会雑誌 98 1 361 - 361 (一社)日本内分泌学会 2022年04月
  • 上垣 里紗, 亀田 啓, 柴山 惟, 野本 博司, 曹 圭龍, 中村 昭伸, 神 茂樹, 的場 光太郎, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 98 1 381 - 381 (一社)日本内分泌学会 2022年04月
  • 中田 健人, 亀田 啓, 桑原 咲, 安井 彩乃, 高橋 由華, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 岡田 絵里, 野津 寛大, 渥美 達也
    日本内分泌学会雑誌 98 1 400 - 400 (一社)日本内分泌学会 2022年04月
  • インスリンデグルデクとDPP-4阻害薬の併用からデグルデク/リラグルチド配合注への切替えは血糖変動とQOLを改善させる
    野本 博司, 大江 悠希, 中村 昭伸, 桑原 咲, 高橋 由華, 安井 彩乃, 宮 愛香, 亀田 啓, 曹 圭龍, 渥美 達也, 三好 秀明
    糖尿病 65 Suppl.1 S - 138 (一社)日本糖尿病学会 2022年04月
  • 日本人肥満2型糖尿病における腹腔鏡下スリーブ状胃切除術が脂肪肝に及ぼす効果 前向きコホート研究
    大江 悠希, 高瀬 崇宏, 曹 圭龍, 小川 浩司, 海老原 裕磨, 吉川 仁人, 西田 睦, 宮 愛香, 野本 博司, 亀田 啓, 荘 拓也, 須田 剛生, 中村 昭伸, 倉島 庸, 阿保 大介, 工藤 與亮, 坂本 直哉, 平野 聡, 渥美 達也, 三好 秀明
    糖尿病 65 Suppl.1 S - 139 (一社)日本糖尿病学会 2022年04月
  • 内臓脂肪面積は内因性インスリン分泌低下型の2型糖尿病において血糖変動の安定性を予測する
    宮 愛香, 中村 昭伸, 半田 喬久, 野本 博司, 亀田 啓, 曹 圭龍, 伊藤 陽一, 永井 聡, 渥美 達也, 三好 秀明
    糖尿病 65 Suppl.1 S - 210 (一社)日本糖尿病学会 2022年04月
  • 肥満糖尿病病態への介入による膵β細胞の細胞内代謝変化
    千葉 幸輝, 野本 博司, 泉原 里美, 亀田 啓, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也
    糖尿病 65 Suppl.1 S - 216 (一社)日本糖尿病学会 2022年04月
  • 高中性脂肪血症合併2型糖尿病におけるペマフィブラートの効果 前向きコホート研究
    鬼頭 健一, 野本 博司, 佐久間 一郎, 曹 圭龍, 山下 久美子, 家坂 光, 大江 悠希, 山内 裕貴, 半田 喬久, 川田 晋一郎, 土田 和久, 柴山 唯, 大森 一乃, 大場 知穂, 宮 愛香, 亀田 啓, 竹内 淳, 永井 聡, 種田 紳二, 沖 一郎, 栗原 義夫, 青木 伸, 中村 昭伸, 渥美 達也, 三好 秀明
    糖尿病 65 Suppl.1 S - 221 (一社)日本糖尿病学会 2022年04月
  • 2型糖尿病におけるDPP-4阻害薬から経口セマグルチド切り替えによる血糖コントロールへの影響 SWITCH SEMA-2 studyプロトコール
    古澤 翔, 野本 博司, 宮 愛香, 亀田 啓, 曹 圭龍, 中村 昭伸, 竹内 淳, 永井 聡, 種田 紳二, 横山 宏樹, 佐久間 一郎, 栗原 義夫, 青木 伸, 渥美 達也, 三好 秀明
    糖尿病 65 Suppl.1 S - 225 (一社)日本糖尿病学会 2022年04月
  • 剖検膵を用いた日本人2型糖尿病膵β細胞における代謝リモデリングの検討
    泉原 里美, 野本 博司, 千葉 幸輝, 亀田 啓, 曹 圭龍, 中村 昭伸, 三好 秀明, 水上 浩哉, 渥美 達也
    糖尿病 65 Suppl.1 S - 281 (一社)日本糖尿病学会 2022年04月
  • 日本人肥満症合併2型糖尿病患者への減量・代謝改善手術により代謝疾患は改善し治療薬を減量し得る
    大藤 悠理, 曹 圭龍, 海老原 裕磨, 大江 悠希, 高瀬 崇宏, 宮 愛香, 野本 博司, 亀田 啓, 中村 昭伸, 平野 聡, 渥美 達也, 三好 秀明
    糖尿病 65 Suppl.1 S - 288 (一社)日本糖尿病学会 2022年04月
  • 耐糖能異常患者における腎移植後の耐糖能変化及びその関連因子
    久住 麻唯子, 中村 昭伸, 宮 愛香, 野本 博司, 亀田 啓, 曹 圭龍, 堀田 記世彦, 篠原 信雄, 三好 秀明, 渥美 達也
    糖尿病 65 Suppl.1 S - 290 (一社)日本糖尿病学会 2022年04月
  • 左上下肢の不随意運動を契機に診断された糖尿病性舞踏病の一例
    横関 恵, 野本 博司, 桑原 咲, 宮 愛香, 亀田 啓, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也
    糖尿病 65 Suppl.1 S - 295 (一社)日本糖尿病学会 2022年04月
  • リラグルチドおよびデュラグルチドからセマグルチド切り替えによる血糖コントロール及びQOLへの影響 SWITCH-SEMA1 study
    高橋 由華, 野本 博司, 横山 宏樹, 濱谷 柚香, 宮崎 あすか, 中田 健人, 泉原 里美, 上垣 里紗, 続木 惇, 宮 愛香, 亀田 啓, 曹 圭龍, 大場 知穂, 竹内 淳, 永井 聡, 土田 和久, 種田 紳二, 高野 善成, 木島 弘道, 山下 久美子, 栗原 義夫, 青木 伸, 中村 昭伸, 渥美 達也, 三好 秀明
    糖尿病 65 Suppl.1 S - 305 (一社)日本糖尿病学会 2022年04月
  • 内臓脂肪面積は内因性インスリン分泌低下型の2型糖尿病において血糖変動の安定性を予測する
    宮 愛香, 中村 昭伸, 半田 喬久, 野本 博司, 亀田 啓, 曹 圭龍, 伊藤 陽一, 永井 聡, 渥美 達也, 三好 秀明
    糖尿病 65 Suppl.1 S - 210 (一社)日本糖尿病学会 2022年04月
  • SGLT2阻害薬はミトコンドリア機能の改善を介し膵β細胞量・機能を保護する
    山内 裕貴, 中村 昭伸, 横田 卓, 高橋 清彦, 川田 晋一朗, 土田 和久, 大森 一乃, 野本 博司, 亀田 啓, 曹 圭龍, 安斉 俊久, 田中 伸哉, 寺内 康夫, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 98 1 361 - 361 (一社)日本内分泌学会 2022年04月
  • Yuka Takahashi, Hiraku Kameda, Aika Miya, Hiroshi Nomoto, Kyu Yong Cho, Akinobu Nakamura, Hiroki Nishimura, Hirokazu Kimura, Masaru Suzuki, Satoshi Konno, Ai Shimizu, Yoshihiro Matsuno, Michinari Okamoto, Hiroaki Motegi, Naoko Iwata, Haruki Fujisawa, Atsushi Suzuki, Yoshihisa Sugimura, Hideaki Miyoshi, Tatsuya Atsumi
    Pituitary 25 2 321 - 327 2022年04月 
    PURPOSE: To explore the clinical significance of anti-rabphillin-3A antibody for the differential diagnosis of lymphocytic panhypophysitis. METHODS AND RESULTS: A 58-year-old Japanese man developed uveitis of unknown cause in 2017. In 2019, he became aware of polyuria. In August 2020, he noticed transient diplopia and was diagnosed with right abducens nerve palsy. At the same time, he complained of fatigue and loss of appetite. Head magnetic resonance imaging demonstrated enlargement of the pituitary stalk and pituitary gland, corresponding to hypophysitis. Hormone stimulation tests showed blunted responses with respect to all anterior pituitary hormones. Central diabetes insipidus was diagnosed on the basis of a hypertonic saline loading test. Taking these findings together, a diagnosis of panhypopituitarism was made. Computed tomography showed enlargement of hilar lymph nodes. Biopsies of the hilar lymph nodes revealed non-caseating epithelioid cell granulomas that were consistent with sarcoidosis. Biopsy of the anterior pituitary revealed mild lymphocyte infiltration in the absence of IgG4-positive cells, non-caseating granulomas, or neoplasia. Western blotting revealed the presence of anti-rabphilin-3A antibody, supporting a diagnosis of lymphocytic panhypophysitis. Because the patient had no visual impairment or severe uveitis, we continued physiological hormone replacement therapy and topical steroid therapy for the uveitis. CONCLUSION: To the best of our knowledge, this is the first case of anti-rabphilin 3A antibody positive lymphocytic panhypophysitis comorbid with sarcoidosis, diagnosed by both pituitary and hilar lymph node biopsy. The utility of anti-rabphilin-3A antibody for the differential diagnosis of hypophysitis like this case should be clarified with further case studies.
  • 大江 悠希, 亀田 啓, 関崎 知紀, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 渥美 達也, 三好 秀明
    日本内分泌学会雑誌 97 5 1161 - 1161 (一社)日本内分泌学会 2022年03月
  • 関崎 知紀, 亀田 啓, 宮 愛香, 野本 博司, 曹 圭龍, 岡本 迪成, 茂木 洋晃, 中村 昭伸, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 97 5 1244 - 1244 (一社)日本内分泌学会 2022年03月
  • 家坂 光, 亀田 啓, 宮 愛香, 野本 博司, ちょう 圭龍, 中村 昭伸, 安部 崇重, 篠原 信雄, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 97 5 1253 - 1253 (一社)日本内分泌学会 2022年03月
  • 減量・代謝改善手術による代謝疾患治療薬の減量と総体重減少率の関連
    大藤 悠理, 曹 圭龍, 大江 悠希, 高瀬 崇宏, 宮 愛香, 野本 博司, 亀田 啓, 中村 昭伸, 渥美 達也, 三好 秀明
    肥満研究 27 Suppl. 318 - 318 (一社)日本肥満学会 2022年03月
  • 減量・代謝改善手術によるインスリン抵抗性と分泌能の変化
    久住 麻唯子, 曹 圭龍, 大江 悠希, 高瀬 崇宏, 宮 愛香, 野本 博司, 亀田 啓, 中村 昭伸, 渥美 達也, 三好 秀明
    肥満研究 27 Suppl. 318 - 318 (一社)日本肥満学会 2022年03月
  • 減量・代謝改善手術後の栄養動態変化
    横関 恵, 曹 圭龍, 大江 悠希, 高瀬 崇宏, 宮 愛香, 野本 博司, 亀田 啓, 中村 昭伸, 渥美 達也, 三好 秀明
    肥満研究 27 Suppl. 322 - 322 (一社)日本肥満学会 2022年03月
  • 耐糖能異常を伴う肥満患者の腹腔鏡下スリーブ状胃切除術の肝脂肪化および肝線維化に対する効果
    古澤 翔, 曹 圭龍, 大江 悠希, 高橋 崇宏, 宮 愛香, 野本 博司, 亀田 啓, 中村 昭伸, 渥美 達也, 三好 秀明
    肥満研究 27 Suppl. 347 - 347 (一社)日本肥満学会 2022年03月
  • 腹腔鏡下スリーブ状胃切除術後の骨密度の変化
    濱谷 柚香, 曹 圭龍, 大江 悠希, 高瀬 崇宏, 宮 愛香, 野本 博司, 亀田 啓, 中村 昭伸, 渥美 達也, 三好 秀明
    肥満研究 27 Suppl. 349 - 349 (一社)日本肥満学会 2022年03月
  • 関崎 知紀, 亀田 啓, 宮 愛香, 野本 博司, 曹 圭龍, 岡本 迪成, 茂木 洋晃, 中村 昭伸, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 97 5 1244 - 1244 (一社)日本内分泌学会 2022年03月
  • Shinichiro Kawata, Akinobu Nakamura, Hideaki Miyoshi, Kelaier Yang, Ikumi Shigesawa, Yuki Yamauchi, Kazuhisa Tsuchida, Kazuno Omori, Kiyohiko Takahashi, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, Yasuo Terauchi, Tatsuya Atsumi
    Diabetes, obesity & metabolism 24 3 391 - 401 2022年03月 
    AIM: To investigate how subchronic administration of a glucokinase activator (GKA) results in attenuation of the hypoglycaemic effect in the diabetic condition. MATERIALS AND METHODS: Six-week-old db/db mice were fed standard chow containing a GKA or the sodium-glucose cotransporter 2 inhibitor ipragliflozin for 1, 6, 14 or 28 days. We performed histological evaluation and gene expression analysis of the pancreatic islets and liver after each treatment and compared the results to those in untreated mice. RESULTS: The unsustained hypoglycaemic effect of GKAs was reproduced in db/db mice in conjunction with significant hepatic fat accumulation. The initial reactions to treatment with the GKA in the liver were upregulation of the gene expression of carbohydrate response element-binding protein beta (Chrebp-b) and downregulation of phosphoenolpyruvate carboxykinase (Pepck) on day 1. Subsequently, the initial changes in Chrebp-b and Pepck disappeared and increases in the expression of genes involved in lipogenesis, including acetyl-CoA carboxylase and fatty acid synthase, were observed. There were no significant changes in the pancreatic β cells nor in hepatic insulin signalling. CONCLUSIONS: The GKA showed an unsustained hypoglycaemic effect and promoted hepatic fat accumulation in db/db mice. Dynamic changes in the expression of hepatic genes involved in lipogenesis and gluconeogenesis could affect the unsustained hypoglycaemic effect of the GKA despite no changes in pancreatic β-cell function and mass.
  • Koki Chiba, Hiraku Kameda, Aika Miya, Hiroshi Nomoto, Kyu Yong Cho, Akinobu Nakamura, Shigeki Jin, Kotaro Matoba, Hideaki Miyoshi, Tatsuya Atsumi
    Thyroid 32 2 219 - 220 2022年02月01日
  • Chiho Oba-Yamamoto, Jun Takeuchi, Akinobu Nakamura, Hiroshi Nomoto, Hiraku Kameda, Kyu Y Cho, Tatsuya Atsumi, Hideaki Miyoshi
    Nutrition, metabolism, and cardiovascular diseases : NMCD 32 2 487 - 493 2022年02月 
    BACKGROUND AND AIMS: Almost all of the energy in noodle dishes is derived from carbohydrates, particularly starch. Recently, we invented a pasta with reduced starch content to about 50% and increased dietary fiber content, designated low-starch high-fiber pasta (LSHFP). In this study, we investigated the ingestion of LSHFP on the postprandial glucose response as a breakfast meal. METHODS AND RESULT: This was a randomized, single-blinded, crossover study. The postprandial glucose area under the curve for 4 h (4h-gluAUC), as the primary outcome, and the extent of postprandial glucose elevation (maxΔBG) were evaluated using a continuous glucose monitoring system in healthy volunteers and patients with type 2 diabetes (T2DM) after intake of LSHFP, standard pasta (SP), and rice. The amount of total carbohydrate was matched between LSHFP and SP. Ten individuals with T2DM and 10 individuals who did not have T2DM and were otherwise healthy were enrolled in this crossover study. The 4h-gluAUC for LSHFP (137.6 ± 42.2 mg/dL・h) was significantly smaller than the 4h-gluAUC for rice (201.7 ± 38.7 mg/dL・h) (p = 0.001) and SP (178.5 ± 59.2 mg/dL・h) (p = 0.020). The maxΔBG for rice (118.6 ± 24.2 mg/dL) was significantly higher than those for SP (87.5 ± 19.9 mg/dL) (p < 0.001) and LSHFP (72.7 ± 26.2 mg/dL) (p = 0.001), while the maxΔBG for LSHFP (p = 0.047) was significantly lower than that for SP, in T2DM patients as well as in healthy participants. CONCLUSIONS: This study demonstrated that LSHFP can reduce postprandial glucose elevation compared with SP in both healthy participants and patients with T2DM.
  • Akinobu Nakamura, Yasuo Terauchi
    Journal of diabetes investigation 13 2 233 - 235 2022年02月
  • Yuki Oe, Hiroshi Nomoto, Akinobu Nakamura, Saki Kuwabara, Yuka Takahashi, Ayano Yasui, Rimi Izumihara, Aika Miya, Hiraku Kameda, Kyu Yong Cho, Tatsuya Atsumi, Hideaki Miyoshi
    Journal of diabetes research 2022 5603864 - 5603864 2022年 
    Incretins reduce glycemic variability (GV) in patients with type 2 diabetes, but it is unknown whether switching from a combination of basal insulin and a DPP-4 inhibitor to insulin degludec/liraglutide (IDegLira) improves GV. We performed an exploratory prospective observational study to compare the effect of IDegLira and the combination on GV. We recruited hospitalized patients with type 2 diabetes who had stable glycemic control with insulin degludec (≤16 units/day) and taking a DPP-4 inhibitor. GV was analyzed using continuous glucose monitoring (CGM) before and after switching the medication to IDegLira. The principal endpoint was the change in mean amplitude of glycemic excursions (MAGE). Other indices of GV and CGM parameters were analyzed as the secondary endpoints. Fifteen participants were enrolled and 12 completed the study. In these participants, the DPP-4 inhibitor and insulin degludec were discontinued, and the equivalent dose of IDegLira was commenced. Switching to IDegLira significantly improved MAGE from 74.9 (60.3, 97.7) mg/dL to 64.8 (52.0, 78.2) mg/dL (P < 0.05), as well as other indices of GV and 24-hour mean blood glucose concentration. Analysis of the ambulatory glucose profile showed marked reductions in postprandial glucose concentration. Nocturnal glucose concentration was similar under the two treatment regimens. IDegLira improved GV as well as the mean and the postprandial glucose concentration by switching from insulin degludec plus DPP-4 inhibitor combination. IDegLira might be beneficial for patients being treated with low-dose basal insulin.
  • 大藤 悠理, 亀田 啓, 桑原 咲, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 97 4 658 - 658 (一社)日本内分泌学会 2021年12月
  • 中田 健人, 亀田 啓, 桑原 咲, 安井 彩乃, 高橋 由華, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 97 4 658 - 658 (一社)日本内分泌学会 2021年12月
  • 宮崎 あすか, 亀田 啓, 亀田 玲奈, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 97 4 658 - 658 (一社)日本内分泌学会 2021年12月
  • 横関 恵, 亀田 啓, 千葉 幸輝, 桑原 咲, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 安倍 崇重, 篠原 信雄, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 97 4 660 - 660 (一社)日本内分泌学会 2021年12月
  • 濱谷 柚香, 亀田 啓, 安井 彩乃, 大江 悠希, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 97 4 660 - 660 (一社)日本内分泌学会 2021年12月
  • 久住 麻唯子, 亀田 啓, 千葉 幸輝, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 大原 克仁, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 97 4 660 - 660 (一社)日本内分泌学会 2021年12月
  • Hikaru Kamoshima, Hiroshi Nomoto, Kumiko Yamashita, Yuka Takahashi, Kazuhisa Tsuchida, Saki Kuwabara, Aika Miya, Kyu Yong Cho, Hiraku Kameda, Akinobu Nakamura, Tatsuya Atsumi, Shinji Taneda, Yoshio Kurihara, Shin Aoki, Yuri Ono, Hideaki Miyoshi
    Endocrine journal 69 5 495 - 509 2021年11月25日 
    Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are well-established means of improving glycemia and preventing cardio-renal events in patients with type 2 diabetes. However, their efficacy and safety have yet to be fully characterized in patients with type 1 diabetes (T1D). We studied patients with T1D who regularly attended one of five diabetes centers and treated with an SGLT2i (ipragliflozin or dapagliflozin) for >52 weeks, and the changes in HbA1c, body mass, insulin dose, and laboratory data were retrospectively evaluated and adverse events (AEs) recorded during December 2018 to April 2021. A total of 216 patients with T1D were enrolled during the period. Of these, 42 were excluded owing to short treatment periods and 15 discontinued their SGLT2i. The mean changes in glycated hemoglobin (HbA1c), body mass, and insulin dose were -0.4%, -2.1 kg, and -9.0%, respectively. The change in HbA1c was closely associated with the baseline HbA1c (p < 0.001), but not with the baseline body mass or renal function. The basal and bolus insulin doses decreased by 18.2% and 12.6%, respectively, in participants with a baseline HbA1c <8%. The most frequent AE was genital infection (2.8%), followed by diabetic ketoacidosis (DKA; 1.4%). None of the participants experienced severe hypoglycemic events. In conclusion, the administration of an SGLT2i in addition to intensive insulin treatment in patients with T1D improves glycemic control and body mass, without increasing the incidence of hypoglycemia or DKA.
  • Yuki Oe, Hiraku Kameda, Hiroshi Nomoto, Keita Sakamoto, Takeshi Soyama, Kyu Yong Cho, Akinobu Nakamura, Koji Iwasaki, Daisuke Abo, Kohsuke Kudo, Hideaki Miyoshi, Tatsuya Atsumi
    Medicine 100 46 e27895  2021年11月19日 
    RATIONALE: Tumor-induced osteomalacia (TIO) is curable by tumor resection, but detection of the tumor can be challenging. Overproduction of fibroblast growth factor 23 (FGF23) by the tumor causes hypophosphatemia and consequently induces inappropriate bone turnover. Conventionally oral phosphate supplementation was the only treatment for TIO, but had risks of hypercalciuria and nephrocalcinosis. Burosumab, a human monoclonal anti-FGF23 antibody, was recently post-marketed in Japan against for FGF23-related hypophosphatemia. Herein, we present a case of TIO with undetectable tumor that was successfully treated with burosumab. PATIENT CONCERNS: A 47-year-old woman was forced to use a wheelchair because of pain in both feet. DIAGNOSIS: Laboratory findings showed hypophosphatemia, elevated bone markers, and high serum FGF23 without renal tubular defects. Imaging studies revealed bone atrophy in the feet, decreased bone density, and multiple pseudofractures in the talar, sacral, and L5 vertebral regions. After excluding drug-induced and hereditary osteomalacia, we diagnosed her as TIO. INTERVENTIONS: Comprehensive imaging studies and stepwise venous sampling failed to localize the tumor, and we started to administer subcutaneous burosumab. OUTCOMES: After administration of burosumab, her serum phosphate was normalized without phosphate supplementation within 2 months. Improvement of pseudofractures, relief of pain evaluated by a visual analog scale, and normalization of bone biomarkers were observed. The patient was able to stand by herself after 6 months administration of burosumab. LESSONS: This is the first report in clinical practice to demonstrate favorable effects of burosumab, including not only normalization of serum phosphate but also improvements of pseudofractures and subjective pain, in a patient with TIO and undetectable tumor.
  • 中田 健人, 亀田 啓, 桑原 咲, 安井 彩乃, 高橋 由華, 高瀬 崇宏, 西尾 太郎, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 安部 崇重, 篠原 信雄, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 97 2 485 - 485 (一社)日本内分泌学会 2021年10月
  • 桑原 咲, 亀田 啓, 関崎 知紀, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 岡本 迪成, 茂木 洋晃, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 97 2 491 - 491 (一社)日本内分泌学会 2021年10月
  • 各務 萌, 亀田 啓, 古澤 翔, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 97 2 496 - 496 (一社)日本内分泌学会 2021年10月
  • 高橋 由華, 亀田 啓, 曹 圭龍, 中村 昭伸, 西村 弘基, 木村 孔一, 清水 亜衣, 岡本 迪成, 茂木 洋晃, 岩田 尚子, 藤沢 治樹, 鈴木 敦詞, 椙村 益久, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 97 2 495 - 495 (一社)日本内分泌学会 2021年10月
  • 宮崎 あすか, 亀田 啓, 大江 悠希, 泉原 里美, 重沢 郁美, 野本 博司, 曹 圭龍, 中村 昭伸, 坂本 圭太, 森田 亮, 曽山 武士, 阿保 大介, 工藤 與亮, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 97 2 521 - 521 (一社)日本内分泌学会 2021年10月
  • Reina Hashimoto-Kameda, Kyu Yong Cho, Hiroshi Nomoto, Akinobu Nakamura, Kazuno Omori, So Nagai, Sachiko Edagawa, Shinichiro Kawata, Jun Takeuchi, Hiraku Kameda, Yoshio Kurihara, Shin Aoki, Tatsuya Atsumi, Hideaki Miyoshi
    Diabetes research and clinical practice 180 109069 - 109069 2021年09月23日 
    AIMS: Sodium-glucose cotransporter-2 inhibitor (SGLT2i) reduces clinic blood pressure (BP), but the effects on BP circadian rhythm remain unclear. The present study aimed to determine the nighttime antihypertensive effect of SGLT2i compared with dipeptidyl peptidase-4 inhibitor (DPP-4i) in patients with type 2 diabetes and hypertension. MATERIALS AND METHODS: In this randomized, open-label, parallel-group trial, patients treated with DPP-4i were either switched to luseogliflozin 2.5 mg/day (Luseo group;n = 30) or continued DPP-4i (DPP-4i group;n = 26). The patients undertook 24-h ambulatory BP monitoring before and 8 weeks after the group allocation. The primary endpoint was mean change in nighttime systolic BP (SBP). RESULTS: Nighttime SBP, as well as daytime SBP, was significantly reduced in the Luseo group compared with the DPP-4i group (nighttime, -4.0 ± 11.4 vs. 3.6 ± 10.7 mmHg,P = 0.01; daytime, -4.4 ± 10.9 vs. 3.7 ± 11.9 mmHg,P = 0.01). Similarly, nighttimepulse rate(PR) was significantly reduced in the Luseo group (-2.0 ± 4.8 vs. 0.9 ± 4.8 bpm,P = 0.03). The proportion of patients with abnormal BP circadian rhythms (non-dipper pattern plus riser pattern) was significantly lower in the Luseo group (36.6% vs. 56.7%,P < 0.05). CONCLUSIONS: Switching from DPP-4i to luseogliflozin decreased nighttime SBP and PR; moreover, BP circadian rhythm was improved.
  • 肥満糖尿病病態におけるHPA軸の活動性亢進機序
    関崎 知紀, 亀田 啓, 柴山 惟, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也
    ACTH RELATED PEPTIDES 31 5 - 6 間脳・下垂体・副腎系研究会 2021年09月
  • 認知・生活機能質問票(DASC-8)を用いた目標HbA1cの達成に関連する患者背景因子の特定
    宮 愛香, 中村 昭伸, 横田 勲, 曹 圭龍, 亀田 啓, 野本 博司, 高瀬 崇宏, 大森 一乃, 永井 聡, 種田 紳二, 小野 真佑子, 渥美 達也, 三好 秀明
    糖尿病合併症 35 Suppl. 172 - 172 (一社)日本糖尿病合併症学会 2021年09月
  • 認知・生活機能質問票(DASC-8)を用いた目標HbA1cの達成に関連する患者背景因子の特定
    宮 愛香, 中村 昭伸, 横田 勲, 曹 圭龍, 亀田 啓, 野本 博司, 高瀬 崇宏, 大森 一乃, 永井 聡, 種田 紳二, 小野 真佑子, 渥美 達也, 三好 秀明
    糖尿病合併症 35 Suppl. 172 - 172 (一社)日本糖尿病合併症学会 2021年09月
  • Chiho Oba-Yamamoto, Hiraku Kameda, Hideaki Miyoshi, Tomonori Sekizaki, Takahiro Takase, Tsuyoshi Yanagimachi, Yukihiro Fujita, Hiroshi Nomoto, Kyu Yong Cho, Akinobu Nakamura, So Nagai, Tatsuya Atsumi
    Internal Medicine 60 15 2375 - 2383 2021年08月01日
  • Akinobu Nakamura, Kazuno Omori, Yasuo Terauchi
    Diabetes, obesity & metabolism 23 10 2199 - 2206 2021年06月09日 
    Glucokinase, which phosphorylates glucose to form glucose-6-phosphate, plays a critical role in regulating blood glucose levels. On the basis of data of glucokinase-knockout and transgenic mice and humans with glucokinase mutations, glucokinase was targeted for drug development aiming to augment its activity, and thereby reduce hyperglycaemia in patients with diabetes. In fact, various small molecule compounds have been developed and clinically tested as glucokinase activators. However, some have been discontinued because of efficacy and safety issues. One of these issues is loss of the drug's efficacy over time. This unsustained glycaemic efficacy may be associated with the excess glycolysis by glucokinase activation in pancreatic beta cells, resulting in beta-cell failure. Recently, we have shown that glucokinase haploinsufficiency ameliorated glucose intolerance by increasing beta-cell function and mass in a mouse model of diabetes. Given that a similar phenotype has been observed in glucokinase-activated beta cells and diabetic beta cells, glucokinase inactivation may be a new therapeutic target for type 2 diabetes.
  • Tomonori Sekizaki, Hiraku Kameda, Hiroshi Nomoto, Kyu Yong Cho, Akinobu Nakamura, Kiyohiko Takahashi, Arina Miyoshi, Norio Wada, Jun Takeuchi, So Nagai, Hideaki Miyoshi, Tatsuya Atsumi
    Journal of diabetes investigation 12 11 1978 - 1982 2021年05月17日 
    Dipeptidyl peptidase-4 (DPP-4), namely CD26, is expressed on the surface of immune cells, suggesting that inhibition of DPP-4 might affect the immune system. The current multicenter observational case-control study was carried out to investigate the effects of DPP-4 inhibitor (DPP-4i) administration on Graves' disease (GD) activity. This study comprised patients with GD and type 2 diabetes, who were administered an oral hypoglycemic agent including DPP-4i. Exacerbation of GD was defined as an increase of antithyroid drug dose by 6 months after oral hypoglycemic agent administration. A total of 80 patients were enrolled and divided into an exacerbation group or a non-exacerbation group. The frequency of DPP-4i administration was significantly higher in the exacerbation group (88%) than that in the non-exacerbation group (31%). In multivariate logistic regression analysis, there was a significant association between DPP-4i administration and GD exacerbation (odds ratio 7.39). The current study suggests that DPP-4i administration is associated with GD exacerbation.
  • Yuki Oe, Hiraku Kameda, Hiroshi Nomoto, Keita Sakamoto, Takeshi Soyama, Kyu Yong Cho, Akinobu Nakamura, Daisuke Abo, Kohsuke Kudo, Tatsuya Atsumi, Hideaki Miyoshi
    Journal of the Endocrine Society 5 Supplement_1 A194 - A194 2021年05月03日 
    Abstract Background: Fibroblast growth factor 23 (FGF23) decreases serum phosphate levels by inhibiting proximal tubular phosphate reabsorption and intestinal phosphate absorption by decreasing serum 1,25-dihydroxyvitamin D level, thereby regulating phosphate metabolism. Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by FGF23 overproduction by tumor tissue. Resecting the responsible tumor is a radical treatment for TIO. When the responsible tumor is undetectable, phosphate and active vitamin D administration is recommended. However, supplementation alone is frequently insufficient to maintain phosphate levels and it is difficult to prevent the complications associated with medical therapy, including hypercalciuria and nephrocalcinosis. Recently, burosumab, a human monoclonal anti-FGF23 antibody, has been approved in Japan as a therapeutic agent for FGF23-related hypophosphatemia. Here, we present a patient with TIO effectively treated with burosumab in the absence of identification of tumour location. Clinical case: A 47-year-old female developed pain and edema of the feet; however, the cause could not be determined at local hospitals. Afterwards, she developed marked bone atrophy in the feet and was referred to our hospital. Her age at symptom onset, hypophosphatemia (serum P, 1.9 mg/dl, 2.7 mg/dl &lt; n &lt; 4.6 mg/dl), high serum FGF23 level (630 pg/ml, 16 pg/ml &lt; n &lt; 69 pg/ml), and decreased 1,25-dihydroxyvitamin D level (12.9 pg/ml, 20 pg/ml &lt; n &lt; 60 pg/ml) indicated FGF23-related osteomalacia. She was not having any medication at the time of diagnosis, including saccharified iron oxide or iron polymaltose. Urinary phosphate excretion increased without renal tubular defect; therefore, hypophosphatemic osteomalacia was diagnosed. MRI showed high signal intensity in the talus, sacral, and L5 vertebral regions, indicating multiple pseudofractures. Comprehensive imaging studies, including systemic CT scan and 111In-pentetreotide scintigraphy, did not reveal any tumors despite the suspicion of TIO. Next, we performed systemic venous sampling, which revealed high FGF23 level in the left external iliac vein. Second venous sampling limited to the left lower limb exhibited high FGF23 level in the posterior tibial vein. However, an additional imaging study limited to the left foot could not identify any tumors. Genetic variation was negative for potentially responsible genes, including PHEX and FGF23. We decided to administer burosumab to normalize serum phosphate level without phosphate supplementation. Within 2 months, pain was relieved and the visual analog scale scores also improved from 10 to 6. Moreover, bone MRI showed improved pseudofractures. Conclusion: Burosumab administration was effective for TIO of unknown origin, and it improved not only laboratory findings but also clinical symptoms in this case.
  • 膵特異的グルコキナーゼの抑制が2型糖尿病病態下の膵β細胞量を保持する
    大森 一乃, 中村 昭伸, 三好 秀明, 川田 晋一朗, 野本 博司, 亀田 啓, 曹 圭龍, 寺内 康夫, 渥美 達也
    糖尿病 64 Suppl.1 I - 3 (一社)日本糖尿病学会 2021年05月
  • 肥満外科治療は糖尿病治療薬の減量・中止および2型糖尿病寛解の期待ができる
    千葉 幸輝, 大江 悠希, 高瀬 崇宏, 曹 圭龍, 野本 博司, 亀田 啓, 中村 昭伸, 渥美 達也, 三好 秀明
    糖尿病 64 Suppl.1 I - 3 (一社)日本糖尿病学会 2021年05月
  • 糖代謝障害を伴った高度肥満症患者における腹腔鏡下スリーブ状胃切除術による糖・脂質代謝および肝臓への好影響
    安井 彩乃, 曹 圭龍, 大江 悠希, 野本 博司, 亀田 啓, 中村 昭伸, 海老原 裕磨, 平野 聡, 渥美 達也, 三好 秀明
    糖尿病 64 Suppl.1 I - 4 (一社)日本糖尿病学会 2021年05月
  • リラグルチドおよびデュラグルチドからセマグルチド切り替えによる血糖コントロール及びQOLへの影響 SWITCH-SEMA1プロトコール
    高橋 由華, 野本 博司, 亀田 啓, 曹 圭龍, 中村 昭伸, 竹内 淳, 永井 聡, 種田 紳二, 横山 宏樹, 栗原 義夫, 青木 伸, 渥美 達也, 三好 秀明
    糖尿病 64 Suppl.1 I - 2 (一社)日本糖尿病学会 2021年05月
  • 2型糖尿病または耐糖能異常合併高血圧患者におけるエサキセレノンの効果
    桑原 咲, 亀田 啓, 野本 博司, 曹 圭龍, 中村 昭伸, 山本 浩平, 種田 紳二, 三次 有奈, 和田 典男, 小梁川 直秀, 竹内 淳, 永井 聡, 栗原 義夫, 三好 秀明, 渥美 達也
    糖尿病 64 Suppl.1 II - 3 (一社)日本糖尿病学会 2021年05月
  • DPP-4阻害薬からSGLT2阻害薬への切替は、高血圧症を合併する2型糖尿病患者の夜間血圧・脈拍を低下させる
    亀田 玲奈, 曹 圭龍, 川田 晋一朗, 大森 一乃, 野本 博司, 亀田 啓, 竹内 淳, 永井 聡, 中村 昭伸, 栗原 義夫, 青木 伸, 渥美 達也, 三好 秀明
    糖尿病 64 Suppl.1 III - 2 (一社)日本糖尿病学会 2021年05月
  • 空腹時内因性インスリン分泌は不安定な血糖変動・低血糖の予測に役立つだけでなく血糖降下薬の選択においても有用である
    宮 愛香, 中村 昭伸, 半田 喬久, 野本 博司, 亀田 啓, 曹 圭龍, 永井 聡, 伊藤 陽一, 渥美 達也, 三好 秀明
    糖尿病 64 Suppl.1 III - 4 (一社)日本糖尿病学会 2021年05月
  • インスリンデグルデクとDPP-4阻害薬の併用からデグルデク/リラグルチド配合注への切り替えは血糖変動を改善する
    大江 悠希, 野本 博司, 中村 昭伸, 桑原 咲, 高橋 由華, 安井 彩乃, 亀田 啓, 曹 圭龍, 渥美 達也, 三好 秀明
    糖尿病 64 Suppl.1 III - 3 (一社)日本糖尿病学会 2021年05月
  • 耐糖能異常合併肥満症患者における腹腔鏡下スリーブ状胃切除後の骨密度低下
    上垣 里紗, 大江 悠希, 亀田 啓, 高瀬 崇宏, 野本 博司, 曹 圭龍, 中村 昭伸, 平野 聡, 渥美 達也, 三好 秀明
    糖尿病 64 Suppl.1 P - 6 (一社)日本糖尿病学会 2021年05月
  • db/dbマウスを用いたグルコキナーゼ活性化薬の血糖降下作用消失機序の解明
    川田 晋一朗, 中村 昭伸, 三好 秀明, 重沢 郁美, 山内 裕貴, 土田 和久, 大森 一乃, 高橋 清彦, 北尾 直之, 野本 博司, 亀田 啓, 曹 圭龍, 寺内 康夫, 渥美 達也
    糖尿病 64 Suppl.1 P - 1 (一社)日本糖尿病学会 2021年05月
  • SGLT2阻害薬はミトコンドリア機能の改善を介し膵β細胞を保護する
    山内 裕貴, 中村 昭伸, 横田 卓, 高橋 清彦, 川田 晋一朗, 土田 和久, 大森 一乃, 野本 博司, 亀田 啓, 曹 圭龍, 安斉 俊久, 田中 伸哉, 寺内 康夫, 三好 秀明, 渥美 達也
    糖尿病 64 Suppl.1 III - 6 (一社)日本糖尿病学会 2021年05月
  • Yuki Yamauchi, Hiraku Kameda, Kazuno Omori, Michio Tani, Kyu Yong Cho, Akinobu Nakamura, Hideaki Miyoshi, Shinya Tanaka, Tatsuya Atsumi
    BMC endocrine disorders 21 1 84 - 84 2021年04月27日 
    BACKGROUND: Subclinical Cushing's disease (SCD) is defined by corticotroph adenoma-induced mild hypercortisolism without typical physical features of Cushing's disease. Infection is an important complication associated with mortality in Cushing's disease, while no reports on infection in SCD are available. To make clinicians aware of the risk of infection in SCD, we report a case of SCD with disseminated herpes zoster (DHZ) with the mortal outcome. CASE PRESENTATION: An 83-year-old Japanese woman was diagnosed with SCD, treated with cabergoline in the outpatient. She was hospitalized for acute pyelonephritis, and her fever gradually resolved with antibiotics. However, herpes zoster appeared on her chest, and the eruptions rapidly spread over the body. She suddenly went into cardiopulmonary arrest and died. Autopsy demonstrated adrenocorticotropic hormone-positive pituitary adenoma, renal abscess, and DHZ. CONCLUSIONS: As immunosuppression caused by SCD may be one of the triggers of severe infection, the patients with SCD should be assessed not only for the metabolic but also for the immunodeficient status.
  • Aika Miya, Akinobu Nakamura, Takahisa Handa, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, So Nagai, Yoichi M Ito, Hideaki Miyoshi, Tatsuya Atsumi
    Scientific reports 11 1 9057 - 9057 2021年04月27日 
    The contribution of endogenous insulin secretion to glycemic variability (GV) may differ between patients with impaired insulin secretion and those with preserved secretion. Our objective was to determine the linearity of the relationship between fasting C-peptide (CPR) as a marker of endogenous insulin secretion and GV in type 2 diabetes (T2DM), regardless of the type of antidiabetic treatment. We conducted a prospective observational study using continuous glucose monitoring obtained from 284 Japanese outpatients with T2DM with various HbA1c values and antidiabetic treatment. We constructed a prediction curve of base-line CPR versus coefficient of variation (CV) and identified the clinical factors associated with CV using multiple regression analysis. Fasting CPR showed a significant negative log-linear relationship with CV (P < 0.0001), and the latter being strikingly high in the low-CPR group. The multiple regression analysis showed that low CPR was an independent predictor of high CV (P < 0.0001). The significant correlations were sustained in both patients with/without insulin treatment. The contribution of endogenous insulin secretion to GV depends on the extent of insulin secretion impairment. Fasting CPR may represent a useful indicator of GV instability in T2DM.
  • 千葉 幸輝, 亀田 啓, 野本 博司, 曹 圭龍, 中村 昭伸, 神 繁樹, 的場 光太郎, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 97 1 225 - 225 (一社)日本内分泌学会 2021年04月
  • 野本 博司, Tudzarova Slavica, Pei Lina, Montemurro Chiara, Gurlo Tatyana, Butler Peter C., 中村 昭伸, 渥美 達也
    日本内分泌学会雑誌 97 1 225 - 225 (一社)日本内分泌学会 2021年04月
  • 関崎 知紀, 亀田 啓, 中村 昭伸, 野本 博司, 曹 圭龍, 伊師 雪友, 茂木 洋晃, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 97 1 261 - 261 (一社)日本内分泌学会 2021年04月
  • 大森 一乃, 中村 昭伸, 三好 秀明, 野本 博司, 亀田 啓, 曹 圭龍, 寺内 康夫, 渥美 達也
    日本内分泌学会雑誌 97 1 275 - 275 (一社)日本内分泌学会 2021年04月
  • 湯野 暁子, 高橋 由華, 亀田 啓, 野本 博司, 曹 圭龍, 中村 昭伸, 山下 優, 中久保 祥, 鎌田 啓佑, 鈴木 雅, 井下 尚子, 今野 哲, 三好 秀明, 渥美 達也, 澤村 豊, 島津 章
    日本内分泌学会雑誌 97 1 260 - 260 (一社)日本内分泌学会 2021年04月
  • Takahisa Handa, Akinobu Nakamura, Aika Miya, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, So Nagai, Narihito Yoshioka, Hideaki Miyoshi, Tatsuya Atsumi
    Diabetology & metabolic syndrome 13 1 37 - 37 2021年04月01日 
    BACKGROUND: This study aimed to explore predictive factors of time below target glucose range (TBR) ≥ 1% among patients' characteristics and glycemic variability (GV) indices using continuous glucose monitoring data in elderly patients with type 2 diabetes. METHODS: We conducted a prospective observational study on 179 (71 female) Japanese outpatients with type 2 diabetes aged ≥ 65 years. The characteristics of the participants with TBR ≥ 1% were evaluated by multivariate logistic regression analysis. Receiver-operating characteristic (ROC) curve analyses of GV indices, comprising coefficient of variation (CV), standard deviation, and mean amplitude of glycemic excursions, were performed to identify the optimal index for the identification of patients with TBR ≥ 1%. RESULTS: In the multivariate logistic regression analysis, none of the clinical characteristics, including HbA1c and C-peptide index, were independent markers for TBR ≥ 1%, while all three GV indices showed significant associations with TBR ≥ 1%. Among the three GV indices, CV showed the best performance based on the area under the curve in the ROC curve analyses. CONCLUSIONS: Among elderly patients with type 2 diabetes, CV reflected TBR ≥ 1% most appropriately among the GV indices examined. Trial registration UMIN-CTR: UMIN000029993. Registered 16 November 2017.
  • Kazuno Omori, Akinobu Nakamura, Hideaki Miyoshi, Yuki Yamauchi, Shinichiro Kawata, Kiyohiko Takahashi, Naoyuki Kitao, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, Yasuo Terauchi, Tatsuya Atsumi
    Diabetes 70 4 917 - 931 2021年04月 
    Efficacy of glucokinase activation on glycemic control is limited to a short-term period. One reason might be related to excess glucose signaling by glucokinase activation toward β-cells. In this study, we investigated the effect of glucokinase haploinsufficiency on glucose tolerance as well as β-cell function and mass using a mouse model of type 2 diabetes. Our results showed that in db/db mice with glucokinase haploinsufficiency, glucose tolerance was ameliorated by augmented insulin secretion associated with the increase in β-cell mass when compared with db/db mice. Gene expression profiling and immunohistochemical and metabolomic analyses revealed that glucokinase haploinsufficiency in the islets of db/db mice was associated with lower expression of stress-related genes, greater expression of transcription factors involved in the maintenance and maturation of β-cell function, less mitochondrial damage, and a superior metabolic pattern. These effects of glucokinase haploinsufficiency could preserve β-cell mass under diabetic conditions. These findings verified our hypothesis that optimizing excess glucose signaling in β-cells by inhibiting glucokinase could prevent β-cell insufficiency, leading to improving glucose tolerance in diabetes status by preserving β-cell mass. Therefore, glucokinase inactivation in β-cells, paradoxically, could be a potential strategy for the treatment of type 2 diabetes.
  • Akira Shimatsu, Akinobu Nakamura, Yutaka Takahashi, Shingo Fujio, Fumitoshi Satoh, Shigeyuki Tahara, Hiroshi Nishioka, Koji Takano, Miho Yamashita, Hiroshi Arima, Atsushi Tominaga, Shohei Tateishi, Yusaku Matsushita
    Endocrine journal 68 7 791 - 805 2021年03月11日 
    Somatostatin analogs are recommended for pharmacotherapy of TSH-secreting pituitary adenoma (TSHoma). A multicenter clinical trial was conducted to evaluate the efficacy and safety of lanreotide autogel treatment for TSHoma. A total of 13 Japanese patients with TSHoma were enrolled from February to December 2018 and treated with lanreotide autogel 90 mg every 4 weeks, with dose adjustments to 60 mg or 120 mg. Analysis was performed on data from patients receiving preoperative treatment (n = 6) up to 24 weeks and from those receiving primary or postoperative treatment (n = 7) up to 52 weeks. The primary efficacy endpoints were serum concentrations of TSH, free triiodothyronine (FT3), and free thyroxine (FT4). The secondary efficacy endpoints were pituitary tumor size and clinical symptoms. The serum concentrations of TSH, FT3, and FT4 decreased with treatment, and euthyroid status was maintained until final assessment. FT4 at final assessment was within reference ranges in 10/13 patients. The median (interquartile range) percent change in pituitary tumor size from baseline at final assessment was -23.8% (-38.1, -19.8). The clinical symptoms were also improved. The patients receiving preoperative treatment did not develop perioperative thyroid storm. Regarding safety, adverse events were observed in 12/13 patients, but none discontinued treatment. The common adverse events were gastrointestinal disorders (12/13 patients) and administration site reactions (5/13 patients). Lanreotide autogel may be effective for controlling thyroid function and reducing the pituitary tumor size, and is tolerable in patients with TSHoma (Japic Clinical Trials Information; JapicCTI-173772).
  • Hiroshi Nomoto, Chiho Oba-Yamamoto, Yuka Takahashi, Jun Takeuchi, So Nagai, Hiroki Yokoyama, Shinji Taneda, Yoshio Kurihara, Shin Aoki, Hiraku Kameda, Kyu Yong Cho, Akinobu Nakamura, Tatsuya Atsumi, Hideaki Miyoshi
    Diabetes therapy : research, treatment and education of diabetes and related disorders 12 3 955 - 964 2021年03月 
    INTRODUCTION: Glucagon-like peptide (GLP)-1 receptor agonists exert potent hypoglycemic effects in patients with type 2 diabetes (T2D) in a blood glucose concentration-dependent manner. Once-weekly subcutaneous administration of the GLP-1 receptor agonist semaglutide has beneficial effects on glycemic and body weight control, but it is currently unclear if semaglutide provides superior glycemic control compared to conventional GLP-1 receptor agonists in the Japanese population. We aim to compare the effects of once-weekly subcutaneous semaglutide with those of liraglutide or dulaglutide administration in Japanese patients with T2D. METHODS: This study is a multicenter, prospective, randomized, open-label, blinded-endpoint, parallel-group trial. In total, 100 participants with T2D who have been treated with liraglutide (0.9-1.8 mg/day in plan A) or dulaglutide (0.75 mg/week in plan B) for more than 12 weeks and have a glycated hemoglobin (HbA1c) level of 6.0-9.9% and a body mass index (BMI) of ≥ 22 kg/m2 will be randomized to either continue using their existing GLP-1 receptor agonist or switch to subcutaneous semaglutide once weekly for 24 weeks. Biochemical analysis, physical assessment, and a quality-of-life questionnaire (DTSQ) will be completed at baseline and at the end of the study. The primary endpoint is the effect of semaglutide on the change in HbA1c. The secondary endpoints are the mean changes in total DTSQ score, body mass, abdominal circumference, systolic and diastolic blood pressure, pulse rate, factors associated with improvement in HbA1c and secondary endpoints, side effects, and other laboratory parameters. PLANNED OUTCOMES: The results of the study will provide useful information regarding the effects of switching to semaglutide from other GLP-1 receptor agonists on glycemic control in patients with T2D. ETHICS AND DISSEMINATION: The Hokkaido University Certified Review Board (CRB no. 1180001) has approved the protocol (no. 018-005). The results will be disseminated in peer-reviewed journals and at scientific conferences. TRIAL REGISTRATION: UMIN000042369 in the University Hospital Medical Information Network (UMIN); jRCT1011200008 in the Japan Registry of Clinical Trials (jRCT); pre-results.
  • Kazuhisa Tsuchida, Akinobu Nakamura, Hideaki Miyoshi, Kelaier Yang, Yuki Yamauchi, Shinichiro Kawata, Kazuno Omori, Kiyohiko Takahashi, Naoyuki Kitao, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, Yusuke Seino, Yasuo Terauchi, Tatsuya Atsumi
    Journal of diabetes investigation 12 9 1545 - 1554 2021年02月27日 
    AIMS/INTRODUCTION: We aimed to determine whether glucokinase is required for beta cell mass expansion induced by high-starch diet (HSTD)-feeding, as has been shown in its high-fat diet-induced expansion. MATERIALS AND METHODS: Eight-week-old male wild-type (Gck+/+ ) or glucokinase haploinsufficient (Gck+/- ) mice were fed either a normal chow (NC) or an HSTD for 15 weeks. The body weight, glucose tolerance, insulin sensitivity, insulin secretion, and beta-cell mass were assessed. RESULTS: Both HSTD-fed Gck+/+ and Gck+/- mice had significantly higher body weight than NC-fed mice. Insulin and oral glucose tolerance tests revealed that HSTD-feeding did not affect insulin sensitivity nor glucose tolerance in either the Gck+/+ or Gck+/- mice. However, during the oral glucose tolerance test, the 15 minutes' plasma insulin concentration after glucose loading was significantly higher in the HSTD group than that in the NC group for Gck+/+ , but not for Gck+/- mice. Beta cell mass was significantly larger in HSTD-fed Gck+/+ mice than that in NC-fed Gck+/+ mice. In contrast, the beta cell mass of the HSTD-fed Gck+/- mice was not different from that of the NC-fed Gck+/- mice. CONCLUSIONS: The results indicated that HSTD-feeding would increase pancreatic beta-cell mass and insulin secretion in Gck+/+ , but not Gck+/- mice. This observation implies that glucokinase in beta-cells would be required for the increase in beta cell mass induced by HSTD-feeding.
  • Kyu Yong Cho, Hiroshi Nomoto, Akinobu Nakamura, Shinichiro Kawata, Hajime Sugawara, Jun Takeuchi, So Nagai, Kazuno Omori, Kazuhisa Tsuchida, Aika Miya, Ikumi Shigesawa, Kenichi Tsuchida, Shingo Yanagiya, Hiraku Kameda, Hiroki Yokoyama, Shinji Taneda, Yoshio Kurihara, Shin Aoki, Naoki Nishimoto, Tatsuya Atsumi, Hideaki Miyoshi
    Journal of diabetes investigation 12 8 1417 - 1424 2021年01月09日 
    AIMS/INTRODUCTION: We recently reported the beneficial effect of the combination of sodium-glucose cotransporter 2 inhibitor and dipeptidyl peptidase-4 inhibitor on daily glycemic variability in patients with type 2 diabetes mellitus. Additional favorable effects of combination therapy were explored in this secondary analysis. MATERIALS AND METHODS: The CALMER study was a multicenter, open-label, prospective, randomized, parallel-group comparison trial for type 2 diabetes mellitus involving continuous glucose monitoring under meal tolerance tests. Patients were randomly assigned to switch from teneligliptin to canagliflozin (SWITCH group) or to add canagliflozin to teneligliptin (COMB group). The continuous glucose monitoring metrics, including time in target range, were investigated. RESULTS: All 99 participants (mean age 62.3 years; mean glycated hemoglobin 7.4%) completed the trial. The time in target range was increased in the COMB group (71.2-82.7%, P < 0.001). The extent of the reduction in time above target range was significantly larger in the COMB group compared with the SWITCH group (-14.8% vs -7.5%, P < 0.01). Area under the curve values for glucose at 120 min after all meal tolerance tests were significantly decreased in the COMB group compared with the SWITCH group (P < 0.05). CONCLUSIONS: Sodium-glucose cotransporter 2 inhibitor combined with dipeptidyl peptidase-4 inhibitor improved the quality of glycemic variability and reduced postprandial hyperglycemia compared with each monotherapy.
  • 安井 彩乃, 亀田 啓, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 96 3 597 - 597 (一社)日本内分泌学会 2021年01月
  • 桑原 咲, 亀田 啓, 家坂 光, 泉原 里美, 大江 悠希, 上垣 里紗, 千葉 幸輝, 宮 愛華, 野本 博司, 曹 圭龍, 中村 昭伸, 安部 崇重, 篠原 信雄, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 96 3 598 - 598 (一社)日本内分泌学会 2021年01月
  • 大江 悠希, 亀田 啓, 野本 博司, 曹 圭龍, 松本 隆児, 大澤 崇宏, 中村 昭伸, 安部 崇重, 篠原 信雄, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 96 3 598 - 598 (一社)日本内分泌学会 2021年01月
  • Akiko Yuno, Yoshiyuki Kenmotsu, Yuka Takahashi, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, Akinobu Nakamura, Yu Yamashita, Junichi Nakamura, Sho Nakakubo, Keisuke Kamada, Masaru Suzuki, Hirokazu Sugino, Naoko Inoshita, Satoshi Konno, Hideaki Miyoshi, Tatsuya Atsumi, Yutaka Sawamura, Akira Shimatsu
    Endocrine journal 68 4 477 - 484 2020年12月24日 
    We provide the details of the successful management of a patient with active Cushing's disease complicated with coronavirus disease 2019 (COVID-19) pneumonia. The patient was a 27-year-old Japanese female healthcare worker who was scheduled to undergo pituitary surgery for Cushing's disease. She had been in close contact with an undiagnosed patient infected with COVID-19 and then developed COVID-19 pneumonia. Despite a lack of known risk factors associated with severe COVID-19 infection, the patient's dyspnea worsened and her respiratory condition deteriorated, as indicated by the need for 7 L/min oxygen supply by mask to maintain her oxygen saturation at >90%. Medical treatment was initiated to control hypercortisolism by the 'block and replace' regimen using steroidogenesis inhibitors and hydrocortisone. The COVID-19 pneumonia improved with multi-modal treatment including antiviral therapy. One month later, after a negative severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) test result and with appropriate protection against virus transmission to medical staff in the operating room and daily medical care nurses, trans-sphenoidal surgery was performed by our highly experienced pituitary surgeon. One month after the surgery, the patient's basal ACTH and cortisol levels and urinary free cortisol were all under the detection limit. Surgical remission was expected. Since hypercortisolism due to active Cushing's disease may worsen a COVID-19 infection, multi-disciplinary management that includes appropriate and prompt treatment strategies is mandatory in such cases.
  • Aika Miya, Akinobu Nakamura, Kyu Yong Cho, Shinichiro Kawata, Hiroshi Nomoto, So Nagai, Hajime Sugawara, Shinji Taneda, Kazuhisa Tsuchida, Kazuno Omori, Hiroki Yokoyama, Jun Takeuchi, Shin Aoki, Yoshio Kurihara, Tatsuya Atsumi, Hideaki Miyoshi
    Journal of diabetes investigation 12 8 1395 - 1399 2020年12月16日 
    AIMS/INTRODUCTION: To identify the effect of combination therapy with a dipeptidyl peptidase-4 (DPP-4) inhibitor and a sodium-glucose co-transporter-2 (SGLT2) inhibitor compared with switching from a DPP-4 inhibitor to a SGLT2 inhibitor on improving the glucose variability in patients with or without impaired endogenous insulin secretion. MATERIALS AND METHODS: A secondary analysis regarding the relationship between endogenous insulin secretion and the change in mean amplitude of glycemic excursions (ΔMAGE) was conducted in a multicenter, prospective, randomized, parallel-group comparison trial that enrolled patients with type 2 diabetes who had been taking teneligliptin and were treated by switching to canagliflozin (SWITCH) or adding canagliflozin (COMB). Participants were categorized into the following four subgroups: SWITCH or COMB and high or low fasting C-peptide (CPR) divided at baseline by the median. RESULTS: ΔMAGE in the COMB group was greatly improved independent of a high or low CPR (-29.2±28.3 vs. -20.0±24.6, respectively; P=0.60). However, ΔMAGE was not ameliorated in the low CPR SWITCH group, and the ΔMAGE was significantly smaller than that in the high CPR COMB group (P<0.01). CONCLUSIONS: COMB would be a better protocol rather than switching teneligliptin to canagliflozin to improve daily glucose variability in patients with impaired endogenous insulin secretion.
  • Yuki Kimura, Issei Higuchi, Masaki Kobayashi, Ayako Furugen, Katsuya Narumi, Yuya Suzuki, Hideaki Miyoshi, Akinobu Nakamura, Tatsuya Atsumi, Ken Iseki
    Drug metabolism and pharmacokinetics 37 100376 - 100376 2020年12月14日 
    Solute carrier (SLC) 16A11 has been reported as a risk gene for type 2 diabetes (T2D). However, the physiological function of SLC16A11 has not yet been clarified, and the relationship between SLC16A11 and T2D condition remains unclear. Therefore, we performed an association analysis between the SLC16A11 genotype and T2D pathology. The SLC16A11 genotype was determined by direct sequencing in 85 Japanese patients with T2D. The genotypes were analyzed by Mann-Whitney's U test and Chi-square test. Six single nucleotide polymorphisms (SNPs) were detected in the SLC16A11 gene, and five of them formed a haplotype (5SNP haplotype). The 5SNP haplotype carriers had significantly higher fasting plasma glucose (FPG), total cholesterol (T-CHO), and low-density lipoprotein cholesterol (LDL-C) than the noncarriers. The SLC16A11 genotype affected the values of laboratory parameters for T2D, particularly of blood lipids. The function of SLC16A11 may be related to lipid metabolism.
  • Kiyohiko Takahashi, Akinobu Nakamura, Sho Furusawa, Kei Yokozeki, Hajime Sugawara, Hideyuki Yanagisawa, Kazumasa Akikawa, Hideaki Kikuchi
    Journal of clinical & translational endocrinology 22 100244 - 100244 2020年12月 
    Introduction: We investigated the renoprotective effects of sodium-glucose cotransporter 2 inhibitors (SGLT2is) on renal function in patients with type 2 diabetes and chronic kidney disease (CKD) with normoalbuminuria. Methods: A retrospective review of clinical records of Japanese participants with type 2 diabetes and CKD (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m2) with normoalbuminuria (urine albumin to creatinine ratio < 30 mg/g Cr and/or urinary protein to creatinine ratio < 150 mg/g Cr) was conducted. Participants were categorized into two groups depending on whether they had started using SGLT2is. The main study outcome was a comparison of the change in renal function evaluated by eGFR after 1 year between the two groups. Then, we identified predictors that were associated with the outcome. Results: Among the 46 participants, 21 were treated with SGLT2is (SGLT2 group) and 25 were treated with other antidiabetic medications (control group). Although eGFR was significantly decreased at 1 year in the control group, the decline in eGFR was not observed in the SGLT2 group. The decrease in eGFR was significantly smaller in the SGLT2 group than in the control group. Additionally, multiple linear regression analysis showed that an initial dip was an independent factor associated with the worsening of renal function in the SGLT2 group. Conclusions: Although more favorable effects of SGLT2is on renal function were observed in patients with type 2 diabetes and CKD with normoalbuminuria, the higher initial dip was a possible marker of worsening renal function after the initiation of SGLT2is.
  • Kazuharu Suzuki, Goki Suda, Yoshiya Yamamoto, Ken Furuya, Masaru Baba, Akinobu Nakamura, Hideaki Miyoshi, Megumi Kimura, Osamu Maehara, Ren Yamada, Takashi Kitagataya, Koji Yamamoto, Taku Shigesawa, Akihisa Nakamura, Masatsugu Ohara, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Shunsuke Ohnishi, Naoya Sakamoto
    Journal of gastroenterology 56 2 168 - 180 2020年11月19日 
    BACKGROUND: Entecavir and tenofovir-disoproxil-fumarate are first-line nucleos(t)ide analogs (NA) for treatment of hepatitis B virus (HBV) infections; however, their long-term administration can impact extrahepatic organs. Herein, we sought to examine the effect of NA on lipid metabolism while also characterizing the associated mechanism. METHODS: A retrospective study was performed on HBV patients administered entecavir or tenofovir-disoproxil-fumarate. Patient clinical information, as well as their preserved serum samples obtained at baseline and 6-12 months after treatment initiation, were analyzed. A 1:1 propensity score matching was applied to the assignment of tenofovir-disoproxil-fumarate or entecavir treatment. Changes in serum cholesterol, including oxidized-LDL, were analyzed. Subsequently, in vitro analysis elucidated the mechanism associated with the effect of NAs on lipid metabolism. RESULTS: Administration of tenofovir-disoproxil-fumarate, not entecavir, to chronic HBV patients, decreased serum cholesterol levels, including non-HDL and oxidized-LDL, which are strongly associated with arteriosclerosis. In vitro analysis revealed that tenofovir-disoproxil-fumarate reduced supernatant cholesterol, and upregulated the scavenger receptor, CD36, in hepatocytes. Meanwhile, silencing of hepatic CD36 increased supernatant cholesterol and negated the cholesterol-reducing effect of tenofovir-disoproxil-fumarate in HepG2-cells. Reporter, microarray, and RT-PCR analyses further revealed that tenofovir-disoproxil-fumarate treatment activates PPAR-α-mediated signaling, and upregulates PPAR-α target genes, including CPT1 and CD36. Alternatively, silencing of PPAR-α reversed the effects of tenofovir-disoproxil-fumarate on CD36. CONCLUSIONS: Tenofovir-disoproxil-fumarate modulates lipid metabolism by upregulating hepatic CD36 via PPAR-α activation. Since dyslipidemia could be associated with arteriosclerosis and hepatocarcinogenesis, these discoveries provide novel insights into anti-HBV therapies, as well as the associated extrahepatic effects of NA.
  • Arina Miyoshi, Hiraku Kameda, So Nagai, Akinobu Nakamura, Aika Miya, Takahiro Takase, Tatsuya Atsumi, Hideaki Miyoshi
    Journal of diabetes investigation 12 7 1293 - 1300 2020年11月03日 
    AIMS/INTRODUCTION: Patients with type 2 diabetes mellitus have a higher bone fracture risk than patients without diabetes. Although denosumab (Dmab) is a potent bone resorption inhibitor, its efficacy in patients with type 2 diabetes mellitus has not been elucidated. In this study, we investigated the effects of switching to Dmab from bisphosphonates (BP) or a selective estrogen receptor modulator (SERM) in postmenopausal type 2 diabetes mellitus patients. MATERIALS AND METHODS: This was a three medical institutions, prospective, observational study for postmenopausal patients with type 2 diabetes mellitus whose T-score of femoral neck or lumbar spine bone mineral density was under -1.0 standard deviation, even after >6 months of BP or SERM administration. After obtaining consent, participants were treated for osteopenia/osteoporosis by either continuing BP (BP-BP group)/SERM (SERM-SERM group), or by switching to Dmab (BP-Dmab or SERM-Dmab groups). Changes in bone mineral density and bone metabolism marker levels were evaluated after 6 months. RESULTS: A total of 48 patients were included in this study, and each group comprised 12 patients. No significant difference existed in baseline characteristics among the groups. The average age and glycated hemoglobin were 71 ± 8 years and 7.2 ± 0.9%, respectively. In the SERM-Dmab group, lumbar spine bone mineral density was significantly increased by 5.0% compared with the SERM-SERM group (P < 0.04). Serum bone-specific alkaline phosphatase and tartrate-resistant acid phosphatase 5b were significantly decreased in the BP-Dmab and SERM-Dmab groups compared with the BP-BP and SERM-SERM groups, respectively. CONCLUSIONS: Switching to Dmab from BP or SERM is beneficial to prevent osteoporosis progression in postmenopausal patients with type 2 diabetes mellitus patients.
  • 血糖管理 内因性インスリン分泌は2型糖尿病における血糖変動の不安定性を予測する
    宮 愛香, 中村 昭伸, 半田 喬久, 野本 博司, 亀田 啓, 曹 圭龍, 永井 聡, 三好 秀明, 渥美 達也
    糖尿病合併症 34 Suppl.1 168 - 168 (一社)日本糖尿病合併症学会 2020年11月
  • 血糖管理 高齢2型糖尿病では、低血糖域の割合は変動係数と関連する
    半田 喬久, 宮 愛香, 中村 昭伸, 野本 博司, 亀田 啓, 曹 圭龍, 永井 聡, 三好 秀明, 吉岡 成人, 渥美 達也
    糖尿病合併症 34 Suppl.1 170 - 170 (一社)日本糖尿病合併症学会 2020年11月
  • Kyu Yong Cho, Akinobu Nakamura, Kazuno Omori, Takahiro Takase, Aika Miya, Kohei Yamamoto, Hiroshi Nomoto, Hiraku Kameda, Shinji Taneda, Yoshio Kurihara, Shin Aoki, Tatsuya Atsumi, Hideaki Miyoshi
    Journal of diabetes investigation 12 7 1272 - 1277 2020年11月01日 
    AIMS/INTRODUCTION: Sodium-glucose cotransporter 2 inhibitors, as well as thiazolidines, suppress nonalcoholic fatty liver disease (NAFLD); however, few comparative studies have been reported. Dapagliflozin has shown non-inferiority compared with pioglitazone for glycemic control, and superiority regarding weight reduction in patients with type 2 diabetes. We carried out a secondary analysis for the favorable effects of sodium-glucose cotransporter inhibitors for NAFLD. MATERIALS AND METHODS: In this multicenter, open-label, prospective, randomized, parallel-group comparison trial, patients taking pioglitazone for ≥12 weeks were randomly switched to dapagliflozin or continued pioglitazone for a further 24 weeks. The fatty liver index (FLI), consisting of body mass index, triglycerides, waist circumference and γ-glutamyl transpeptidase, was used for the evaluation of NAFLD. RESULTS: A total of 53 participants with NAFLD (27 dapagliflozin; 26 pioglitazone) were included in this analysis. FLI decreased significantly in the dapagliflozin group (48.7 ± 23.4 to 42.1 ± 23.9) compared with the pioglitazone group (49.0 ± 26.1 to 51.1 ± 25.8; P < 0.01). Multiple linear regression analysis showed that the changes in FLI had a significantly positive correlation with changes in glycated hemoglobin (P = 0.03) and insulin level (P < 0.01) in the dapagliflozin group. CONCLUSION: Dapagliflozin might be more beneficial than pioglitazone in patients with NAFLD. Improvements in FLI would be closely related to glycemic control.
  • Hiroyuki Nakamura, Yuichiro Fujieda, Akinobu Nakamura, Tatsuya Atsumi
    Modern rheumatology 1 - 10 2020年10月07日 [査読有り][通常論文]
     
    Glucocorticoid-induced hyperglycemia (GIH) is an important complication to be managed by rheumatologists as it can affect morbidity and mortality of patients. Before administration of glucocorticoids, risk for the development of GIH should be assessed in every patient. A meta-analysis identified male gender, older age, family history of diabetes mellitus, current smoking history, past history of hypertension, higher body mass index, higher fasting plasma glucose (PG) and higher hemoglobin A1c (HbA1c) levels as risk factors for GIH. Then, rheumatologists need to carefully monitored PG levels including 2-h after meals because glucocorticoids particularly affect postprandial glucose metabolism. Fasting PG level ≥ 126 mg/dL and/or post-meal PG level ≥ 200 mg/dL are considered as GIH regardless of HbA1c level. Treatment strategy for GIH should center on insulin injection since the effectiveness of oral hypoglycemic agents for GIH has been uncertain. But, rheumatologists may try oral hypoglycemic agents in advance of insulin therapy for mild GIH, whereas diabetologists should be consulted in case of intractable GIH. More strict control of GIH could be possible using intensive insulin protocol. Rheumatologists are encouraged to be interested in the management of GIH for providing patients superior care, working closely with diabetologists.
  • Aika Miya, Akinobu Nakamura, Takahisa Handa, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, So Nagai, Hideaki Miyoshi, Tatsuya Atsumi
    Journal of diabetes investigation 12 5 738 - 746 2020年10月06日 [査読有り][通常論文]
     
    AIMS/INTRODUCTION: To identify the coefficient of variation (CV) threshold for unstable glucose variability (GV) and hypoglycemia, and to characterize a patient population with unstable GV and hypoglycemia. MATERIALS AND METHODS: This was an observational study that enrolled 284 Japanese outpatients with type 2 diabetes who underwent continuous glucose monitoring. The C-peptide index (CPI = [(fasting serum C-peptide)/(plasma glucose)] × 100) was used as a marker of endogenous insulin secretion. The CV threshold between stable and unstable GV was defined as the upper limit of the CV distribution in the subgroup of patients who did not receive insulin nor insulin secretagogues (relatively stable GV subgroup [RSGV subgroup], n=104). The optimal CV range corresponding to time below target range (TBR) ≥4% was determined for all patients using receiver-operating characteristic curve analysis. Various characteristics of patients with unstable GV and hypoglycemia were extracted using multivariate logistic regression analysis. RESULTS: The upper limit of the CV in the RSGV subgroup was 40. The optimal CV range corresponding to TBR ≥4% was also defined as CV ≥40 (area under the curve [AUC]: 0.85) for all patients. CPI was an independent risk for CV ≥40 (odds ratio: 0.17; 95% CI: 0.04 to 0.50; P <0.01). The optimal cut-off point for CPI to predict a CV cut-off value of 40 was equivalent to 0.81 (AUC: 0.80). CONCLUSIONS: A CV of 40 discriminates unstable GV and hypoglycemia from stable GV in Japanese outpatients with type 2 diabetes. Impaired insulin secretion may affect the stability of GV.
  • Natsuki Baba, Hiraku Kameda, Akinobu Nakamura, Kyu Yong Cho, Hiroshi Nomoto, Tomoko Mitsuhashi, Hideaki Miyoshi, Tatsuya Atsumi
    Endocrine journal 68 2 195 - 200 2020年10月06日 [査読有り][通常論文]
     
    A silent pituitary adenoma (SPA) is characterized by the expression of pituitary hormones, detected by immunohistochemical staining, in the absence of clinical signs or symptoms of hormonal excess. Compared with functional pituitary adenomas, little is known regarding the involvement of SPAs in metabolic disorders. This study aimed to examine the correlations between SPAs and metabolic disorders, including obesity, abnormal glucose tolerance, hypertension and dyslipidemia. Seventy-four patients with nonfunctional pituitary adenomas who underwent a pituitary adenomectomy in Hokkaido University Hospital from 2008 to 2016 were retrospectively examined. Pituitary adenomas were immunohistochemically classified into pituitary hormone positive or negative groups. Twenty whole hormone-negative pituitary adenomas were excluded because we couldn't identify pituitary transcription factors which is necessary for the diagnosis of a null cell adenoma. The preoperative rates of obesity, abnormal glucose tolerance, hypertension and dyslipidemia were compared between each group. Twenty-seven GH positive adenomas (50.0%), 32 gonadotroph positive adenomas (59.3%), 28 TSH positive adenomas (51.9%) and 21 ACTH positive adenomas (38.9%) were identified. Evaluation of the preoperative clinical data showed 25 cases of obesity (46.2%), 16 cases of abnormal glucose tolerance (29.6%), 29 cases of hypertension (53.7%) and 35 cases of dyslipidemia (64.8%). The rate of hypertension was significantly lower in the GH positive group (37.0%) than the GH negative group (70.4%) (p = 0.0140). In the GH negative group, postoperative systolic and diastolic blood pressure levels were significantly lower than preoperative values. GH positive SPAs may affect the homeostasis of blood pressure.
  • 高橋 由華, 亀田 啓, 野本 博司, 曹 圭龍, 中村 昭伸, 湯野 暁子, 澤村 豊, 島津 章, 山下 優, 中久保 祥, 鎌田 啓佑, 鈴木 雅, 今野 哲, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 96 2 504 - 504 (一社)日本内分泌学会 2020年10月
  • 泉原 里美, 亀田 啓, 家坂 光, 大江 悠希, 千葉 幸輝, 上垣 里紗, 重沢 郁美, 亀田 玲奈, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 96 2 548 - 548 (一社)日本内分泌学会 2020年10月
  • 上垣 里紗, 亀田 啓, 野本 博司, 曹 圭龍, 中村 昭伸, 清水 亜衣, 笹野 公伸, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 96 2 532 - 532 (一社)日本内分泌学会 2020年10月
  • 大江 悠希, 亀田 啓, 家坂 光, 泉原 里美, 上垣 里紗, 亀田 玲奈, 野本 博司, 坂本 圭太, 曽山 武士, 曹 圭龍, 中村 昭伸, 阿保 大介, 工藤 與亮, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 96 2 529 - 529 (一社)日本内分泌学会 2020年10月
  • Keiko Naruse, Atsuko Abiko, Hitomi Nakayama, Nobue Tanaka, Kaori Ikeda, Hitomi Imachi, Emi Usigome, Yutaka Umayahara, Setsu Ota, Yukiko Okada, Noriko Kodani, Noriko Takahashi, Ai Terai, Akinobu Nakamura, Rumi Fujikawa, Junnosuke Miura, Emiko Morita, Miyuki Yanagimachi, Kojiro Ueki
    Diabetology international 11 4 299 - 308 2020年10月 
    The Japan Diabetes Society's Committee to Promote Female Diabetologists conducted a questionnaire survey from May to June 2017 to investigate the work style and living situation of diabetologists. The survey targeted 5298 Board Certified Diabetologists (diabetologists), with answers obtained from 1566 diabetologists (male, n = 1003: females, n = 563). Ninety-four percent of the males and 72% of the females worked full time. Twenty-one percent of the male subjects and 7% of the female subjects were heads of clinical departments, and 23% of the male subjects and 13% of the female subjects were diabetes training instructors, showing that there were fewer women than men in both roles. Regarding the allocation of time per day, men spent 10.7 h working, while women spent 8.5 h working. Both men and women slept 6.3 h. Men spent 1.0 h on housework, while women spent 3.3 h on housework. Men spent 0.7 h on childcare and nursing care, while women, spent 2.8 h. Among diabetologists in the childrearing generation, men spent 1.4 h providing childcare and nursing care, while women spent 4.9 h, showing that women spent significantly more time on these tasks than men. To encourage female diabetologists to work more actively, to reduce overworking on the part of male diabetologists, and to enhance the careers of both men and women as diabetologists, we conclude it necessary to improve the workplace environment and for the Japan Diabetes Society to offer support.
  • Takahiro Takase, Akinobu Nakamura, Hideaki Miyoshi, Minori Koga, Atsuhito Toyomaki, Ichiro Kusumi, Rikako Kino, Yasuyuki Konishi, Yoshinobu Kiso, Tatsuya Atsumi
    Phytotherapy research : PTR 34 9 2303 - 2312 2020年09月 [査読有り][通常論文]
     
    BACKGROUND: Red algae have been reported to improve lipid and glucose metabolism in rats. We investigated the effects of Palmaria palmata (P. palmata), a red alga from northern Japan, on lipid metabolism and glycemic control in participants with hypercholesterolemia. METHODS: We conducted an 8-week, randomized, double-blind, placebo-controlled, and parallel-group comparison trial. The study enrolled Japanese participants with a serum low-density protein cholesterol (LDL-C) ≥120 mg/dL. The participants were randomly assigned to take either capsules containing P. palmata (2 g/day) or placebo capsules. The primary endpoint was the change in LDL-C from baseline to week 8 and the secondary endpoints were the changes in other lipid parameters and glycemic control. RESULTS: Of the 104 participants completed the study protocol. There were no significant differences in change in LDL-C, body mass index, waist circumference, or glycemic control between the two groups. However, serum triglyceride showed significantly greater improvement in women in the P. palmata group (-9.0 [-25.0, +5.0]) vs. those in the placebo group (-1.0 [-11.0, +19.0]; p = .03). CONCLUSIONS: The present study did not show that P. palmata had significant effect on serum LDL-C nor glycemic control, but hypertriglyceridemia could be ameliorated by administration of P. palmata in women.
  • 転移性腎癌に対するニボルマブとイピリムマブの併用療法により破壊性甲状腺炎に続いて劇症1型糖尿病を発症した1例
    家坂 光, 亀田 啓, 安部 崇重, 亀田 玲奈, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 篠原 信雄, 三好 秀明, 渥美 達也
    糖尿病 63 Suppl.1 S - 173 (一社)日本糖尿病学会 2020年08月
  • 1型糖尿病患者へのSGLT2阻害薬の投与は血糖変動を改善する
    泉原 里美, 亀田 啓, 千葉 幸輝, 野本 博司, 曹 圭龍, 中村 昭伸, 山下 久美子, 栗原 義夫, 渥美 達也, 三好 秀明
    糖尿病 63 Suppl.1 S - 193 (一社)日本糖尿病学会 2020年08月
  • 欧米人2型糖尿病患者膵島ではHIF1α/PFKFB3経路が活性化することで膵島内代謝が解糖系へとシフトする
    野本 博司, Tudzarova Slavica, Pei Lina, Montemurro Chiara, Gurlo Tatyana, Butler Peter C., 中村 昭伸, 渥美 達也
    糖尿病 63 Suppl.1 S - 194 (一社)日本糖尿病学会 2020年08月
  • 肥満外科治療は薬剤の減量・中止および糖尿病寛解を期待できる
    大江 悠希, 高瀬 崇宏, 曹 圭龍, 野本 博司, 亀田 啓, 中村 昭伸, 三好 秀明, 渥美 達也
    糖尿病 63 Suppl.1 S - 216 (一社)日本糖尿病学会 2020年08月
  • SGLT2阻害薬ルセオグリフロジンによる膵β細胞保護作用の機序の解明
    山内 裕貴, 中村 昭伸, 三好 秀明, 関崎 知紀, 川田 晋一朗, 土田 和久, 柴山 惟, 大森 一乃, 高橋 清彦, 野本 博司, 亀田 啓, 曹 圭龍, 寺内 康夫, 渥美 達也
    糖尿病 63 Suppl.1 S - 239 (一社)日本糖尿病学会 2020年08月
  • グルコキナーゼ活性化薬の長期投与に伴う血糖降下作用の消失機序の解明
    川田 晋一朗, 中村 昭伸, 山内 裕貴, 関崎 知紀, 土田 和久, 柴山 惟, 大森 一乃, 高橋 清彦, 野本 博司, 亀田 啓, 曹 圭龍, 寺内 康夫, 三好 秀明, 渥美 達也
    糖尿病 63 Suppl.1 S - 308 (一社)日本糖尿病学会 2020年08月
  • 高血圧症合併2型糖尿病患者におけるDPP-4阻害薬からSGLT2阻害薬への切替による血圧・脈拍への影響に関する検討(プロトコール)
    曹 圭龍, 亀田 玲奈, 野本 博司, 中村 昭伸, 竹内 淳, 永井 聡, 栗原 義夫, 青木 伸, 渥美 達也, 三好 秀明
    糖尿病 63 Suppl.1 S - 311 (一社)日本糖尿病学会 2020年08月
  • 高炭水化物食長期摂取による膵β細胞量増加作用におけるグルコキナーゼの役割
    土田 和久, 中村 昭伸, 三好 秀明, Kelaier Yang, 関崎 知紀, 山内 裕貴, 川田 晋一朗, 柴山 惟, 大森 一乃, 野本 博司, 亀田 啓, 曹 圭龍, 清野 祐介, 寺内 康夫, 渥美 達也
    糖尿病 63 Suppl.1 S - 260 (一社)日本糖尿病学会 2020年08月
  • 地域一般集団での血清遊離脂肪酸とプロインスリンとの関連
    千葉 幸輝, 中村 昭伸, 三好 秀明, 鵜川 重和, 中村 幸志, 中川 貴史, 寺内 康夫, 玉腰 暁子, 渥美 達也
    糖尿病 63 Suppl.1 S - 130 (一社)日本糖尿病学会 2020年08月
  • 血清高分子量アディポネクチンとプロインスリンとの関連 DOSANCO Health studyによる検討
    中村 昭伸, 三好 秀明, 鵜川 重和, 中村 幸志, 中川 貴史, 寺内 康夫, 玉腰 暁子, 渥美 達也
    糖尿病 63 Suppl.1 S - 134 (一社)日本糖尿病学会 2020年08月
  • 地域住民横断調査におけるプロインスリンと肝の脂肪化との関連 DOSANCO Health Study
    宮 愛香, 中村 昭伸, 三好 秀明, 鵜川 重和, 中村 幸志, 中川 貴史, 寺内 康夫, 玉腰 暁子, 渥美 達也
    糖尿病 63 Suppl.1 S - 280 (一社)日本糖尿病学会 2020年08月
  • 地域住民横断調査におけるプロインスリンと肝の脂肪化との関連 DOSANCO Health Study
    宮 愛香, 中村 昭伸, 三好 秀明, 鵜川 重和, 中村 幸志, 中川 貴史, 寺内 康夫, 玉腰 暁子, 渥美 達也
    糖尿病 63 Suppl.1 S - 280 (一社)日本糖尿病学会 2020年08月
  • 野本 博司, Tudzarova Slavica, Pei Lina, Montemurro Chiara, Gurlo Tatyana, Butler Peter C., 中村 昭伸, 渥美 達也
    日本内分泌学会雑誌 96 1 247 - 247 (一社)日本内分泌学会 2020年08月
  • 泉原 里美, 亀田 啓, 家坂 光, 大江 悠希, 千葉 幸輝, 小野 渉, 上垣 里紗, 重沢 郁美, 亀田 玲奈, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 96 1 324 - 324 (一社)日本内分泌学会 2020年08月
  • 上垣 里紗, 亀田 啓, 家坂 光, 泉原 里美, 大江 悠希, 千葉 幸輝, 小野 渉, 重沢 郁美, 亀田 玲奈, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 96 1 345 - 345 (一社)日本内分泌学会 2020年08月
  • 小野 渉, 亀田 啓, 家坂 光, 泉原 里美, 大江 悠希, 上垣 里紗, 千葉 幸輝, 亀田 玲奈, 野本 博司, 曹 圭龍, 中村 昭伸, 林 良敬, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 96 1 347 - 347 (一社)日本内分泌学会 2020年08月
  • 千葉 幸輝, 亀田 啓, 野本 博司, 曹 圭龍, 中村 昭伸, 神 繁樹, 的場 光太郎, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 96 1 366 - 366 (一社)日本内分泌学会 2020年08月
  • Chiho Oba-Yamamoto, Jun Takeuchi, Akinobu Nakamura, Ryoko Takikawa, Ayano Ozaki, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, Tatsuya Atsumi, Hideaki Miyoshi
    Journal of diabetes investigation 12 4 651 - 657 2020年07月29日 
    AIMS/INTRODUCTION: Alcohol consumption has been reported to cause hypoglycemia. However, the mechanism involved has not been unequivocally established. This study comprised healthy volunteers. We carried out a prospective trial to compare the effects of glucose and alcohol consumption, alone or in combination, on glucose and lipid metabolism. MATERIALS AND METHODS: A 75-g oral glucose tolerance test (OGTT), a combined 75-g glucose plus 20-g alcohol tolerance test (OGATT) and a 20-g alcohol tolerance test (OATT) were carried out in the participants. Plasma glucose, insulin, triglyceride and ethanol concentrations during each test were compared. RESULTS: We studied 10 participants. Their plasma glucose concentrations 15 and 30 min after the intake of 75 g of glucose were significantly higher during the OGATT than the OGTT. Hypoglycemia occurred in five participants after the OGATT, which was significantly more frequently than after the OGTT (P = 0.046). Hypoglycemia did not occur after the OATT, and the ethanol concentration was significantly lower after the OGATT than the OATT. The changes in triglyceride concentration from 30 min after the consumption of 75 g of glucose were significantly greater during the OGATT than the OGTT. The plasma insulin concentrations peaked after 60 min during both the OGTT and OGATT, and were significantly higher during the OGATT (P = 0.047). There were no differences between the two interventions in the Matsuda or disposition indexes. CONCLUSIONS: Hypoglycemia occurred more frequently after the simultaneous consumption of alcohol plus glucose than after the consumption of glucose alone, suggesting that alcohol in the combination of glucose induces reactive hypoglycemia.
  • Koki Chiba, Hiroshi Nomoto, Akinobu Nakamura, Kyu Yong Cho, Kumiko Yamashita, Yui Shibayama, Aika Miya, Hiraku Kameda, Yoshio Kurihara, Shin Aoki, Tatsuya Atsumi, Hideaki Miyoshi
    Journal of diabetes investigation 12 2 176 - 183 2020年06月27日 [査読有り][通常論文]
     
    AIMS/INTRODUCTION: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are used worldwide because of their multiple benefits for patients with type 2 diabetes. The purpose of this study was to determine the efficacy and safety of SGLT2i in patients with type 1 diabetes. MATERIALS AND METHODS: Patients with type 1 diabetes who had been treated with SGLT2i for >12 weeks were included in this retrospective observation study. We recorded the changes in body mass, insulin dose, blood and urine test data, and adverse events. The changes in day-to-day glucose variability, as the primary end-point, was evaluated using the interquartile range (P25/P75) of the ambulatory glucose data obtained using continuous glucose monitoring. RESULTS: A total of 51 patients (37 women; mean age 52.7 years) were included. Glycated hemoglobin and body mass significantly decreased by 0.4% and 1.6 kg, respectively. The total required insulin dose decreased by 9.4% (42.7 ± 26.6-38.7 ± 24.3 units/day). Continuous glucose monitoring data were obtained from 30 patients. P25/P75 decreased by 17.6 ± 20.7% during SGLT2i treatment (P < 0.001). The percentage of time per day within the target glucose range of 70-180 mg/dL significantly increased (from 42.2 to 55.5%, P < 0.001), without an increase in the percentage of time spent in the hypoglycemic range (<70 mg/dL). Urinary ketone bodies were detected in four patients (7.8%), but none developed ketoacidosis. CONCLUSIONS: SGLT2i improved day-to-day glucose variability and time in the target glucose range, without increasing frequency of hypoglycemia, in patients with type 1 diabetes, and reduced glycated hemoglobin, body mass and the required insulin dose.
  • Akinobu Nakamura, Hideaki Miyoshi, Shigekazu Ukawa, Koshi Nakamura, Takafumi Nakagawa, Yasuo Terauchi, Akiko Tamakoshi, Tatsuya Atsumi
    Journal of diabetes investigation 12 1 63 - 66 2020年06月12日 [査読有り][通常論文]
     
    Serum high-molecular-weight adiponectin (HMWA) has a positive correlation with insulin secretion in a Japanese population. To validate this correlation, we investigated the correlation between serum HMWA and proinsulin, a marker of beta-cell dysfunction, in this population. 488 participants (53.9% females) aged 35 to 79 years without having oral hypoglycemic agents and/or insulin were enrolled. HMWA was significantly and inversely correlated with proinsulin adjusted for age and sex (partial regression coefficient: β= -0.37; 95% confidence interval: -0.46 to -0.28). When the participants were divided into two groups by median values of body mass index (23.2 kg/m2 ), serum insulin (4.3 µU/mL), or homeostasis model assessment of insulin resistance (1.0), similar inverse correlations were observed adjusted for age and sex in both groups. Our results demonstrated that the HMWA level was inversely correlated with the proinsulin level in a general Japanese population.
  • DPP-4阻害薬服用中の糖尿病患者に生じた水疱性類天疱瘡
    氏家 英之, 岩田 浩明, 葭本 倫大, 氏家 韻欣, 中村 昭伸, 三好 秀明, 清水 宏
    糖尿病 63 5 355 - 355 (一社)日本糖尿病学会 2020年05月
  • トランジション後に糖尿病性ケトアシドーシスを発症した小児発症1型糖尿病の1例
    宮 愛香, 亀田 啓, 中村 昭伸, 馬場 菜月, 平田 恵里奈, 柴山 惟, 宮野 有希恵, 亀田 玲奈, 三好 秀明, 渥美 達也
    糖尿病 63 5 357 - 357 (一社)日本糖尿病学会 2020年05月
  • 1型糖尿病患者へのSGLT-2阻害薬投与の有効性と安全性
    千葉 幸輝, 亀田 啓, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 山下 久美子, 栗原 義夫, 渥美 達也, 三好 秀明
    糖尿病 63 5 352 - 352 (一社)日本糖尿病学会 2020年05月
  • 1型糖尿病患者におけるSensor Augmented Pump療法(SAP)への変更の効果
    川田 晋一朗, 亀田 啓, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也
    糖尿病 63 5 353 - 353 (一社)日本糖尿病学会 2020年05月
  • 糖尿病合併肥満症患者に対する腹腔鏡下スリーブ状胃切除術への術前寛解予測スコアの検討
    小野 渉, 中村 昭伸, 海老原 裕磨, 曹 圭龍, 亀田 玲奈, 亀田 啓, 野本 博司, 渥美 達也, 三好 秀明, 平野 聡
    糖尿病 63 5 354 - 354 (一社)日本糖尿病学会 2020年05月
  • グルコキナーゼ活性化薬の長期投与に伴う血糖降下作用の消失機序の解明
    川田 晋一朗, 中村 昭伸, 三好 秀明, 山内 裕貴, 土田 和久, 大森 一乃, 高橋 清彦, 野本 博司, 亀田 啓, 曹 圭龍, 寺内 康夫, 渥美 達也
    日本臨床分子医学会学術総会プログラム・抄録集 57回 56 - 56 日本臨床分子医学会 2020年04月
  • Kyu Yong Cho, Hiroshi Nomoto, Akinobu Nakamura, Shinichiro Kawata, Hajime Sugawara, Jun Takeuchi, So Nagai, Kazuhisa Tsuchida, Kazuno Omori, Hiroki Yokoyama, Naoki Manda, Yoshio Kurihara, Shin Aoki, Tatsuya Atsumi, Hideaki Miyoshi
    Diabetes, obesity & metabolism 22 3 458 - 462 2020年03月 [査読無し][通常論文]
     
    This multicentre, prospective, randomized, open-label, blinded-endpoint, parallel-group, short-term (4-5 weeks) controlled trial was conducted to investigate the superiority of the effect of reducing mean amplitude of glycaemic excursions (MAGE) during meal tolerance tests (MTTs) for the combination of dipeptidyl peptidase-4 (DPP-4) inhibitor and sodium-glucose co-transporter-2 (SGLT2) inhibitor compared with SGLT2 inhibitor monotherapy. Ninety-nine patients with type 2 diabetes who were taking teneligliptin (20 mg/d) were randomized to one of the following two groups: those who switched to 100 mg/d of canagliflozin (SWITCH group) or those who added 100 mg/d of canagliflozin (COMB group). MAGE in the COMB group was significantly decreased compared with that in the SWITCH group (COMB 117.5 ± 39.8 to 92.2 ± 28.0 mg/dL vs SWITCH 110.7 ± 29.8 to 104.2 ± 27.6 mg/dL; P<0.01). Mean blood glucose decreased significantly during MTTs in both groups, although the extent of the reduction was significantly greater in the COMB group (COMB 142.3 ± 28.7 to 119.5 ± 25.1 mg/dL vs SWITCH 146.4 ± 25.5 to 135.5 ± 22.4 mg/dL; P < 0.01). SGLT2 inhibitor combined with DPP-4 inhibitor therapy strongly reduced glycaemic fluctuation compared with SGLT2 inhibitor monotherapy.
  • Reina Kameda, Hiroshi Nomoto, Kyu Yong Cho, Shinichiro Kawata, Kazuno Omori, Jun Takeuchi, So Nagai, Yoshio Kurihara, Shin Aoki, Akinobu Nakamura, Tatsuya Atsumi, Hideaki Miyoshi
    BMJ open 10 2 e034883  2020年02月06日 [査読無し][通常論文]
     
    INTRODUCTION: Nocturnal hypertension is clinically important for patients with type 2 diabetes (T2D), considering its strong correlation with cardiovascular events. We aim to test the hypothesis that the sodium-glucose cotransporter 2 inhibitor, luseogliflozin, ameliorates nocturnal hypertension more effectively than a dipeptidyl peptidase (DPP)-4 inhibitor in patients with T2D. METHODS AND ANALYSIS: This study is a multicentre, prospective, randomised, open-label, blinded endpoint parallel-group trial. Sixty participants with T2D and hypertension who have been treated with a DPP-4 inhibitor for more than 4 weeks and who have a glycated haemoglobin A1c (HbA1c) level of 6.0%-9.0% will be randomised based on age, body mass index (BMI) and HbA1c to continue taking their DPP-4 inhibitor or to switch to luseogliflozin 2.5 mg once daily for 8 weeks. Twenty-four-hour ambulatory blood pressure monitoring (ABPM) will be performed twice at baseline and at the end of the study. All participants will continue their diet and exercise therapy, and the doses of concomitant medications will not be adjusted during the study. The primary endpoint is the effect of luseogliflozin on the mean change in systolic blood pressure (SBP) during the night, as measured by ABPM. The secondary endpoints are mean change in diastolic blood pressure (DBP) during the night, 24 hours of SBP and DBP, daytime SBP and DBP, pulse rate, BP M-value, trough SBP and DBP for 1 hour before the next dose, and other laboratory parameters. The sample size was calculated for a two-sided test at 90% power for the detection of a difference between treatments. ETHICS AND DISSEMINATION: The Ethics Review Board of Hokkaido University Hospital has approved the protocol. The results will be disseminated in peer-reviewed journals and at scientific conferences. TRIAL REGISTRATION NUMBERS: The University Hospital Medical Information Network (UMIN000031451); Japan Registry of Clinical Trials (jRCTs011180019); Pre-results.
  • 柴山 惟, 和田 典男, 馬場 周平, 小原 慎司, 亀田 啓, 中村 昭伸, 山崎 有人, 笹野 公伸, 渥美 達也
    日本内分泌学会雑誌 95 4 1706 - 1706 (一社)日本内分泌学会 2020年02月
  • Issei Higuchi, Yuki Kimura, Masaki Kobayashi, Katsuya Narumi, Ayako Furugen, Hideaki Miyoshi, Akinobu Nakamura, Takehiro Yamada, Tatsuya Atsumi, Ken Iseki
    Drug metabolism and pharmacokinetics 35 1 131 - 138 2020年02月 [査読有り][通常論文]
     
    The present study aimed to characterize the relationships between plasma lactate, plasma alanine, monocarboxylate transporter (MCT) polymorphisms, and indices of diabetes in patients with type 2 diabetes (T2D) in Japan. Eighty-three patients with T2D were prospectively enrolled. The gluconeogenesis and glycogenolysis are enhanced and uptake of glucose is decreased in the T2D liver. Since the liver plays an important role in maintaining glucose metabolism, we examined the relationships between liver enzymes and indices of diabetes. Some studies have reported that MCT1 (SLC16A1) polymorphism causes metabolic diseases. In addition, a high frequency of MCT1 polymorphism was reported in a healthy Japanese population. However, little is known about the relationships between T2D and MCT polymorphisms. Plasma l-lactate concentration positively correlated with indices of diabetes (fasting plasma glucose [FPG] and hemoglobin A1c [HbA1c]) and with the liver enzymes alanine aminotransferase (ALT) and gamma-glutamyl transpeptidase (γ-GTP). MCT1 polymorphisms were associated with all of these markers. We identified no significant correlations between d-lactate or alanine concentrations and any of these markers, but a significant association was observed between l-lactate, a marker of oxidative capacity, and indices of diabetes. We conclude that plasma l-lactate concentration may represent a predictor of the progression or severity of T2D.
  • Aika Miya, Akinobu Nakamura, Hideaki Miyoshi, Shigekazu Ukawa, Koshi Nakamura, Takafumi Nakagawa, Yasuo Terauchi, Akiko Tamakoshi, Tatsuya Atsumi
    Journal of diabetes investigation 11 4 964 - 970 2020年01月30日 [査読有り][通常論文]
     
    AIMS/INTRODUCTION: We explored the association between fatty liver and pancreatic β-cell dysfunction in a general population. MATERIALS AND METHODS: This cross-sectional study included 489 (53.8% women) community-dwelling Japanese adults. The extent of fatty liver was estimated using the fatty liver index (FLI). After all participants were divided into three groups - low (FLI <30), moderate (30 ≤FLI <60) or high (FLI ≥ 60) degree of fatty liver - serum proinsulin levels transformed into natural logarithms were compared among the three groups. To determine whether obesity modified the association of interest, the participants were stratified into two groups according to the median body mass index. Next, to determine whether hyperinsulinemia modified the association of interest, a similar stratified analysis was carried out using the median serum insulin level. RESULTS: Logarithm (proinsulin) was significantly higher in the high FLI group than in the moderate and low groups, and it was significantly higher in the moderate group than in the low group after adjustment for age and sex (P < 0.05). Logarithm (proinsulin) was significantly higher in the high FLI group than in the low FLI group, regardless of body mass index, after adjustment for age and sex. A similar pattern was observed regardless of serum insulin levels. CONCLUSIONS: The degree of fatty liver was positively associated with proinsulin level, regardless of the presence of obesity or hyperinsulinemia, suggesting that fatty liver reflects pancreatic β-cell dysfunction.
  • Yui Shibayama, Norio Wada, Shuhei Baba, Shinji Obara, Hidetsugu Sakai, Hiroaki Usubuchi, Satoshi Terae, Akinobu Nakamura, Tatsuya Atsumi
    Endocrine Journal 67 6 623 - 629 2020年 
    Patients with primary aldosteronism (PA) are complicated by metabolic syndrome more frequently than those without PA. Hyperaldosteronism has been reported to be associated with a higher prevalence of non-alcoholic fatty liver disease (NAFLD). We aimed to clarify the risk factors for hepatic steatosis in the two subtypes of PA, comparing the status of hepatic steatosis in each of these subtypes. This was a retrospective observational study. We enrolled patients with an aldosterone producing adenoma (APA) (n = 33) or idiopathic hyperaldosteronism (IHA) (n = 56). Hepatic fat content was evaluated using the ratio of liver to spleen (L/S) X-ray attenuation on unenhanced computed tomography. L/S ratio < 1.0 was utilized for assessing as hepatic steatosis. Age, sex distribution, visceral fat percentage (VF%), and visceral fat area (VFA) did not differ between patients with the two PA subtypes. The percentages of patients with L/S ratio < 1.0 was not different between the two subtypes (APA: 21.2 % (7/33) vs. IHA: 19.6 % (11/56), p = 1.00). In both subtypes, the L/S ratio negatively correlated with VF% (APA: r = –0.66, p < 0.001 IHA: r = –0.66, p < 0.001) and with VFA (APA: r = –0.44, p < 0.01 IHA: r = –0.37, p < 0.01). The status of hepatic steatosis, evaluated using L/S ratio, did not differ between patients with APA or IHA. Hepatic steatosis was affected by the amount of visceral fat.
  • Miho Sato, Hideaki Miyoshi, Akinobu Nakamura, Naomi Sumi, Hikaru Kamoshima, Yuri Ono
    Japan journal of nursing science : JJNS 17 1 e12279  2020年01月 
    AIM: The Chronic Illness Resources Survey (CIRS) is a tool for assessing multiple levels of resources for self-management in people with chronic illnesses. This study aimed to examine the reliability and validity of the Japanese version of the CIRS (CIRS-J) among patients with diabetes. METHODS: This study included 102 Japanese patients with diabetes. Patients completed the CIRS-J on two occasions with additional measurements, including the multidimensional scale of perceived social support (MSPSS), the summary of diabetes self-care activities (SDSCA), and the perceived health competence scale (PHCS). The construct validity, internal consistency reliability, and test-retest reliability were evaluated. RESULTS: Factor analysis resulted in six factors. The Cronbach's α coefficient was 0.82, indicating a high internal consistency. The intraclass correlation coefficient was 0.87, indicating that the CIRS-J is stable over time. The CIRS-J showed a positive moderate association with MSPSS, SDSCA, and PHCS, with a correlation coefficient value ranging from .34 to .44. CONCLUSION: This study showed preliminary support for the reliability and validity of the CIRS-J. The availability of this instrument will help identify the spectrum of resources available for Japanese people with diabetes in both research and practical settings.
  • Akinobu Nakamura, Hideaki Miyoshi, Hiraku Kameda, Kumiko Yamashita, Yoshio Kurihara
    Diabetology & metabolic syndrome 12 4 - 4 2020年 [査読有り][通常論文]
     
    Background: We compared the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on renal function in participants with type 2 diabetes and chronic kidney disease (CKD) classified by degree of albuminuria. Methods: A retrospective review of the clinical records of Japanese participants with type 2 diabetes (age > 20 years; SGLT2 inhibitor treatment > 2 years; estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2) was conducted. Based on the urinary albumin-to-creatinine ratio (UACR) or urinary protein-to-creatinine ratio (UPCR) at the start of SGLT2 inhibitor administration, participants were categorized into three groups: normoalbuminuria (A1; UACR < 30 mg/g Cr or UPCR < 0.15 g/g Cr), microalbuminuria (A2; UACR 30 to < 300 mg/g Cr or UPCR 0.15 to < 0.50 g/g Cr), and macroalbuminuria (A3; UACR ≥ 300 mg/g Cr or UPCR ≥ 0.50 g/g Cr). The study outcome was a comparison of the rates of change in renal function evaluated by eGFR at 2 years after starting SGLT2 inhibitor among the three groups. Results: A total of 87 participants (40 females, 47 males) were categorized into three groups: A1 (n = 46), A2 (n = 25), and A3 (n = 16). eGFR was similarly decreased at 2 years before starting SGLT2 inhibitor in all three groups. However, the decline in eGFR was ameliorated at 2 years after starting SGLT2 inhibitor, and eGFR was rather increased in the A1 and A2 groups. Interestingly, the rate of change in eGFR at 2 years after starting SGLT2 inhibitor in the A1 group was significantly higher than that in the A3 group. Conclusions: These results demonstrate that more favorable effects of SGLT2 inhibitors on renal function were observed in participants with type 2 diabetes and CKD with normoalbuminuria compared with those with macroalbuminuria.Trial registration UMIN-CTR: UMIN000035263. Registered 15 December 2018.
  • Akinobu Nakamura, Hideaki Miyoshi, Shigekazu Ukawa, Koshi Nakamura, Takafumi Nakagawa, Yasuo Terauchi, Akiko Tamakoshi, Tatsuya Atsumi
    Journal of diabetes investigation 11 1 75 - 79 2020年01月 [査読有り][通常論文]
     
    AIMS/INTRODUCTION: We investigated associations between glucose tolerance and β-cell function using a series of estimation methods in a population-based study. MATERIALS AND METHODS: Data from the Dynamics of Lifestyle and Neighborhood Community on Health Study were analyzed. A total of 489 participants (263 women) were divided into three groups: normal glucose tolerance (NGT), prediabetes (PDM) and diabetes group. We estimated β-cell function by the homeostasis model assessment of β-cell function, proinsulin level (PI), C-peptide index, proinsulin-to-C-peptide ratio (PI/CPR) and proinsulin-to-insulin ratio. Because data on all five parameters of β-cell function showed skewed distributions, the values of these parameters were normalized by natural logarithmic (ln) transformation. Next, the association between glucose tolerance and β-cell function among participants without diabetes was examined. In this analysis, glucose tolerance was assessed based on glycated hemoglobin levels. RESULTS: In the crude analysis, ln(PI) and ln(PI/CPR) were significantly higher in the diabetes group than those in the PDM and NGT groups, and these parameters were significantly higher in the PDM group than in the NGT group. Only ln(PI) in the PDM group was significantly higher compared with that in the NGT group after adjustment for age, sex and body mass index (ln[PI]: PDM group 2.38 pmol/L, 95% confidence interval 2.29-2.47 pmol/L; NGT group 2.17 pmol/L, 95% confidence interval 2.12-2.22 pmol/L; P < 0.05). In addition, ln(PI) levels were significantly and positively correlated with glycated hemoglobin quartile in participants without diabetes. CONCLUSIONS: Our results showed that PI was the most sensitive to reflect glucose intolerance.
  • Miyazaki T, Shirakawa J, Nagakura J, Shibuya M, Kyohara M, Okuyama T, Togashi Y, Nakamura A, Kondo Y, Satoh S, Nakajima S, Taguri M, Terauchi Y
    Internal medicine (Tokyo, Japan) 58 23 3361 - 3367 2019年12月01日 [査読有り][通常論文]
     
    Objective Delays in insulin initiation can lead to the development of complications in the management of type 2 diabetes. Methods In this study, the effects of the timing of insulin initiation on glycemic control in patients with type 2 diabetes were evaluated retrospectively. Changes in the HbA1c levels of 237 patients were analyzed after insulin initiation. Results The patients were divided into 4 groups according to the duration of diabetes at the time of insulin initiation: ≤3 years, 4 to 6 years, 7 to 9 years, or ≥10 years. Patients with a diabetes duration of ≤3 years were more frequently hospitalized at the time of insulin initiation, had a higher HbA1c level before insulin initiation and a lower HbA1c level at 1 year after insulin initiation and exhibited significant decreases in HbA1c at 1, 3, or 5 years after insulin initiation than those in the other 3 groups with longer durations of diabetes. In the group receiving 4 insulin injections per day, the reduction in HbA1c after 5 years of treatment was larger in patients with a diabetes duration at the time of insulin initiation of ≤3 years than in those with a duration of 7 to 9 years or ≥10 years. Conclusion Our results suggested that an earlier initiation of insulin therapy was crucial for sustaining glycemic control in Japanese patients with type 2 diabetes, particularly in those with a history of obesity or receiving multiple insulin injections daily.
  • Kyu Yong Cho, Akinobu Nakamura, Chiho Oba-Yamamoto, Kazuhisa Tsuchida, Shingo Yanagiya, Naoki Manda, Yoshio Kurihara, Shin Aoki, Tatsuya Atsumi, Hideaki Miyoshi
    Diabetes & metabolism journal 44 4 532 - 541 2019年11月22日 [査読無し][通常論文]
     
    BACKGROUND: To explore the efficacy and safety of switching from once-daily basal insulin therapy to once-daily pre-meal injection insulin degludec/insulin aspart (IDegAsp) with respect to the glycemic control of participants with type 2 diabetes mellitus (T2DM). METHODS: In this multicenter, open-label, prospective, randomized, parallel-group comparison trial, participants on basal insulin therapy were switched to IDegAsp (IDegAsp group; n=30) or continued basal insulin (Basal group; n=29). The primary endpoint was the superiority of IDegAsp in causing changes in the daily blood glucose profile, especially post-prandial blood glucose concentration after 12 weeks. RESULTS: Blood glucose concentrations after dinner and before bedtime were lower in the IDegAsp group, and the improvement in blood glucose before bedtime was significantly greater in the IDegAsp group than in the Basal group at 12 weeks (-1.7±3.0 mmol/L vs. 0.3±2.1 mmol/L, P<0.05). Intriguingly, glycemic control after breakfast was not improved by IDegAsp injection before breakfast, in contrast to the favorable effect of injection before dinner on blood glucose after dinner. Glycosylated hemoglobin significantly decreased only in the IDegAsp group (58 to 55 mmol/mol, P<0.05). Changes in daily insulin dose, body mass, and recorded adverse effects, including hypoglycemia, were comparable between groups. CONCLUSION: IDegAsp was more effective than basal insulin at reducing blood glucose after dinner and before bedtime, but did not increase the incidence of hypoglycemia. Switching from basal insulin to IDegAsp does not increase the burden on the patient and positively impacts glycemic control in patients with T2DM.
  • Suda G, Kimura M, Shigesawa T, Suzuki K, Nakamura A, Ohara M, Kawagishi N, Nakai M, Sho T, Maehara O, Shimazaki T, Morikawa K, Natsuizaka M, Ogawa K, Sakamoto N
    Hepatology research : the official journal of the Japan Society of Hepatology 49 11 1275 - 1285 2019年11月 [査読有り][通常論文]
     
    AIMS: Development of direct-acting antivirals (DAAs) has made antihepatitis C virus (HCV) treatment highly safe and effective. However, the emergence of resistant-associated variants (RAVs) after failure of DAA therapy affects retreatment outcomes. In particular, genotype 1 HCV with P32 deletion has been reported to be highly resistant to all approved non-structural protein (NS)5A inhibitors. However, analysis of RAVs in genotype 2 HCV has been limited. Accordingly, in this study, we evaluated the roles of genotype 2 HCV variants in antiviral drug efficacy. METHODS: We utilized HCV-2b/2a (JFH-1) chimeric virus (genotype 2a), which replicates more robustly than JFH-1. We constructed various genotype 2a JFH-1-based HCV cell culture systems with NS3 (D168E), NS5A (F28S, F28S/M31I, P32 deletion, and Y93H), and NS5B (S282 T) RAVs and analyzed the replication ability and sensitivity to various anti-HCV reagents. RESULTS: Genotype 2a-based HCV with NS5A-P32 deletion could not replicate even in long-term cultures. Genotype 2a-based HCV with NS5A-F28S/M31I showed significantly higher replication ability than the wild-type strain, and replication could not be suppressed, even with high concentrations of NS5A inhibitors, including pibrentasvir and velpatasvir (<1000-10 000 fold-resistance compared with the wild-type strain). However, genotype 2a-based HCV with NA5A-F28S/M31I was sensitive to HCV protease inhibitor, NS5B inhibitor, interferon-α, and ribavirin. Genotype 2a-based HCV with NS5B-S282 T was resistant to sofosbuvir, but was highly sensitive to ribavirin compared with the control. CONCLUSIONS: When undertaking retreatment for genotype 2a HCV-infected patients who fail to respond to DAAs, the optimized retreatment should be chosen according to the sensitivity of the emerging RAVs to anti-HCV drugs.
  • Tomonori Sekizaki, Hiraku Kameda, Chiho Oba, Kyu Yong Cho, Akinobu Nakamura, Hideaki Miyoshi, Takahiro Osawa, Nobuo Shinohara, Tatsuya Atsumi
    Endocrine journal 66 10 937 - 941 2019年10月28日 [査読有り][通常論文]
     
    A 62-year-old man was referred to our department for elevation of plasma ACTH and cortisol levels during nivolumab administration for renal cell carcinoma. Although his ACTH and cortisol levels had been maintained within their reference ranges, they were elevated to 232.7 pg/mL and 21.9 μg/dL, respectively, after eight courses of nivolumab without any subjective symptoms or Cushing's sign. He was hospitalized for endocrinological investigation. ACTH and cortisol returned to their normal ranges (29.18 pg/mL and 11.4 μg/dL, respectively) in the early morning on day 1, but fell down sharply to 3.7 pg/mL and 1.6 μg/dL, respectively, in the early morning on day 2 without subjective symptoms or vital sign changes. Brain magnetic resonance imaging showed no abnormality in his pituitary gland. ACTH response to CRH was apparently normal, but cortisol did not respond to increased ACTH. A rapid ACTH stimulation test showed slightly reduced response of cortisol to exogenous ACTH (1-24). These findings and his clinical course suggested secondary adrenal insufficiency arising from nivolumab-induced hypophysitis. In previous reports, most cases of immune checkpoint inhibitor (ICI)-induced hypophysitis were diagnosed based on adrenal insufficiency symptoms or hyponatremia with low ACTH and cortisol. The ACTH elevation observed in the present case may reflect destruction of the pituitary gland, suggesting that this finding may be important for early detection of ICI-induced hypophysitis. Our case underlines the necessity of close monitoring for subsequent onset of adrenal insufficiency when ACTH elevation is observed during ICI administration.
  • 柴山 惟, 亀田 啓, 中村 昭伸, 三好 秀明, 秋川 和聖, 安部 崇重, 坪内 駿, 菊地 央, 松本 隆児, 大澤 崇宏, 篠原 信雄, 土井 和尚, 高桑 恵美, 笹野 公伸, 渥美 達也
    日本内分泌学会雑誌 95 2 765 - 765 (一社)日本内分泌学会 2019年10月
  • Shibayama Y, Kameda H, Ota S, Tsuchida K, Cho KY, Nakamura A, Miyoshi H, Atsumi T
    Journal of diabetes investigation 10 5 1385 - 1387 2019年09月 [査読有り][通常論文]
     
    With the expansive use of immune checkpoint inhibitors, the frequency of immune-related adverse events, including autoimmune type 1 diabetes, has been exponentially increased. The anti-programmed death-ligand 1 antibody, avelumab, has recently been approved for metastatic Merkel cell carcinoma therapy. Here, we report a patient that developed fulminant type 1 diabetes during avelumab treatment. An 81-year-old woman with no history of diabetes received avelumab for metastatic Merkel cell carcinoma. Elevated plasma glucose level (483 mg/dL), hemoglobin A1c level (7.5%) and ketosis were observed after 10 courses of avelumab without any symptoms related to hyperglycemia. As the laboratory tests showed insulin depletion, we diagnosed her with fulminant type 1 diabetes induced by avelumab. This is the first reported case of avelumab-induced type 1 diabetes, illustrating the necessity for close monitoring of glycemic control during avelumab therapy, as well as other immune checkpoint inhibitors.
  • Kazuno Omori, Akinobu Nakamura, Hideaki Miyoshi, Kiyohiko Takahashi, Naoyuki Kitao, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, Ryo Takagi, Kanako C Hatanaka, Yasuo Terauchi, Tatsuya Atsumi
    Metabolism: clinical and experimental 98 27 - 36 2019年09月 [査読有り][通常論文]
     
    OBJECTIVE: To explore the beneficial effects of dapagliflozin and/or insulin glargine on the pancreatic beta cell mass and hepatic steatosis in db/db mice. METHODS: Six-week-old db/db mice were assigned to one of four groups: untreated (Placebo), treated with dapagliflozin (Dapa), treated with insulin glargine (Gla), or treated with dapagliflozin and insulin glargine (Dapa+Gla). After 8 weeks of treatment, we determined glucose tolerance, beta cell mass, hepatic lipid content and gene expression. RESULTS: Glucose tolerance was significantly ameliorated in the three treated groups to the same degree compared with the Placebo group. Immunohistochemical analysis revealed that the pancreatic beta cell mass was significantly maintained in the Dapa and Dapa+Gla groups, but not in the Gla group, compared with the Placebo group (Placebo 2.25 ± 1.44 mg, Dapa 5.01 ± 1.63 mg, Gla 3.79 ± 0.96 mg, Dapa+Gla 5.19 ± 1.78 mg). However, the triglyceride content of the liver was markedly elevated in the Gla group compared with that in the other three groups (Placebo 24.1 ± 11.5 mg, Dapa 30.6 ± 12.9 mg, Gla 128 ± 49.7 mg, Dapa+Gla 54.4 ± 14.1 mg per gram liver). The expression levels of genes related to fatty acid synthesis and lipid storage were significantly upregulated in the Gla group. CONCLUSIONS: Our results showed that beta cell mass was sustained and hepatic steatosis was prevented, after 8 weeks of treatment with either dapagliflozin or dapagliflozin plus insulin glargine, but not with insulin glargine alone, in db/db mice.
  • Suzuki K, Suda G, Yamamoto Y, Furuya K, Baba M, Kimura M, Maehara O, Shimazaki T, Yamamoto K, Shigesawa T, Nakamura A, Ohara M, Kawagishi N, Nakai M, Sho T, Natsuizaka M, Morikawa K, Ogawa K, Sakamoto N, NORTE Study Group
    Hepatology research : the official journal of the Japan Society of Hepatology 49 11 1294 - 1304 2019年07月 [査読有り][通常論文]
     
    AIM: Entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) are first-line nucleos(t)ide analogues for hepatitis B virus (HBV)-infected patients. However, consecutive TDF treatment causes renal dysfunction, and the safety and efficacy of TAF have not been established in severe renal dysfunction patients, including hemodialysis patients. The efficacy and safety of ETV in these populations has not been clarified. The study aimed to clarify this. METHODS: In this retrospective multicenter study, between 2006 and 2018, a total of 567 HBV-infected patients treated with ETV monotherapy were screened. Patients were included if >20 years old, treated with ETV monotherapy for >1 year, and had proper clinical information. The efficacy of ETV and changes in renal function were evaluated according to renal function. RESULTS: A total of 273 patients were included: 9.2% (25/273), 1.8% (5/273), and 3.7% (10/273) had chronic kidney disease (CKD) stage G3, CKD stage G4/5, and were on hemodialysis, respectively. Overall, 84.2%, 94.0%, and 96.2% of patients experienced serum HBV-DNA disappearance at 1, 2, and 3 years, respectively, after treatment initiation. In patients with CKD stage G3-5, estimated glomerular filtration rate tended to restore with time, which was in contrast to patients without renal dysfunction. The rate of disappearance in serum HBV-DNA, alanine transaminase normalization, and virological breakthrough was similar between patients with or without renal dysfunction. ETV showed high efficacy for all 10 hemodialysis patients without virological breakthrough. CONCLUSIONS: Entecavir for HBV-infected patients with severe renal dysfunction, including hemodialysis patients, is highly effective and does not affect renal function.
  • Aika Miya, Akinobu Nakamura, Hiraku Kameda, Kandai Nozu, Hideaki Miyoshi, Tatsuya Atsumi
    Medicine 98 28 e16408  2019年07月 [査読有り][通常論文]
     
    RATIONALE: The Gitelman's syndrome (GS) is characterized by metabolic alkalosis, hypokalemia, hypomagnesemia, and hypocalciuria. However, the involvement of this deranged electrolyte balance in patients with GS in parathyroid hormone action has not been known. PATIENT CONCERNS: We report a 34-year-old woman with muscle weakness and tetany/seizures caused by electrolyte imbalance. She had hyperphosphatemia and hypocalciuric hypocalcemia in addition to severe hypomagnesemia with low potassium in the absence of metabolic alkalosis. We identified 2 heterozygous mutations in the solute carrier family 12 member 3 gene in this case (c.1732G>A, p.Val578Met and c.2537_38delTT, p.846fs) by targeted sequence for all causative genes of salt-losing tubulopathies. DIAGNOSES: A diagnosis of GS. Hypocalcemia and hyperphosphatemia were suggested to relate with the secondary obstruction of appropriate parathyroid hormone release following severe hypomagnesemia in GS. INTERVENTIONS: She was treated with single oral magnesium oxide administration. OUTCOMES: The electrolyte imbalance including hypocalcemia and hyperphosphatemia were resolved with a remission of clinical manifestations. LESSONS: These observations, in this case, suggest that even severe hypomagnesemia caused by GS was associated with resistance to appropriate parathyroid hormone secretion. Through this case, we recognize that secondary hypoparathyroidism would be triggered by severe hypomagnesemia in GS.
  • Yamauchi Y, Nakamura A, Takahashi K, Takase T, Yamamoto C, Yokota I, Atsumi T, Miyoshi H
    Endocrine journal 66 11 995 - 1000 2019年07月 [査読有り][通常論文]
     
    We investigated the factors associated with fatty liver remission via treatment with ipragliflozin. The analysis was obtained from our multi-center prospective observational study, including 200 Japanese patients with type 2 diabetes treated with ipragliflozin (50 mg/day) for 24 weeks. The extent of fatty liver was estimated using a fatty liver index (FLI). Based on the FLI after the treatment with ipragliflozin, patients were classified into remission group (FLI < 30) and non-remission group (FLI ≥ 30). After treatment with ipragliflozin for 24 weeks, FLI significantly improved from 64.5 ± 21.6 to 51.9 ± 26.5 (p < 0.01). Body weight, body mass index, waist circumference, aspartate aminotransferase, alanine aminotransferase, and FLI in the remission group were significantly lower compared with those of the non-remission group. Stepwise analysis showed that the baseline FLI (Odds ratio 0.86; 95% confidence interval 0.81-0.90, p < 0.01) was an independent factor associated with FLI remission. Using a receiver operating characteristic (ROC) analysis, the adequate cut-off value for the remission was 50. The area under the ROC curve was 0.93 with the sensitivity and specificity 84.6% and 90.1% respectively. In conclusion, ipragliflozin ameliorated fatty liver. These results suggest that patients with fatty liver with a lower FLI are more likely to attain remission by the treatment with ipragliflozin.
  • Izumi T, Sho T, Morikawa K, Shigesawa T, Suzuki K, Nakamura A, Ohara M, Kawagishi N, Umemura M, Shimazaki T, Kimura M, Nakai M, Suda G, Natsuizaka M, Ogawa K, Kudo Y, Nishida M, Ono K, Baba M, Furuya K, Sakamoto N
    Hepatology research : the official journal of the Japan Society of Hepatology 49 10 1207 - 1217 2019年06月 [査読有り][通常論文]
     
    AIM: Ultrasound technology can now be used for liver stiffness measurement (LSM) and for evaluating the amount of hepatic fat quantitatively known as the controlled attenuation parameter (CAP). This study aimed to determine the applicable cut-off values of LSM and the CAP for primary hepatocellular carcinoma (HCC), and to investigate their clinical usefulness for assessing HCC risk in patients with chronic liver disease. METHODS: A total of 1054 patients (88 with primary HCC and 966 without HCC) whose LSM and the CAP were measured by transient elastography with clinically evident hepatitis C virus (419 patients), hepatitis B virus (377 patients), and non-alcoholic fatty liver disease (258 patients) were enrolled in this study. Subsequently, a total of 966 patients who did not have HCC initially were followed, and the usefulness of the cut-off values of LSM and CAP for HCC development were evaluated. RESULTS: In hepatitis C virus patients, the incidence of HCC development was significantly higher among those with a combination of LSM ≥8.0 kPa and CAP ≤221 dB/m than among those with other values (log-rank test 0.0239, hazard ratio 2.66, 95%CI 1.07-6.47, P = 0.0362). In non-alcoholic fatty liver disease patients, the incidence of HCC development was significantly higher among those with a combination of LSM ≥5.4 kPa and CAP ≤265 dB/m than among others (log-rank test 0.0040, hazard ratio 8.91, 95% CI 1.47-67.97, P = 0.0192). CONCLUSION: In the hepatitis C virus and non-alcoholic fatty liver disease groups, a combination of LSM and the CAP cut-off values would be useful for screening to identify the high-risk group for primary HCC development.
  • Takahiro Takase, Akinobu Nakamura, Chiho Yamamoto, Hiroshi Nomoto, Aika Miya, Midori Dannoura, Kyu Yong Cho, Yoshio Kurihara, Naoki Manda, Shin Aoki, Tatsuya Atsumi, Hideaki Miyoshi
    Journal of diabetes investigation 10 3 699 - 705 2019年05月 [査読有り][通常論文]
     
    AIMS/INTRODUCTION: We compared treatment satisfaction in type 2 diabetes patients taking daily and weekly glucagon-like peptide-1 receptor agonists. MATERIALS AND METHODS: The study was a 12-week, multicenter, open-label, prospective, randomized, parallel-group comparison trial. The participants were Japanese patients with type 2 diabetes being administered with the glucagon-like peptide-1 receptor agonist, liraglutide, daily for >3 months. Patients were randomly assigned to either continue taking liraglutide once daily (Lira group) or switch to dulaglutide once weekly (Dula group). The primary outcome was the change in the Diabetes Treatment Satisfaction Questionnaire score from baseline to week 12 in the two groups. The secondary outcomes comprised changes in the Diabetes Therapy-Related Quality of Life score, body mass and glycemic control. RESULTS: A total of 33 participants were initially enrolled in the trial, and 31 participants completed the protocol. The change in the Diabetes Treatment Satisfaction Questionnaire score in the Dula group was significantly greater than that in the Lira group (+0.1 ± 4.7 in the Lira group vs +4.9 ± 5.2 in the Dula group; P = 0.013). The change in Diabetes Therapy-Related Quality of Life score in the Dula group was significantly greater than that in the Lira group (-3.7 ± 6.9 vs +8.9 ± 15.1; P = 0.007). There were no significant differences between groups in the changes in body mass, plasma glucose or glycated hemoglobin. CONCLUSIONS: Weekly administration of dulaglutide was superior to liraglutide with regard to treatment satisfaction in patients with type 2 diabetes, in the absence of any negative effect on glycemic control.
  • 山内 裕貴, 亀田 啓, 馬場 菜月, 関崎 知紀, 平田 恵里奈, 大森 一乃, 高瀬 崇宏, 亀田 玲奈, 大場 知穂, 谷 道夫, 曹 圭龍, 中村 昭伸, 三好 秀明, 田中 伸哉, 渥美 達也
    日本内分泌学会雑誌 95 1 492 - 492 (一社)日本内分泌学会 2019年04月
  • 大場 知穂, 亀田 啓, 桑原 健, 高桑 恵美, 馬場 菜月, 関崎 知紀, 山内 裕貴, 平田 恵里奈, 高瀬 崇宏, 亀田 玲奈, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 95 1 481 - 481 (一社)日本内分泌学会 2019年04月
  • 関崎 知紀, 亀田 啓, 馬場 菜月, 山内 裕貴, 平田 恵里奈, 柴山 惟, 宮野 有希恵, 高瀬 崇宏, 亀田 玲奈, 大場 知穂, 曹 圭龍, 中村 昭伸, 三好 秀明, 大澤 崇宏, 篠原 信雄, 渥美 達也
    日本内分泌学会雑誌 95 1 477 - 477 (一社)日本内分泌学会 2019年04月
  • DPP-4阻害薬とSGLT2阻害薬併用による血糖変動平坦化の増強効果
    曹 圭龍, 中村 昭伸, 川田 晋一朗, 土田 和久, 大森 一乃, 菅原 基, 野本 博司, 本庄 潤, 竹内 淳, 永井 聡, 横山 宏樹, 萬田 直紀, 栗原 義夫, 青木 伸, 渥美 達也, 三好 秀明
    糖尿病 62 Suppl.1 S - 244 (一社)日本糖尿病学会 2019年04月
  • 早期膵β細胞機能障害マーカーとしての血清プロインスリンの有用性
    中村 昭伸, 三好 秀明, 鵜川 重和, 中村 幸志, 中川 貴史, 寺内 康夫, 玉腰 暁子, 渥美 達也
    糖尿病 62 Suppl.1 S - 318 (一社)日本糖尿病学会 2019年04月
  • Miyoshi H, Kameda H, Yamashita K, Nakamura A, Kurihara Y
    Journal of diabetes investigation 10 6 1510 - 1517 2019年04月 [査読有り][通常論文]
     
    AIMS/INTRODUCTION: The risk of end-stage kidney disease increases in proportion to the decline in the estimated glomerular filtration rate (eGFR). Although protective effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on the eGFR decline were shown in several large-scale clinical trials, there are no studies investigating patients with a high risk of end-stage kidney disease. We investigated the efficacy and safety of SGLT2i in advanced renal dysfunction patients (stage G3 or G4 of chronic kidney disease) with a rapid decline in eGFR. MATERIALS AND METHODS: This retrospective, longitudinal study enrolled patients with type 2 diabetes who were treated with SGLT2i, and whose eGFR was <60 mL/min/1.73 m2 and had declined >20% over 2 years (%ΔeGFR-2y) before initiating SGLT2i. The primary end-point was the change in eGFR 2 years after initiation (%ΔeGFR+2y) compared with %ΔeGFR-2y. RESULTS: A total of 17 patients among 553 patients treated with SGLT2i for ≥2 years were included in the study. The average age, glycated hemoglobin and eGFR at SGLT2i initiation were 68.5 years, 7.3% and 38.3 mL/min/1.73 m2 , respectively. %ΔeGFR+2y in patients who were treated with SGLT2i was significantly increased compared with the patients not treated with SGLT2i (2.3 and -21.7%, respectively; P < 0.0001). A multiple regression analysis showed that only the proportion of the rate of eGFR decline was the independent factor associated with improvement of %ΔeGFR+2y. There was no increase in serious adverse events including acute kidney injury. CONCLUSIONS: SGLT2i was safe, and prevented further eGFR decline in patients with type 2 diabetes and advanced renal dysfunction.
  • Kazuno Omori, Hiroshi Nomoto, Akinobu Nakamura, Takahiro Takase, Kyu Yong Cho, Kota Ono, Naoki Manda, Yoshio Kurihara, Shin Aoki, Tatsuya Atsumi, Hideaki Miyoshi
    Journal of diabetes investigation 10 2 367 - 374 2019年03月 [査読有り][通常論文]
     
    AIMS/INTRODUCTION: Glinides are antidiabetic drugs that enhance the early phase of insulin secretion, but have been considered to be less effective at lowering blood glucose than sulfonylureas. However, glinides show a lower risk of hypoglycemia and a greater effect on postprandial hyperglycemia, and are particularly recommended for use in elderly patients with type 2 diabetes. We investigated the efficacy and safety of repaglinide compared with sulfonylurea for the treatment of elderly patients. MATERIALS AND METHODS: In the present multicenter, prospective, randomized, open-label, controlled trial, 57 elderly lean patients with type 2 diabetes who were being treated with sulfonylureas were studied. They were either switched to repaglinide (Repa group) or continued a sulfonylurea (SU group) for 12 weeks. The primary outcome comprised the change in glycemic control, and among the secondary outcomes was the presence of hypoglycemia and drug compliance. RESULTS: Although glycated hemoglobin (HbA1c) was not significantly different between the two groups (SU +0.02% vs Repa -0.07%), greater improvements in the glycated albumin (GA) and GA to HbA1c ratio (GA/HbA1c) were observed in the Repa group (ΔGA, SU +0.12% vs Repa -1.15%; ΔGA/HbA1c, SU +0.01 vs Repa -0.13; each P < 0.01) without increasing hypoglycemia. When the Repa group was subdivided according to whether GA improved, the SU dose before switching to repaglinide was significantly smaller and the homeostatic model assessment of β-cell function was significantly higher in the GA improvement subgroup. CONCLUSIONS: Switching from SU to Repa improved GA and GA/HbA1c, and had favorable effects on glucose fluctuation in elderly patients with type 2 diabetes.
  • Kiyohiko Takahashi, Kyu Yong Cho, Akinobu Nakamura, Aika Miya, Arina Miyoshi, Chiho Yamamoto, Hiroshi Nomoto, Hirokatsu Niwa, Kiyohito Takahashi, Naoki Manda, Yoshio Kurihara, Shin Aoki, Yoichi M Ito, Tatsuya Atsumi, Hideaki Miyoshi
    Journal of diabetes investigation 10 2 429 - 438 2019年03月 [査読有り][通常論文]
     
    AIMS/INTRODUCTION: We investigated the difference in efficacy and safety between discontinuation and maintaining of sulfonylurea when adding a sodium-glucose cotransporter 2 inhibitor. MATERIALS AND METHODS: In the present multicenter, prospective observational study, 200 patients with type 2 diabetes treated with sulfonylurea and with a need to add ipragliflozin were enrolled and divided into two groups: discontinued sulfonylurea (Discontinuation group) or maintained sulfonylurea, but at the lowest dose (Low-dose group) when adding ipragliflozin. We compared the two groups after 24 weeks using propensity score matching to adjust for differences between the groups. RESULTS: In the matched cohort (58 patients in each group), baseline characteristics of both groups were balanced. The primary outcome of the proportion of patients with non-exacerbation in glycated hemoglobin after 24 weeks was 91.4% in the Low-dose group and 75.9% in the Discontinuation group, a significant difference (P = 0.024). However, bodyweight was significantly decreased in the Discontinuation group compared with the Low-dose group (-4.4 ± 2.1 kg vs -2.9 ± 1.9 kg, P < 0.01). Similarly, liver enzyme improvement was more predominant in the Discontinuation group. A logistic regression analysis showed that high-density lipoprotein cholesterol, age and sulfonylurea dose were independent factors associated with non-exacerbation of glycated hemoglobin in the Discontinuation group. CONCLUSIONS: The purpose of using ipragliflozin should be considered when making the decision to discontinue or maintain sulfonylurea at the lowest dose. Furthermore, low high-density lipoprotein cholesterol level, low dose of sulfonylurea and younger age were possible markers to not show worsening of glycemic control by discontinuing sulfonylurea.
  • Kyu Yong Cho, Akinobu Nakamura, Kazuno Omori, Takahiro Takase, Aika Miya, Naoki Manda, Yoshio Kurihara, Shin Aoki, Tatsuya Atsumi, Hideaki Miyoshi
    Diabetes, obesity & metabolism 21 3 710 - 714 2019年03月 [査読有り][通常論文]
     
    The effects of dapagliflozin (DAP) and pioglitazone (PIO) on body weight and glycaemic control were compared in patients with type 2 diabetes mellitus. Seventy-one patients on PIO were either switched to DAP (n = 36) at 5 mg per day or continued on PIO (n = 35). Primary endpoints were superiority of body weight loss and non-inferiority of HbA1c level after 24 weeks with DAP. Body weight decrease was greater with DAP than with PIO (75.3 ± 14.9 to 71.3 ± 15.1 kg vs. 74.7 ± 13.8 to 75.2 ± 13.9 kg; P < 0.01). Change in the HbA1c level was comparable (P = 0.64). The level of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and urinary albumin : creatinine ratio (ACR) decreased only with DAP (NT-proBNP, P < 0.01; ACR, P = 0.02), and the change in NT-proBNP correlated negatively with baseline NT-proBNP level (ρ = -0.68, P < 0.01) and log-converted ACR (ρ = -0.35, P < 0.05). DAP promotes body weight loss in type 2 diabetes mellitus and may decrease fluid retention, thus reducing the occurrence of cardiovascular events.
  • Nomoto H, Kameda H, Nakamura A, Tsuchida K, Nagai S, Atsumi T, Miyoshi H
    Frontiers in endocrinology 10 131 - 131 2019年 [査読有り][通常論文]
     
    Patients with acromegaly are at increased risk of developing certain tumors, including goiter and thyroid nodules, and occasionally autonomous thyroid nodules. A 53-year-old woman presented at our hospital with untreated acromegaly. She had typical physical features of acromegaly with pituitary adenoma, and thyrotoxicosis with thyroid-stimulating hormone suppression was also confirmed. Thyroid ultrasonography and scintigraphy showed an autonomously functioning thyroid nodule on her right lobe. Because her thyrotoxicosis was mild, she was initially treated with octreotide for acromegaly. However, 1 month after octreotide administration, she developed neck pain and fever with transient thyrotoxicosis. The blood flow around the nodule then decreased and the excess trapping of isotope detected by scintigraphy was reduced, followed by normalization of insulin-like growth factor-1 levels and thyroid function. This case suggests that octreotide may have unexpected effects on autonomous thyroid nodules. However, further studies are needed to determine the clinical course of autonomously functioning thyroid nodules, including thyroid function and tumor manifestations, during octreotide therapy.
  • Sho T, Suda G, Kimura M, Shimazaki T, Maehara O, Shigesawa T, Suzuki K, Nakamura A, Ohara M, Umemura M, Izumi T, Kawagishi N, Baba M, Nakai M, Natsuizka M, Morikawa K, Ogawa K, Sakamoto N, NORTE Study Group
    Internal medicine (Tokyo, Japan) 58 6 797 - 802 2018年11月 [査読有り][通常論文]
  • Shibayama Y, Wada N, Baba S, Miyano Y, Obara S, Iwasaki R, Nakajima H, Sakai H, Usubuchi H, Terae S, Nakamura A, Atsumi T
    Journal of the Endocrine Society 2 11 1236 - 1245 2018年11月 [査読有り][通常論文]
  • 服薬アドヒアランスの悪い高齢者2型糖尿病に週1回GLP-1受容体作動薬が有用であった1例
    高瀬 崇宏, 三好 秀明, 大森 一乃, 高橋 清彦, 北尾 直之, 山本 浩平, 野本 博司, 曹 圭龍, 中村 昭伸, 渥美 達也
    日本老年医学会雑誌 55 4 699 - 699 (一社)日本老年医学会 2018年10月
  • Akinobu Nakamura, Hideaki Miyoshi, Shigekazu Ukawa, Koshi Nakamura, Takafumi Nakagawa, Yasuo Terauchi, Akiko Tamakoshi, Tatsuya Atsumi
    Journal of diabetes investigation 9 5 1106 - 1109 2018年09月 [査読有り][通常論文]
     
    We investigated the association between serum high molecular weight (HMW) adiponectin and insulin secretion in a population-based study, with or without adjustment for insulin sensitivity. A total of 488 participants (263 women) were included in the present study. Insulin secretion was estimated using the homeostasis model assessment of β-cell function ± adjustment for insulin resistance using the disposition index. Multivariate analysis showed that HMW adiponectin was significantly and inversely associated with homeostasis model assessment of β-cell function (partial regression coefficient -0.19, 95% confidence interval -0.28, -0.10, P < 0.0001). However, HMW adiponectin was significantly and positively associated with disposition index (partial regression coefficient 0.15, 95% confidence interval 0.06, 0.24, P = 0.0016). The present study showed that a positive association between HMW adiponectin levels and insulin secretion evaluated using an index incorporating adjustment for insulin resistance was identified, and vice versa using an index that did not adjust for insulin resistance.
  • Shingo Yanagiya, Kyu Yong Cho, Akinobu Nakamura, Hiroshi Nomoto, Yasuyuki Kawamoto, Kazumichi Kawakubo, Yoshito Komatsu, Tomoko Mitsuhashi, Hideaki Miyoshi, Tatsuya Atsumi
    Internal medicine (Tokyo, Japan) 57 17 2527 - 2531 2018年09月01日 [査読有り][通常論文]
     
    An 84-year-old Japanese woman with metastatic insulinoma suffered from frequent hypoglycemic events. Continuous glucose monitoring (CGM) confirmed severe and frequent symptomatic/asymptomatic hypoglycemia. After the initiation of everolimus treatment, the hypoglycemic events were rapidly eliminated. CGM revealed that her blood glucose levels were maintained without hypoglycemia throughout the day. Furthermore, everolimus reduced the duration of time above the upper limit (>180 mg/dL) along with the standard deviation and mean amplitude of glycemic excursions. This case shows the potential effects of everolimus on hypoglycemia and glycemic control in a patient with inoperable metastatic insulinoma evaluated by CGM.
  • Naoyuki Kitao, Akinobu Nakamura, Hideaki Miyoshi, Hiroshi Nomoto, Kiyohiko Takahashi, Kazuno Omori, Kohei Yamamoto, Kyu Yong Cho, Yasuo Terauchi, Tatsuya Atsumi
    Metabolism: clinical and experimental 85 48 - 58 2018年08月 [査読有り][通常論文]
     
    OBJECTIVE: We investigated whether glucokinase and insulin receptor substrate-2 were required for beta cell proliferation induced by short-term high-fat (HF) diet feeding, as has been shown for long-term HF diet. METHODS: Eight-week-old C57BL/6J mice were exposed to either a standard chow (SC) or HF diet. After 1 week on the diet, histopathological beta cell proliferation and gene expression in isolated islets were examined. Additionally, 8-week-old beta cell-specific glucokinase haploinsufficient (Gck+/-) and Irs2 knockout (Irs2-/-) mice were exposed to either an SC or HF diet. RESULTS: Immunohistochemical analysis revealed that short-term HF diet feeding resulted in a significant increase in BrdU incorporation rate compared with SC consumption in wild-type mice. Western blot analysis demonstrated that Irs2 expression levels did not differ between the two diets. Moreover, there was a significant increase in the BrdU incorporation rate in the HF diet group compared with the SC group in both Gck+/- and Irs2-/- mice. Gene expression profiling of isolated islets from mice fed an HF diet for 1 week revealed that the expression levels of downstream genes of Foxm1 were coordinately upregulated. One week of HF diet feeding stimulated beta cell proliferation with Foxm1 upregulation in 48-week-old mice as well as in 8-week-old. CONCLUSIONS: The mechanism of pancreatic beta cell proliferation induced by short-term HF diet feeding in mice could involve a glucokinase- and Irs2-independent pathway. Our results suggest that the pathways that induce beta cell proliferation in response to short-term HF diet feeding may differ from those in response to sustained HF diet feeding.
  • Kohei Yamamoto, Hideaki Miyoshi, Kyu Yong Cho, Akinobu Nakamura, Andrew S Greenberg, Tatsuya Atsumi
    Data in brief 19 179 - 182 2018年08月 [査読有り][通常論文]
     
    The data presented here are related to the research article entitled "Overexpression of Perilipin1 protects against atheroma progression in apolipoprotein E knockout mice" [1]. This paper describes data that were obtained from perilipin 1 (PLIN1) transgenic mice (Plin1Tg) regarding atherosclerosis. The main aim of collecting the data was to clarify the role of PLIN1 in the pathophysiology of atherosclerosis. The data were collected from C57BL/6J mice, apolipoprotein E knockout mice (ApoeKO) and Plin1Tg/ApoeKO. The atherosclerotic lesion areas of aorta were 3.3 ± 1.2% in C57BL/6J mice, 14.2 ± 3.2% in ApoeKO, and 5.6 ± 1.9% in Plin1Tg/ApoeKO. Body weight, gonadal adipose mass and plasma triglyceride concentrations were comparable among the three groups [1]. Furthermore, PLIN1 overexpression did not affect the gene expressions related to cholesterol influx and efflux in macrophage.
  • Takahiro Takase, Akinobu Nakamura, Chiho Yamamoto, Tatsuya Atsumi, Hideaki Miyoshi
    Expert Opinion on Pharmacotherapy 19 7 631 - 632 2018年05月03日 [査読有り][通常論文]
  • Hideyuki Ujiie, Ken Muramatsu, Taisei Mushiroda, Takeshi Ozeki, Hideaki Miyoshi, Hiroaki Iwata, Akinobu Nakamura, Hiroshi Nomoto, Kyu Yong Cho, Norihiro Sato, Machiko Nishimura, Takamasa Ito, Kentaro Izumi, Wataru Nishie, Hiroshi Shimizu
    The Journal of investigative dermatology 138 5 1201 - 1204 2018年05月 [査読有り][通常論文]
  • Kiyohiko Takahashi, Akinobu Nakamura, Hideaki Miyoshi, Hiroshi Nomoto, Naoyuki Kitao, Kazuno Omori, Kohei Yamamoto, Kyu Yong Cho, Yasuo Terauchi, Tatsuya Atsumi
    Scientific reports 8 1 6864 - 6864 2018年05月01日 [査読有り][通常論文]
     
    To examine the effects of luseogliflozin, a sodium-glucose cotransporter 2 inhibitor, on pancreatic beta cell mass in db/db mice of different ages. db/db mice aged 6, 10, 14 and 24 weeks old were fed either standard chow (control group) or standard chow containing 0.01% luseogliflozin (luseo group). After 4 weeks, immunohistochemistry and gene expression tests were conducted. In 6-week-old db/db mice, immunohistochemistry revealed a significant increase in beta cell mass in the luseo group compared with the control group after 4 weeks of treatment. Gene expression profiling of isolated islets showed upregulation Mafa, Pdx1, Ki67 and Ccnd2 in the luseo group. Beta cell mass decreased with age in db/db mice in the control group. Beta cell mass in the luseo group significantly increased compared with the control group regardless of age, although beta cell mass in the 28-week-old luseo group (4 weeks of treatment in 24-week-old db/db mice) was significantly lower than in the 10-week-old luseo group (4 weeks of treatment in 6-week-old db/db mice). Luseogliflozin preserved beta cell mass in db/db mice. The protective effect was more evident in the earlier phase of diabetes.
  • イプラグリフロジンを開始する際にSU薬は中止すべきか少量残すべきか?
    高橋 清彦, 三好 秀明, 宮 愛香, 三次 有奈, 山本 知穂, 野本 博司, 曹 圭龍, 中村 昭伸, 丹羽 祐勝, 高橋 清仁, 萬田 直紀, 栗原 義夫, 青木 伸, 渥美 達也
    糖尿病 61 Suppl.1 S - 232 (一社)日本糖尿病学会 2018年04月
  • 高齢者2型糖尿病患者におけるSU薬からレパグリニド切り替えはグリコアルブミン(GA)/HbA1c比を改善する
    大森 一乃, 高瀬 崇宏, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也
    糖尿病 61 Suppl.1 S - 237 (一社)日本糖尿病学会 2018年04月
  • GLP-1受容体作動薬連日投与製剤からデュラグルチド切り替えによる患者満足度の改善効果
    高瀬 崇宏, 三好 秀明, 檀浦 みどり, 山本 知穂, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 栗原 義夫, 青木 伸, 渥美 達也
    糖尿病 61 Suppl.1 S - 351 (一社)日本糖尿病学会 2018年04月
  • Aika Miya, Akinobu Nakamura, Hideaki Miyoshi, Yoshinari Takano, Kana Sunagoya, Koji Hayasaka, Chikara Shimizu, Yasuo Terauchi, Tatsuya Atsumi
    Frontiers in Endocrinology 9 81  2018年03月20日 [査読有り][通常論文]
     
    Objective: The aim of this study was to examine the fluctuations in CD4+ T cells, CD8+ T cells, and natural CD4+CD25+FoxP3+T-regulatory (Treg) cells following an oral glucose tolerance test (OGTT) in participants with and those without type 2 diabetes (T2DM). Methods: 19 Japanese participants with T2DM (DM group) and 21 participants without diabetes (non-DM group) were recruited and underwent a 75-g OGTT. The cell numbers of leukocytes, lymphocytes, and the T cell compartment, such as CD4+, CD8+, and Treg, were calculated for blood samples obtained after an overnight 12 h fast and during a 75-g OGTT at 60 and 120 min. Results: Before glucose loading, no differences in the cell numbers of leukocytes, lymphocytes, CD4+, CD8+, and Treg were observed between the DM group and the non-DM group. The proportion of CD8+ was significantly reduced, whereas the proportion of CD4+ was significantly increased, after 120 min of glucose loading in both groups. The proportion of Treg was not affected. Furthermore, a significant positive correlation was observed between the AUC0-120 min of CD8+ and the change in the free fatty acid level following the OGTT (ρ = 0.39, P < 0.05), but not that of glucose or insulin. Conclusion: The proportion of CD4+ T cells was increased and that of CD8+ T cells was reduced after glucose loading in both subjects with and without diabetes. These findings suggest that glucose loading dynamically affects the balance of the circulating T lymphocyte subset, regardless of glucose tolerance.
  • GLP-1受容体作動薬連日投与製剤からデュラグルチド切り替えによる患者満足度の検討
    高瀬 崇宏, 三好 秀明, 檀浦 みどり, 山本 知穂, 宮 愛香, 野本 博司, 中村 昭伸, 栗原 義夫, 青木 伸, 渥美 達也
    糖尿病 61 3 142 - 142 (一社)日本糖尿病学会 2018年03月
  • 肥満2型糖尿病に対する腹腔鏡下スリーブ状胃切除術の治療効果
    土田 和久, 高瀬 崇宏, 三好 秀明, 海老原 裕磨, 北尾 直之, 山本 浩平, 野本 博司, 曹 圭龍, 中村 昭伸, 平野 聡, 渥美 達也
    糖尿病 61 3 144 - 144 (一社)日本糖尿病学会 2018年03月
  • Mayuko Oita, Hideaki Miyoshi, Kota Ono, Akinobu Nakamura, Kyu Yong Cho, Hiroshi Nomoto, Kohei Yamamoto, Kazuno Omori, Naoki Manda, Yoshio Kurihara, Shin Aoki, Tatsuya Atsumi
    Endocrine journal 65 2 141 - 150 2018年02月26日 [査読有り][通常論文]
     
    We compared treatment satisfaction between daily dipeptidyl peptidase-4 (DPP-4) inhibitors and a weekly DPP-4 inhibitor in patients with type 2 diabetes. The study was a 12-week, open-label, randomized, multicenter, controlled trial. Participants were Japanese patients with type 2 diabetes who had received daily DPP-4 inhibitors for more than 3 months. Patients were randomly assigned to a treatment cohort: (1) a group that continued taking daily DPP-4 inhibitors (daily group); or (2) a group that switched from daily DPP-4 inhibitors to a weekly DPP-4 inhibitor, trelagliptin (weekly group). The primary outcome was the change in treatment satisfaction levels from baseline to 12 weeks between the two groups, according to Diabetes Treatment Satisfaction Questionnaire (DTSQ) and Diabetes Therapy-Related Quality of Life (DTR-QOL) questionnaire scores. The changes in glycemic control and body weight were also assessed. Of 49 patients initially enrolled in the study, 47 completed the study. The change in DTSQ scores in the weekly group was not significantly different from that in the daily group. However, the improvements in total score and subscale domains 1 and 2 in the DTR-QOL analysis, which relate to burden on social/daily activities and anxiety/dissatisfaction with treatment, were significantly greater in the weekly group than the daily group (p = 0.048, 0.013 and 0.045, respectively). Mean changes in glycated hemoglobin levels and body weight were comparable between the groups. Switching from daily DPP-4 inhibitors to a weekly DPP-4 inhibitor, trelagliptin, could partially improve treatment satisfaction levels in patients with type 2 diabetes without affecting glycemic control.
  • Kohei Yamamoto, Hideaki Miyoshi, Kyu Yong Cho, Akinobu Nakamura, Andrew S Greenberg, Tatsuya Atsumi
    Atherosclerosis 269 192 - 196 2018年02月 [査読有り][通常論文]
     
    BACKGROUND AND AIMS: Perilipin1 (PLIN1), a lipid droplet-associated protein, plays an important role in the regulation of lipolysis and lipid storage in adipocytes. PLIN1 has recently been reported to be expressed in macrophages within atheroma plaques, suggesting PLIN1 may play a role in the accumulation of lipids at the arterial wall and in the development of atherosclerosis. To clarify the role of PLIN1 in the pathophysiology of atherosclerosis, we assessed the progression of atherosclerosis in PLIN1 transgenic mice (Plin1Tg). METHODS: Plin1Tg were crossed with apolipoprotein E knockout mice (ApoeKO). C57BL/6J mice, ApoeKO and Plin1Tg/ApoeKO received a normal chow diet for 20 weeks. Body weight, gonadal fat mass and plasma lipid concentrations were measured. Aortas were collected for quantification of atheroma lesions and histological analysis by Oil Red O staining. RESULTS: Body weight, gonadal adipose mass and plasma triglyceride concentrations were not significantly different among the three groups. In contrast, the atherosclerotic lesion area was significantly increased in ApoeKO (14.2 ± 3.2%; p < .01) compared with C57BL/6J mice (3.3 ± 1.2%) and Plin1Tg/ApoeKO (5.6 ± 1.9%). CONCLUSIONS: Overexpressed PLIN1 in macrophages had a protected role against atheroma progression in ApoeKO in the absence of changes in gonadal fat mass or plasma lipid levels, presumably due to modification of the stability and/or inflammatory profile of macrophages.
  • Hiroshi Nomoto, Hideaki Miyoshi, Akinobu Nakamura, So Nagai, Chikara Shimizu, Tatsuya Atsumi
    Internal Medicine 57 3 453  2018年 [査読有り][通常論文]
  • Babu GR, Nakamura A, Jurišić Eržen D
    Frontiers in endocrinology 9 575  2018年 [査読有り][通常論文]
  • Naoki Kawagishi, Goki Suda, Akinobu Nakamura, Megumi Kimura, Osamu Maehara, Kazuharu Suzuki, Akihisa Nakamura, Masatsugu Ohara, Takaaki Izumi, Machiko Umemura, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Yusuke Kudo, Mutsumi Nishida, Hideaki Miyoshi, Naoya Sakamoto
    PloS one 13 12 e0209615  2018年 [査読有り][通常論文]
     
    AIM: We comprehensively analyzed how hepatitis C virus (HCV) eradication by interferon (IFN)-free direct-acting-antiviral-agents (DAAs) affects liver steatosis and atherogenic risk. METHODS: Patients treated with IFN-free-DAAs who underwent transient elastography before and at 24-weeks post-treatment, including controlled attenuation parameter (CAP), and achieved sustained viral response (SVR) were enrolled. The association between changes in liver steatosis, lipid-metabolism, and genetic and clinical factors was analyzed. RESULTS: A total of 117 patients were included. The mean CAP and low-density lipoprotein cholesterol (LDL-C) levels were significantly elevated at SVR24. However, baseline LDL-C and CAP values were significantly negatively correlated with changes in these values after HCV eradication, indicating that in patients with high baseline values, the values generally decreased after HCV eradication. Mean small-dense LDL-C (sdLDL-C), which has greater atherogenic potential, was significantly elevated only in patients with both dyslipidemia (LDL-C >140 mg/dL) and liver steatosis (CAP >248 dB/m) at SVR24. Those patients had significant higher baseline BMI, LDL-C, and total-cholesterol levels. CONCLUSIONS: Generally, successful HCV eradication by IFN-free-DAAs decreases CAP and LDL-C in patients with high baseline values. However, elevated LDL-C was accompanied with elevated sdLDL-C only in patients with liver steatosis and dyslipidemia at SVR24; therefore, those patients may require closer monitoring.
  • Aika Miya, Akinobu Nakamura, Hideaki Miyoshi, Kyu Yong Cho, So Nagai, Yoshio Kurihara, Shin Aoki, Masataka Taguri, Yasuo Terauchi, Tatsuya Atsumi
    Journal of diabetes investigation 9 1 119 - 126 2018年01月 [査読有り][通常論文]
     
    AIMS/INTRODUCTION: We compared the satisfaction levels of patients with type 2 diabetes undergoing combination therapy with lixisenatide (LIX) and basal insulin with that of patients undergoing multiple daily insulin injection (MDI) therapy. MATERIALS AND METHODS: The study was a 12-week open-label, randomized, multicenter, controlled trial. Participants were Japanese patients with type 2 diabetes receiving MDI for >3 months. Patients were randomly assigned to each treatment cohort: (i) a group that continued MDI (MDI group); and (ii) a group that switched from MDI to combination therapy with LIX and basal insulin (LIX group). The primary outcome was change in Diabetes Treatment Satisfaction Questionnaire scores from baseline to 12 weeks between these two groups. Key secondary outcomes were glycated hemoglobin and body weight changes. RESULTS: A total of 31 patients were initially enrolled in the study, and 26 of them completed the study. The change in Diabetes Treatment Satisfaction Questionnaire scores in the LIX group was significantly greater compared with that in the MDI group. Mean changes in glycated hemoglobin levels were -0.05 ± 0.37% in the MDI group and 0.04 ± 0.38% in the LIX group (P = 0.36). Mean changes in body weight were +0.6 ± 1.8 kg in the MDI group and -2.5 ± 1.8 kg in the LIX group (P < 0.01). CONCLUSIONS: Switching from MDI to combination therapy with LIX and basal insulin improved satisfaction levels while maintaining glycemic control in Japanese patients with type 2 diabetes.
  • 桑原 咲, 川田 晋一朗, 馬場 菜月, 続木 惇, 半田 喬久, 枝川 幸子, 高瀬 崇宏, 山本 浩平, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 93 3 658 - 658 (一社)日本内分泌学会 2017年12月
  • Akiko Kameda, Akinobu Nakamura, Yoshinobu Kondo, Mari Kimura, Yasuo Terauchi
    Diabetology International 8 4 383 - 391 2017年11月01日 [査読有り][通常論文]
     
    Aims: We investigated the effects of switching from other statins, such as pravastatin (5 or 10 mg/day), rosuvastatin (2.5 mg/day), or pitavastatin (1 or 2 mg/day), to low-dose rosuvastatin (5 mg/day) on glucose metabolism and lipid profiles in Japanese patients with type 2 diabetes and dyslipidemia. Methods: This was a prospective, two-center, open-label, single-arm, interventional trial. Several clinical parameters were analyzed at baseline and 24 weeks after switching from other statins to rosuvastatin at 5 mg/day. The primary endpoints were changes in hemoglobin (Hb) A1c level and lipid profile. Results: Forty-five patients were enrolled in the trial. The mean HbA1c level increased significantly from 7.1 ± 0.7 to 7.5 ± 0.9% (P <  0.001), whereas the mean low-density lipoprotein cholesterol (LDL-C) level decreased significantly from 108.9 ± 16.5 to 91.6 ± 24.5 mg/dL (P <  0.001). Multiple linear regression analysis showed that changes in HbA1c levels were significantly and positively correlated with fasting plasma glucose (FPG) levels at baseline. Receiver operating characteristic (ROC) curve analysis examining the relationship between HbA1c and FPG showed that FPG was a significant predictor of changes in HbA1c levels (area under the curve, 0.72). The cutoff FPG value of 168 mg/dL had a sensitivity of 47% and a specificity of 93%. Conclusions: Switching to a low dose of rosuvastatin impaired glucose metabolism in Japanese patients with type 2 diabetes and dyslipidemia. Patients with high FPG levels were particularly prone to an exacerbation of glucose metabolism.
  • Naoyuki Kitao, Hideaki Miyoshi, Tomoo Furumoto, Kota Ono, Hiroshi Nomoto, Aika Miya, Chiho Yamamoto, Atsushi Inoue, Kenichi Tsuchida, Naoki Manda, Yoshio Kurihara, Shin Aoki, Akinobu Nakamura, Tatsuya Atsumi
    CARDIOVASCULAR DIABETOLOGY 16 1 125  2017年10月 [査読有り][通常論文]
     
    Background: Dipeptidyl peptidase-4 (DPP-4) inhibitors may have protective effects in the early stage of atherosclerosis in patients with type 2 diabetes, although similar effects in advanced atherosclerosis were not shown in recent randomized placebo-controlled studies. Therefore, we investigated the efficacy of DPP-4 inhibitor on endothelial function and glycemic metabolism compared with high-dose metformin. Methods: In this multicenter, open-labeled, prospective, randomized, parallel-group comparison study, patients with type 2 diabetes treated with low-dose metformin (500-750 mg/day) were enrolled and randomly assigned to a vildagliptin, a DPP-4 inhibitor, add-on group (Vilda) or a double dose of metformin group (high Met) for 12 weeks. Flow-mediated dilation (FMD) and serum metabolic markers were assessed before and after treatment. In addition, glycemic control and metabolic parameters were also assessed. Results: Ninety-seven subjects (aged 58.7 +/- 11.0 years; body mass index, 25.9 +/- 4.4 kg/m(2); HbA1c, 7.3 +/- 0.5%; FMD, 5.8 +/- 2.6%) were enrolled. Eight subjects dropped out by the end of the study. There were no significant differences between the two groups in baseline characteristics. After 12 weeks, HbA1c was significantly improved in the Vilda group compared with the high Met group (-0.80 +/- 0.38% vs. -0.40 +/- 0.47%, respectively; p < 0.01). However, there were no significant differences in FMD (-0.51 [-1.08-0.06]% vs. -0.58 [-1.20-0.04]%). Although the apolipoprotein B/apolipoprotein A1 ratio was significantly reduced in the Vilda group compared with baseline (0.66-0.62; p < 0.01), the change did not differ significantly between the two groups (-0.04 vs. 0.00; p = 0.27). Adiponectin levels were significantly increased in the Vilda group compared with the high Met group (0.75 mu g/mL vs. 0.01 mu g/mL; p < 0.01). Conclusions: Regardless of glycemic improvement, combination therapy of vildagliptin and metformin did not affect endothelial function but may exert favorable effects on adipokine levels and lipid profile in patients with type 2 diabetes without advanced atherosclerosis.
  • 血管・動脈硬化 ペリリピン1過剰発現マウスにおける動脈硬化進展抑制効果についての検討
    山本 浩平, 三好 秀明, 野本 博司, Cho Kyu Yong, 中村 昭伸, 渥美 達也
    糖尿病合併症 31 Suppl.1 239 - 239 (一社)日本糖尿病合併症学会 2017年10月
  • 膵島・インスリン分泌 血清高分子アディポネクチン値とインスリン分泌との関連 DOSANCO Health studyによる検討
    中村 昭伸, 三好 秀明, 鵜川 重和, 中村 幸志, 中川 貴史, 寺内 康夫, 玉腰 暁子, 渥美 達也
    糖尿病合併症 31 Suppl.1 297 - 297 (一社)日本糖尿病合併症学会 2017年10月
  • 高瀬 崇宏, 三好 秀明, 海老原 裕磨, 川田 晋一朗, 続木 惇, 馬場 葉月, 半田 喬久, 土田 和久, 柳谷 真悟, 枝川 幸子, 大森 一乃, 高橋 清彦, 檀浦 みどり, 北尾 直之, 山本 浩平, 野本 博司, 曹 圭龍, 中村 昭伸, 平野 聡, 渥美 達也
    肥満研究 23 Suppl. 206 - 206 (一社)日本肥満学会 2017年09月
  • 續木 惇, 野本 博司, 土田 和久, 半田 喬久, 川田 晋一朗, 馬場 菜月, 柳谷 慎吾, 枝川 幸子, 大森 一乃, 高瀬 崇宏, 高橋 清彦, 檀浦 みどり, 北尾 直之, 山本 浩平, 曹 圭毅, 中村 昭伸, 三好 秀明, 渥美 達也
    肥満研究 23 Suppl. 207 - 207 (一社)日本肥満学会 2017年09月
  • Hiroshi Nomoto, Hideaki Miyoshi, Akinobu Nakamura, So Nagai, Naoyuki Kitao, Chikara Shimizu, Tatsuya Atsumi
    MEDICINE 96 39 e8147  2017年09月 [査読有り][通常論文]
     
    Rationale: Saccharated ferric oxide has been shown to lead to elevation of fibroblast growth factor 23, hypophosphatemia, and, consequently, osteomalacia. Moreover, mineral imbalance is often observed in patients with short-bowel syndrome to some degree. Patient concerns: A 62-year-old woman with short-bowel syndrome related with multiple resections of small intestines due to Crohn disease received regular intravenous administration of saccharated ferric oxide. Over the course of treatment, she was diagnosed with tetany, which was attributed to hypocalcemia. Additional assessments of the patient revealed not only hypocalcemia, but also hypophosphatemia, hypomagnesemia, osteomalacia, and a high concentration of fibroblast growth factor 23 (314 pg/mL). Diagnoses: We diagnosed her with mineral imbalance-induced osteomalacia due to saccharated ferric oxide and short-bowel syndrome. Interventions: Magnesium replacement therapy and discontinuation of saccharated ferric oxide alone. Outcomes: These treatments were able to normalize her serum mineral levels and increase her bone mineral density. Lessons: This case suggests that adequate evaluation of serum minerals, including phosphate and magnesium, during saccharated ferric oxide administration may be necessary, especially in patients with short-bowel syndrome.
  • Hiroshi Nomoto, Hideaki Miyoshi, Hajime Sugawara, Kota Ono, Shingo Yanagiya, Mayuko Oita, Akinobu Nakamura, Tatsuya Atsumi
    DIABETOLOGY & METABOLIC SYNDROME 9 54  2017年07月 [査読有り][通常論文]
     
    Background: Dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose co-transporter 2 (SGLT2) inhibitors improve hyperglycemia, and the usefulness of co-administration of DPP-4 inhibitors and insulin therapy has been well established. However, it has been still uncertain whether combination therapy of SGLT2 inhibitors and insulin is superior to that of DPP-4 inhibitors and the latter. Therefore, we investigated the superiority of dapagliflozin on glucose fluctuation compared with DPP-4 inhibitors in patients with type 2 diabetes mellitus (T2DM) on insulin using a continuous glucose monitoring (CGM) system. Methods: In this prospective, randomized, open-label controlled trial, 36 patients with T2DM and treated with DPP-4 inhibitors and insulin therapy, were enrolled and allocated into two groups. The patients either switched their DPP-4 inhibitors to dapagliflozin 5 mg for 12 weeks, or continued their DPP-4 inhibitors for the same period. CGM analyses and metabolic markers were assessed before and after treatment periods. Results: In total, data from 29 patients were analyzed. There were no significant differences in the mean amplitude of glycemic excursions and other CGM profiles in either group after treatment. Within the dapagliflozin treatment group, significant reductions of body mass index and albuminuria, and increases of HbA1c, hemoglobin and hematocrit were observed, but improvement of albuminuria was not significant if compared with the DPP-4 continuation group. Conclusions: Combination therapy of dapagliflozin and insulin was not superior in glucose fluctuation to DPP-4 inhibitors on insulin. However, dapagliflozin may in part provide favorable effects on metabolism in patients with T2DM treated with insulin therapy.
  • ペリリピン1過剰発現マウスにおける動脈硬化進展抑制効果についての検討
    山本 浩平, 三好 秀明, 野本 博司, 曹 圭龍, 中村 昭伸, 渥美 達也
    日本動脈硬化学会総会プログラム・抄録集 49回 198 - 198 (一社)日本動脈硬化学会 2017年06月
  • Aki Kondo, Akinobu Nakamura, Jun Takeuchi, Hideaki Miyoshi, Tatsuya Atsumi
    DIABETES CARE 40 6 E67 - E68 2017年06月 [査読有り][通常論文]
  • 腎移植前耐糖能異常症例では移植前OGTT60分値が耐糖能改善の予測因子である
    大森 一乃, 中村 昭伸, 岩見 大基, 三好 秀明, 寺内 康夫, 篠原 信雄, 渥美 達也
    糖尿病 60 Suppl.1 S - 265 (一社)日本糖尿病学会 2017年04月
  • A. Nakamura, D. Iwami, H. Miyoshi, K. Morita, M. Taguri, Y. Terauchi, N. Shinohara, T. Atsumi
    Diabetic Medicine 34 4 569 - 576 2017年04月
  • 北尾 直之, 中村 昭伸, 高橋 清彦, 山本 浩平, 野本 博司, チョウ 圭龍, 三好 秀明, 寺内 康夫, 渥美 達也
    日本内分泌学会雑誌 93 1 289 - 289 (一社)日本内分泌学会 2017年04月
  • 高瀬 崇宏, 野本 博司, 鬼頭 健一, 土田 和久, 平田 恵里奈, 柳谷 真悟, 枝川 幸子, 老田 真佑子, 大森 一乃, 近藤 亜樹, 高橋 清彦, 北尾 直之, 山本 浩平, 亀田 友香, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 93 1 337 - 337 (一社)日本内分泌学会 2017年04月
  • 檀浦 みどり, 竹内 淳, 大森 一乃, 高橋 清彦, 北尾 直之, 山本 浩平, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 93 1 356 - 356 (一社)日本内分泌学会 2017年04月
  • インスリン使用中の2型糖尿病患者におけるDPP-4阻害薬からダパグリフロジンへの切替え効果(第二報)
    土田 和久, 野本 博司, 枝川 幸子, 鬼頭 健一, 平田 恵里奈, 柳谷 慎吾, 老田 真佑子, 大森 一乃, 高瀬 崇宏, 高橋 清彦, 北尾 直之, 山本 浩平, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也
    糖尿病 60 Suppl.1 S - 146 (一社)日本糖尿病学会 2017年04月
  • テルミサルタン合剤を用いた糖尿病腎症合併2型糖尿病患者におけるARBの次に追加すべき降圧薬の検討
    山本 浩平, 野本 博司, 宮 愛香, 近藤 琢磨, 栗原 義夫, 青木 伸, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也
    糖尿病 60 Suppl.1 S - 238 (一社)日本糖尿病学会 2017年04月
  • 持続血糖モニタリング下で術前オクトレオチド投与を行い低血糖の消失を確認できたインスリノーマの一例
    老田 真佑子, 柳谷 真悟, 土田 和久, 大森 一乃, 高瀬 崇宏, 高橋 清彦, 北尾 直之, 山本 浩平, 亀田 友香, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也
    糖尿病 60 Suppl.1 S - 252 (一社)日本糖尿病学会 2017年04月
  • SGLT2阻害薬Luseogliflozinの膵β細胞保護作用
    高橋 清彦, 中村 昭伸, 大森 一乃, 北尾 直之, 野本 博司, 三好 秀明, 寺内 康夫, 渥美 達也
    糖尿病 60 Suppl.1 S - 395 (一社)日本糖尿病学会 2017年04月
  • 短期高脂肪食負荷誘導性膵β細胞増殖メカニズムの検討
    北尾 直之, 中村 昭伸, 山本 浩平, 野本 博司, 曹 圭龍, 三好 秀明, 寺内 康夫, 渥美 達也
    日本臨床分子医学会学術総会プログラム・抄録集 54回 75 - 75 日本臨床分子医学会 2017年04月
  • 日本人の耐糖能障害における加齢の影響 DOSANCO Health studyによる検討
    中村 昭伸, 三好 秀明, 鵜川 重和, 中村 幸志, 中川 貴史, 玉腰 暁子, 渥美 達也
    糖尿病 60 Suppl.1 S - 149 (一社)日本糖尿病学会 2017年04月
  • Atsushi Narahira, Teruki Yanagi, Kyu Yong Cho, Akinobu Nakamura, Hideaki Miyoshi, Hiroo Hata, Keisuke Imafuku, Shinya Kitamura, Hiroshi Shimizu
    JOURNAL OF DERMATOLOGY 44 4 E70 - E70 2017年04月 [査読有り][通常論文]
  • Kiyohiko Takahashi, Akinobu Nakamura, Hideaki Miyoshi, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, So Nagai, Chikara Shimizu, Masataka Taguri, Yasuo Terauchi, Tatsuya Atsumi
    ENDOCRINE JOURNAL 64 4 387 - 392 2017年04月 [査読有り][通常論文]
     
    We attempted to identify the predictors of an inadequate hypoglycemia in insulin tolerance test (ITT), defined as a blood glucose level higher than 2.8 mmol/L after insulin injection, in Japanese patients with suspected or proven hypopituitarism. A total of 78 patients who had undergone ITT were divided into adequate and inadequate hypoglycemia groups. The relationships between the subjects' clinical parameters and inadequate hypoglycemia in ITT were analyzed. Stepwise logistic regression analysis identified high systolic blood pressure (SBP) and high homeostasis model assessment of insulin resistance (HOMA-IR) as being independent factors associated with inadequate hypoglycemia in ITT. Receiver operating characteristic (ROC) curve analysis revealed the cutoff value for inadequate hypoglycemia was 109 mmHg for SBP and 1.4 for HOMA-IR. The areas under ROC curve for SBP and HOMA-IR were 0.72 and 0.86, respectively. We confirmed that high values of SBP and HOMA-IR were associated with inadequate hypoglycemia in ITT, regardless of the degree of reduction of pituitary hormone levels. Furthermore, the strongest predictor of inadequate hypoglycemia was obtained by using the cutoff value of HOMA-IR. Our results suggest that HOMA-IR is a useful pre-screening tool for ITT in these populations.
  • Hiroshi Nomoto, Kimihiko Kimachi, Hideaki Miyoshi, Hiraku Kameda, Kyu Yong Cho, Akinobu Nakamura, So Nagai, Takuma Kondo, Tatsuya Atsumi
    ENDOCRINE JOURNAL 64 4 417 - 424 2017年04月 [査読有り][通常論文]
     
    To date, several clinical trials have compared differences in glucose fluctuation observed with dipeptidyl peptidase-4 inhibitor treatment in patients with type 2 diabetes mellitus. However, most patients were assessed for limited periods or during hospitalization. The aim of the present study was to evaluate the effects of switching from sitagliptin to vildagliptin, or vice versa, on 12-week glucose fluctuations using self-monitoring of blood glucose in the standard care setting. We conducted a multicenter, prospective, open-label controlled trial in Japanese patients with type 2 diabetes. Thirty-two patients were treated with vildagliptin (50 mg) twice daily or sitagliptin (50 mg) once daily and were allocated to one of two groups: vildagliptin treatment for 12 weeks before switching to sitagliptin for 12 weeks, or vice versa. Daily profiles of blood glucose were assessed several times during each treatment period, and the mean amplitude of glycemic excursions and M-value were calculated. Metabolic biomarkers such as hemoglobin Alc (HbAlc), glycated albumin, and 1,5-anhydroglucitol were also assessed. With vildagliptin treatment, mean amplitude of glycemic excursions was significantly improved compared with sitagliptin treatment (57.9 +/- 22.2 vs. 68.9 +/- 33.0 mg/dL; p=0.0045). M-value (p=0.019) and mean blood glucose (p=0.0021) were also lower with vildagliptin, as were HbAlc, glycated albumin, and 1,5-anhydroglucitol. There were no significant differences in other metabolic parameters evaluated. Reduction of daily blood glucose profile fluctuations by vildagliptin was superior to that of sitagliptin in Japanese patients with type 2 diabetes.
  • Junko Hamai, Akinobu Nakamura, Shingo Kato, Yasuo Terauchi
    Diabetology international 8 1 23 - 29 2017年03月 [査読有り][通常論文]
     
    Purpose: Cardiac magnetic resonance imaging (MRI) can provide noninvasive and accurate quantitative assessment of the left ventricular (LV) structure and function. We investigated the association between LV MRI measures and glycemic control in patients with old myocardial infarction (OMI). Materials and methods: The study population consisted of 51 OMI patients. By using a 1.5-T MRI scanner, we acquired cine MRI and late gadolinium-enhanced MRI. We calculated the LV volume, LV mass (LVM), LV function and percentage of infarcted myocardial volume over the total LV myocardial volume (%LGE). Patients were allocated to three groups: normal glucose tolerance (NGT), n = 9; impaired glucose tolerance (IGT)/impaired fasting glucose (IFG), n = 15; diabetes mellitus (DM), n = 27; respectively. Results: LVM was significantly increased in the DM group compared with the NGT group (p = 0.002). Multiple linear regression analysis demonstrated that HbA1c levels were significantly and independently associated with LVM after adjustment for risk factors of congestive heart failure and  %LGE (p = 0.009). The LV ejection fraction (EF) was not associated with HbA1c levels. Conclusion: Our findings suggest that glucose tolerance in patients with OMI may be associated with LV wall thickness. LVM calculation by cine MRI might be useful for longitudinal follow-up of the effect of diabetic treatment on OMI patients.
  • Hiroshi Nomoto, Hideaki Miyoshi, Akinobu Nakamura, Tatsuya Atsumi, Naoki Manda, Yoshio Kurihara, Shin Aoki, on behalf of SAIS Study Group
    Clinical Trials in Degenerative Diseases 2 1 2017年
  • Hiroshi Nomoto, Hideaki Miyoshi, Akinobu Nakamura, Tatsuya Atsumi, Naoki Manda, Yoshio Kurihara, Shin Aoki
    Current Trends in Cardiology 01 01 2017年
  • Takahiro Takase, Akinobu Nakamura, Hideaki Miyoshi, Chiho Yamamoto, Tatsuya Atsumi
    ENDOCRINE JOURNAL 64 3 363 - 367 2017年 [査読有り][通常論文]
     
    In this study, we investigated the ameliorating effects of ipragliflozin on fatty liver in patients with type 2 diabetes. The factors that influenced the amelioration of fatty liver were also examined. Analysis included data of 21 Japanese patients with type 2 diabetes obtained from our prospective observational study. After obtaining patients' informed consent, once-daily ipragliflozin (50 mg/day) was given for 16 weeks. In addition to several clinical parameters, body composition was also compared before and after 16 weeks of treatment. The extent of fatty liver was estimated using a fatty liver index (FLI). After 16 weeks, FLI significantly decreased, from 70.1 +/- 19.4 to 60.3 +/- 25.5 (p = 0.0009) as well as levels of fasting plasma glucose (FPG), HbA1c, body weight, visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and fat mass. To reveal the factors influencing the FLI changes observed on ipragliflozin treatment, correlations between changes in FLI and several other measured parameters were examined. Changes in FPG (correlation coefficient = 0.4683, p = 0.0323) and HbA1c (correlation coefficient = 0.4383, p = 0.0469) showed significant positive correlations with changes in FLI. On the other hand, no correlations of changes in FLI were observed with body weight, VAT, SAT nor fat mass. In conclusion, ipragliflozin ameliorated FLI in Japanese patients with type 2 diabetes. Improvement in FLI was associated with that of glucose intolerance.
  • Kyu Yong Cho, Hideaki Miyoshi, Akinobu Nakamura, Takashi Kurita, Tatsuya Atsumi
    ENDOCRINE JOURNAL 64 2 235 - 236 2017年 [査読有り][通常論文]
  • 佐藤 三穂, 佐藤 仁美, 鷲見 尚己, 中村 昭伸, 三好 秀明, 渥美 達也
    糖尿病ケア 13 12 1146 - 1150 (株)メディカ出版 2016年12月 
    特定機能病院における糖尿病療養支援の方向性について、看護師の視点から明らかにすることを目的に、2012年1月〜12月に特定機能病院である当院の糖尿病専門外来を初診で受診した糖代謝異常患者399名(男性209名、女性190名、平均年齢58±16歳)の診療録を後ろ向きに調査した。その結果、初診患者の27.1%が周術期管理目的で、初診時から1年以上継続して当外来を受診している患者は31.1%、1年間に外来看護師による看護介入があったのは11.5%であった。これらの結果に、複数の診療科を有し専門的治療の役割を担う特定機能病院の特徴を勘案し、特定機能病院における糖尿病療養支援の方向性として、周術期、または糖尿病以外の疾患を抱える糖尿病患者への支援、病診連携による医療スタッフ間の効果的な情報共有や連携方法の検討、さらに療養支援が必要な患者を拾い上げて効果的なタイミングで介入するための、看護師と医師の情報共有やスクリーニングの方法について、今後検討していく必要があると考えられた。
  • 鬼頭 健一, 曹 圭龍, 土田 和久, 平田 恵里奈, 柳谷 真悟, 老田 真佑子, 大森 一乃, 高瀬 崇宏, 高橋 清彦, 北尾 直之, 山本 浩平, 亀田 友香, 野本 博司, 中村 昭伸, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 92 S.Branc 12 - 12 (一社)日本内分泌学会 2016年12月
  • Junko Oikawa, Koshi Nakamura, Shigekazu Ukawa, Tomoko Kishi, Akinobu Nakamura, Akiko Tamakoshi
    Diabetology international 7 4 391 - 397 2016年12月 [査読有り][通常論文]
     
    Using data on health checkups performed in one Japanese town, we investigated the effect on health checkups of the methods used to measure hemoglobin A1c (HbA1c). The study included 337 participants undergoing health checkups at two facilities. At facility 1, HbA1c was measured by high-performance liquid chromatography (HPLC) in 2012 and by immunoassay (IA) in 2013, while at facility 2, HbA1c was measured by HPLC in both years. At facility 1, the mean HbA1c was significantly decreased from 2012 to 2013 (5.83 vs 5.50 %, respectively; P < 0.001), although the mean fasting plasma glucose (FPG) was significantly increased from 2012 to 2013 (91.7 vs 95.2 mg/dL, respectively; P = 0.02). Of the 202 participants at facility 1, 97 who had an HbA1c of ≥5.6 % in 2012 had an HbA1c of <5.6 % in 2013. At facility 2, the mean HbA1c marginally increased, while there were similar FPG levels in both years. An additional study of single blood samples from 27 healthy participants who were tested at the same facility using both HPLC and IA found that the mean HbA1c was significantly lower for IA than for HPLC (5.19 vs 5.50 %, respectively; P < 0.001). In summary, we found a substantial decrease in the mean HbA1c and the prevalence of impaired glucose tolerance and diabetes mellitus in study participants who underwent health checkups for two consecutive years when different methods were used to measure HbA1c. The lack of standardization of HbA1c measurement methods may have a large effect on health checkups.
  • 老田 真佑子, 中村 昭伸, 枝川 幸子, 大森 一乃, 高瀬 崇宏, 近藤 亜樹, 菅原 基, 一山 芽衣, 山本 浩平, 山本 知穂, 亀田 友香, 野本 博司, 曹 圭龍, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 92 2 481 - 481 (一社)日本内分泌学会 2016年10月
  • 大森 一乃, 老田 真佑子, 高瀬 崇宏, 高橋 清彦, 北尾 直之, 山本 浩平, 山本 知穂, 亀田 友香, 野本 博司, ちょう 圭龍, 中村 昭伸, 永井 聡, 清水 力, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 92 2 489 - 489 (一社)日本内分泌学会 2016年10月
  • 高橋 由華, 曹 圭龍, 大森 一乃, 老田 真佑子, 高瀬 崇宏, 高橋 清彦, 北尾 直之, 山本 浩平, 亀田 友香, 野本 博司, 中村 昭伸, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 92 2 495 - 495 (一社)日本内分泌学会 2016年10月
  • 山本 知穂, 亀田 啓, 三好 秀明, 柳町 剛司, 藤田 征弘, 園田 祥子, 千葉 活, 高瀬 崇弘, 半田 喬久, チョウ 圭龍, 中村 昭伸, 永井 聡, 清水 力, 浄土 智
    日本内分泌学会雑誌 92 2 461 - 461 (一社)日本内分泌学会 2016年10月
  • Naohide Koyanagawa, Hideaki Miyoshi, Kota Ono, Akinobu Nakamura, Kyu Yong Cho, Kohei Yamamoto, Yoshinari Takano, Midori Dan-noura, Tatsuya Atsumi
    ENDOCRINE JOURNAL 63 8 747 - 753 2016年08月 [査読有り][通常論文]
     
    The dipeptidyl peptidase-4 inhibitors vildagliptin and sitagliptin are effective in treating patients with type 2 diabetes mellitus. Patients receiving standard doses of sitagliptin plus insulin may require increased doses of sitagliptin or switching to vildagliptin to improve blood glucose control. This study compared the effects of increasing sitagliptin and switching to vildagliptin in type 2 diabetes patients receiving standard doses of sitagliptin plus insulin. This prospective, randomized, parallel-group comparison trial enrolled 33 type 2 diabetes patients receiving 50 mg sitagliptin once daily plus insulin. Seventeen patientg were randomized to 50 mg vildagliptin twice daily, and 16 to 100 mg sitagliptin once daily, and evaluated by continuous glucose monitoring at baseline and after 8 weeks. The primary end-point was the change in mean amplitude of glycemic excursions (MAGE). MAGE decreased from baseline in both the vildagliptin (-13.4 +/- 35.7 mg/dL) and sitagliptin (-8.4 +/- 24.3 mg/dL) groups, but neither within-nor between-group changes were statistically significant. Similarly, the areas under the curve for blood glucose levels >= 180 mg/dL and <70 mg/dL tended to improve in both groups, but these differences were not statistically significant. In contrast, HbAlc was significantly reduced only in the vildagliptin group, from 7.1 +/- 0.6% at baseline to 6.8 +/- 0.6% at 8 weeks (p=0.006). Increasing sitagliptin dose and switching to vildagliptin had limited effects in improving MAGE in type 2 diabetic patients treated with standard doses of sitagliptin.
  • 高瀬 崇宏, 三好 秀明, 亀田 玲奈, 枝川 幸子, 老田 真佑子, 大森 一乃, 近藤 亜樹, 菅原 基, 宮 愛香, 山本 知穂, 亀田 友香, 中村 昭伸, 渥美 達也
    Diabetes Frontier Online 3 e1 004 - 004 2016年06月21日 [査読有り]
  • Chiho Yamamoto, Hideaki Miyoshi, Kota Ono, Hajime Sugawara, Reina Kameda, Mei Ichiyama, Kohei Yamamoto, Hiroshi Nomoto, Akinobu Nakamura, Tatsuya Atsumi
    ENDOCRINE JOURNAL 63 6 589 - 596 2016年06月 [査読有り][通常論文]
     
    To investigate if ipraglifiozin, a novel sodium-glucose co-transporter 2 inhibitor, alters body composition and to identify variables associated with reductions in visceral adipose tissue in Japanese patients with type 2 diabetes mellitus. This prospective observational study enrolled Japanese participants with type 2 diabetes mellitus. Subjects were administered ipraglifiozin (50 mg/day) once daily for 16 weeks. Body composition, visceral adipose tissue volume and plasma variables were measured at 0, 8, and 16-weeks. The subjects' lifestyle habits including diet and exercise were evaluated at baseline and 16 weeks. The primary endpoint was defined as the decrease of visceral adipose tissue mass. Twenty-four of 26 enrolled participants completed the study. The visceral adipose tissue decreased significantly (110 +/- 33 to 101 +/- 36 cm(2), p = 0.005) as well as other parameters for metabolic insufficiency including hemoglobin A1c. Seventy-one % of the total body weight reduction (-2.49 kg) was estimated by a decrease in fat mass (-1.77 kg), and the remaining reduction (22%) by water volume (-0.55 kg). A minor but significant reduction in the skeletal muscle index was also observed. Correlation analyses were performed to identify variables associated with changes in visceral adipose tissue and the only significant variable identified was diet therapy (Spearman's r = -0.416, p = 0.043). Ipragliflozin significantly decreased visceral adipose tissue, and improved parametres for metabolic dysfunction. Adequate diet therapy would be necessary to induce and enhance the therapeutic merit.
  • 中村 昭伸, 岩見 大基, 三好 秀明, 森田 研, 田栗 正隆, 寺内 康夫, 篠原 信雄, 渥美 達也
    日本内分泌学会雑誌 92 1 213 - 213 (一社)日本内分泌学会 2016年04月
  • 日本人腎移植症例における移植2年後の耐糖能の推移
    大森 一乃, 中村 昭伸, 岩見 大基, 三好 秀明, 森田 研, 篠原 信雄, 渥美 達也
    糖尿病 59 Suppl.1 S - 295 (一社)日本糖尿病学会 2016年04月
  • シタグリプチンとグリメピリドの抗動脈硬化作用及び膵β細胞機能改善効果における比較研究Sapporo Athero-Incretin Study 1
    野本 博司, 三好 秀明, 古本 智夫, 井上 篤, 曹 圭龍, 中村 昭伸, 渥美 達也, 萬田 直紀, 栗原 義夫, 青木 伸
    糖尿病 59 Suppl.1 S - 290 (一社)日本糖尿病学会 2016年04月
  • Yumiko Komatsu, Akinobu Nakamura, Masahiro Takihata, Yuichiro Inoue, Satoko Yahagi, Kazuki Tajima, Hirohisa Tsuchiya, Tatsuro Takano, Tadashi Yamakawa, Masahiro Yoshida, Hideaki Miyoshi, Yasuo Terauchi
    ENDOCRINE JOURNAL 63 3 311 - 314 2016年03月 [査読有り][通常論文]
     
    Diazoxide is a non-diuretic benzothiadiazine derivative, one of a group of substances introduced into clinical practice in the 1950s for the treatment of hypertension. Fajans reported the use of diazoxide for the treatment of insulinoma in 1979. Although patients with hyperinsulinemic hypoglycemia worldwide have been treated with diazoxide for more than 30 years, there are no recent reports about the adverse effects of this drug in Asian patients, including Japanese patients. Herein, we report the results of our retrospective clinical record review of 6 Japanese patients (3 females and 3 males, ranging in age from 58 to 91 years) with hyperinsulinemic hypoglycemia and inoperable insulinoma treated with diazoxide. Diazoxide improved control of hypoglycemic symptoms and maintained normoglycemia in 5 of the 6 patients, and was ineffective in one patient. Surprisingly, although all 6 patients received diazoxide according to the treatment strategy recommended in Western patients, 5 of the 6 patients developed edema and two developed congestive heart failure. Thus, when starting treatment with diazoxide in Japanese patients, the symptoms and signs of fluid retention should be evaluated carefully. Also, appropriate protocols for treatment with diazoxide should be evaluated by means of clinical trials in Japanese patients with hyperinsulinemic hypoglycemia.
  • 腎移植後に耐糖能異常は改善される
    中村 昭伸, 岩見 大基, 三好 秀明, 森田 研, 寺内 康夫, 篠原 信雄, 渥美 達也
    日本内科学会雑誌 105 Suppl. 253 - 253 (一社)日本内科学会 2016年02月
  • Akinobu Nakamura, Tomoko Mitsuhashi, Yoshinari Takano, Hideaki Miyoshi, Hiraku Kameda, Hiroshi Nomoto, So Nagai, Yutaka Hatanaka, Chikara Shimizu, Yasuo Terauchi, Tatsuya Atsumi
    ENDOCRINE JOURNAL 63 2 135 - 142 2016年02月 [査読有り][通常論文]
     
    We investigated the relationship between the results of the octreotide test and somatostatin receptor (SSTR) 2 expression in insulinoma patients, to evaluate the usefulness of this test for predicting SSTR2 expression in insulinomas in Japanese patients. Five females and one male were included in the study. All patients underwent the octreotide test before the surgery carried out to resect the tumor, and histopathological examination of the resected tumor was performed by a single experienced pathologist. SSTR2 expression was evaluated by the SSTR2 immunohistochemistry scoring system. Insulinoma was clinically diagnosed and surgically resected in all six patients. In the octreotide test, suppression of insulin secretion was sufficient after loading in patients 1-4 and 6. In patient 5, however, the suppression of insulin secretion was insufficient, which resulted in severe hypoglycemia with endogenous relative hyperinsulinemia after the octreotide loading. The histopathological findings revealed SSTR2 expression in the insulinomas of patients 1-4 and 6, but not in the insulinoma of patient 5. In conclusion, improvement of hyperinsulinemic hypoglycemia by octreotide in Japanese insulinoma patients was associated with SSTR2 expression in the tumor. Our results suggest that the octreotide test could be useful for predicting SSTR2 expression in the tumor.
  • Chiho Yamamoto, Hideaki Miyoshi, Yutaka Fujiwara, Reina Kameda, Mei Ichiyama, Hiroshi Nomoto, Hiraku Kameda, Akinobu Nakamura, Tatsuya Atsumi
    ENDOCRINE JOURNAL 63 1 53 - 60 2016年01月 [査読有り][通常論文]
     
    To investigate the differences in glycemic variability between the long-acting insulins glargine and degludec using continuous glucose monitoring, we conducted an open-label, multicenter, prospective, observational study that enrolled 21 participants with type 1 diabetes mellitus currently receiving basal-bolus insulin therapy with glargine. To avoid the potential influence of diet and exercise on glycemic control, all participants were housed and monitored within the hospital for the duration of the study. Once glycemic control was achieved with glargine, glycemic variability was evaluated using continuous glucose monitoring for 3 days. Glargine was then replaced by degludec and glycemic variability again assessed via continuous glucose monitoring. The primary outcome measure of mean amplitude of glycemic excursions was significantly reduced with degludec (p = 0.028), as was area under the curve for daily blood glucose level <70 mg/dL (p = 0.046). The required insulin dose was reduced up to 25% in the degludec group, although 24-h mean glucose concentrations were not different between groups. In conclusion, once or twice daily glargine was successfully replaced by a daily injection of degludec. When replacing glargine with degludec, a lower dose should be utilized to avoid hypoglycemia. Degludec is an effective and promising long-acting insulin that reduced hypoglycemia and daily blood glucose variability in participants with type 1 diabetes.
  • Arina Miyoshi, Mai Yamada, Haruki Shida, Daigo Nakazawa, Yoshihiro Kusunoki, Akinobu Nakamura, Hideaki Miyoshi, Utano Tomaru, Tatsuya Atsumi, Akihiro Ishizu
    Pathobiology : journal of immunopathology, molecular and cellular biology 83 5 243 - 51 2016年 [査読有り][通常論文]
     
    OBJECTIVES: Although intensive therapy for type 2 diabetes (T2D) prevents microvascular complications, 10% of well-controlled T2D patients develop microangiopathy. Therefore, the identification of risk markers for microvascular complications in well-controlled T2D patients is important. Recent studies have demonstrated that high-dose glucose induces neutrophil extracellular trap (NET) formation, which can be a risk for microvascular disorders. Thus, we attempted to determine the correlation of circulating NET levels with clinical/laboratory parameters in well-controlled T2D patients and to reveal the mechanism of NET formation induced by high-dose glucose. METHODS: Circulating NET levels represented by myeloperoxidase (MPO)-DNA complexes in the serum of 11 well-controlled T2D patients and 13 healthy volunteers were determined by enzyme-linked immunosorbent assay. The pathway involved in the NET formation induced by high-dose glucose was determined using specific inhibitors. RESULTS: Serum MPO-DNA complex levels were significantly higher in some well-controlled T2D patients in correlation with the clinical/laboratory parameters which have been regarded as risk markers for microvascular complications. The aldose reductase inhibitor, ranirestat, could inhibit the NET formation induced by high-dose glucose. CONCLUSIONS: Elevated levels of circulating NETs can be a risk marker for microvascular complications in well-controlled T2D patients. The polyol pathway is involved in the NET formation induced by high-dose glucose.
  • Miya A, Nakamura A, Miyoshi H, Kameda H, Nomoto H, Nagai S, Omori Y, Hatanaka CK, Kobayashi H, Shimizu C, Atsumi T
    International Journal of Diabetes and Clinical Research 2 6 2015年12月31日 [査読有り]
  • Nomoto H, Kondo T, Miyoshi H, Nakamura A, Hida Y, Yamashita K, Sharma AJ, Atsumi T
    Endocrinology 156 10 3570 - 3580 2015年10月 [査読有り][通常論文]
     
    The large-Maf transcription factor v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA) has been found to be crucial for insulin transcription and synthesis and for pancreatic beta-cell function and maturation. However, insights about the effects of small Maf factors on beta-cells are limited. Our goal was to elucidate the function of small-Maf factors on beta-cells using an animal model of endogenous small-Maf dysfunction. Transgenic (Tg) mice with beta-cell-specific expression of dominant-negative MafK (DN-MafK) experiments, which can suppress the function of all endogenous small-Mafs, were fed a high-fat diet, and their in vivo phenotypes were evaluated. Phenotypic analysis, glucose tolerance tests, morphologic examination of beta-cells, and islet experiments were performed. DN-MafK-expressed MIN6 cells were also used for in vitro analysis. The results showed that DN-MafK expression inhibited endogenous small-Maf binding to insulin promoter while increasing MafA binding. DN-MafK Tg mice under high-fat diet conditions showed improved glucose metabolism compared with control mice via incremental insulin secretion, without causing changes in insulin sensitivity or MafA expression. Moreover, up-regulation of insulin and glucokinase gene expression was observed both in vivo and in vitro under DN-MafK expression. We concluded that endogenous small-Maf factors negatively regulates beta-cell function by competing for MafA binding, and thus, the inhibition of small-Maf activity can improve beta-cell function.
  • 1型糖尿病患者におけるインスリンデグルデクの血糖変動の検討
    瀧本 理子, 北尾 直之, 山本 知穂, 一山 芽衣, 宮 愛香, 山本 浩平, 三次 有奈, 野本 博司, 中村 昭伸, 三好 秀明, 渥美 達也
    糖尿病 58 9 723 - 723 (一社)日本糖尿病学会 2015年09月
  • 2型糖尿病患者におけるインスリンをベースとしたシタグリプチンとビルダグリプチンの血糖変動に及ぼす効果
    檀浦 みどり, 小梁川 直秀, 宮 愛香, 一山 芽衣, 山本 知穂, 山本 浩平, 野本 博司, 中村 昭伸, 三好 秀明, 渥美 達也
    糖尿病 58 9 723 - 723 (一社)日本糖尿病学会 2015年09月
  • 2型糖尿病に対するリキシセナチドと基礎インスリン製剤との併用療法の有用性
    重沢 郁美, 宮 愛香, 中村 昭伸, 橋本 玲奈, 北尾 直之, 一山 芽衣, 山本 知穂, 野本 博司, 三好 秀明, 渥美 達也
    糖尿病 58 9 732 - 732 (一社)日本糖尿病学会 2015年09月
  • 自己血糖測定器(SMBG)を用いたシタグリプチンとビルダグリプチン投与下血糖変動の交差比較
    一山 芽衣, 耒海 公彦, 北尾 直之, 宮 愛香, 山本 知穂, 山本 浩平, 野本 博司, 亀田 啓, 中村 昭伸, 三好 秀明, 渥美 達也
    糖尿病 58 9 736 - 736 (一社)日本糖尿病学会 2015年09月
  • 2型糖尿病患者におけるSGLT2阻害薬の有効性の検討
    山本 知穂, 橋本 玲奈, 北尾 直之, 一山 芽衣, 宮 愛香, 山本 浩平, 三次 有奈, 野本 博司, 中村 昭伸, 三好 秀明, 渥美 達也
    糖尿病 58 9 738 - 738 (一社)日本糖尿病学会 2015年09月
  • Yuichiro Inoue, Akinobu Nakamura, Yoshinobu Kondo, Kumiko Hamano, Shinobu Satoh, Yasuo Terauchi
    JOURNAL OF CLINICAL PHARMACOLOGY 55 7 831 - 838 2015年07月 [査読有り][通常論文]
     
    This study aimed to compare the efficacy and safety of liraglutide versus insulin detemir plus sitagliptin in Japanese patients with type 2 diabetes treated with a basal-bolus insulin regimen. In this multicenter, open-label trial, 90 patients whose diabetes had been controlled well or moderately (glycated hemoglobin [HbA(1c)] 7.3%) with basal-bolus insulin regimen were randomly assigned to a liraglutide group or a detemir group and were followed up for 24 weeks. The primary end point was HbA(1c) change from baseline to 24 weeks. Of the 90 enrolled patients, 82 completed this trial. At 24 weeks, the mean changes in HbA(1c) from baseline were 0.1%+/- 0.9% versus 0.3%+/- 0.8% in the liraglutide versus detemir groups, respectively (P=.46). The overall satisfaction score for the Diabetes Treatment Satisfaction Questionnaire changed from 25.2 +/- 7.4 to 29.9 +/- 5.3 (P<.001) and from 26.4 +/- 6.1 to 28.3 +/- 6.4 (P=.12) in the liraglutide and detemir groups, respectively. Although the mean change difference in HbA(1c) between both groups was not significant, switching from a basal-bolus insulin regimen to liraglutide once daily improved patient satisfaction levels without loss of glycemic control.
  • Masahiro Takihata, Akinobu Nakamura, Yoshinobu Kondo, Satsuki Kawasaki, Mari Kimura, Yasuo Terauchi
    PLOS ONE 10 5 e0125519  2015年05月 [査読有り][通常論文]
     
    Objective This study compared the efficacy and safety of azelnidipine with that of trichlormethiazide in Japanese type 2 diabetic patients with hypertension. Methods In a multicenter, open-label trial, 240 patients with adequately controlled diabetes (HbA1c <= 7.0%) under lifestyle modification and/or administration of hypoglycemic agents and inadequately controlled hypertension (systolic blood pressure [sBP] >= 130 mmHg or diastolic blood pressure [dBP] >= 80 mmHg) who were being treated with olmesartan were enrolled. Participants were randomly assigned to an azelnidipine group or a trichlormethiazide group and were followed up for 48 weeks. Main outcome measure was the difference in the change in HbA1c levels from the baseline values at 48 weeks between these two groups. Results Of the 240 subjects that were enrolled, 209 subjects (azelnidipine group: 103 patients, trichlormethiazide group: 106 patients) completed this trial. At 48 weeks, the following changes were observed in the azelnidipine and trichlormethiazide groups, respectively: HbA1c levels, 0.19 +/- 0.52% and 0.19 +/- 0.54%; sBP/dBP, -10.7 +/- 9.6/-6.6 +/- 6.6 mmHg and -7.1 +/- 7.7/-3.3 +/- 6.1 mmHg (P < 0.001 for both sBP and dBP). In both groups, dizziness (12 patients [11.7%] and 16 patients [15.1%]) and edema (16 patients [15.5%] and 7 patients [6.6%], P = 0.047) were observed during the 48-week follow-up period. Conclusions Azelnidipine was more effective for controlling blood pressure than trichlormethiazide in Japanese type 2 diabetes patients, whereas trichlormethiazide was more effective for reducing albuminuria than azelnidipine. Both of these agents, however, similarly exacerbated glycemic control in type 2 diabetic patients with hypertension.
  • 特定機能病院おける糖尿病外来初診患者の臨床的特徴
    佐藤 三穂, 佐藤 仁美, 鷲見 尚己, 中村 昭伸, 三好 秀明, 渥美 達也
    糖尿病 58 Suppl.1 S - 312 (一社)日本糖尿病学会 2015年04月 [査読有り][通常論文]
  • 腎移植前後の耐糖能の推移に関する検討
    中村 昭伸, 岩見 大基, 三好 秀明, 森田 研, 篠原 信雄, 渥美 達也
    糖尿病 58 Suppl.1 S - 355 (一社)日本糖尿病学会 2015年04月
  • 腎移植が耐糖能に与える影響
    中村 昭伸, 岩見 大基, 三好 秀明, 森田 研, 篠原 信雄, 寺内 康夫, 渥美 達也
    日本臨床分子医学会学術総会プログラム・抄録集 52回 71 - 71 日本臨床分子医学会 2015年04月
  • 当院におけるリナグリプチンの2型糖尿病腎症に対する尿アルブミン量減少効果についての検討
    菅原 基, 宮 愛香, 野本 博司, 高橋 清彦, 檀浦 みどり, 橋本 玲奈, 北尾 直之, 三次 有奈, 山本 浩平, 山本 知穂, 中村 昭伸, 三好 秀明, 渥美 達也
    糖尿病 58 Suppl.1 S - 303 (一社)日本糖尿病学会 2015年04月
  • Akinobu Nakamura, Yasuo Terauchi
    JOURNAL OF DIABETES INVESTIGATION 6 2 124 - 132 2015年03月 [査読有り][通常論文]
     
    Glucokinase is one of four members of the hexokinase family of enzymes. Its expression is limited to the major organs (such as the pancreas, liver, brain and the gastrointestinal tract) that are thought to have an integrated role in glucose sensing. In the liver, phosphorylation of glucose by glucokinase promotes glycogen synthesis, whereas in the -cells, it results in insulin release. Studies of glucokinase-linked genetically-modified mice and mutations in humans have illustrated the important roles played by glucokinase in whole-body glucose homeostasis, and suggest that the use of pharmacological agents that augment glucokinase activity could represent a viable treatment strategy in patients with type 2 diabetes. Since 2003, many glucokinase activators (GKAs) have been developed, and their ability to lower the blood glucose has been shown in several animal models of type 2 diabetes. Also, we and others have shown in mouse models that GKAs also have the effect of stimulating the proliferation of -cells. However, the results of recent phase II trials have shown that GKAs lose their efficacy within several months of use, and that their use is associated with a high incidence of hypoglycemia; furthermore, patients treated with GKAs frequently developed dyslipidemia. A better understanding of the role of glucokinase in metabolic effects is required to resolve several issues identified in clinical trials.
  • 宮 愛香, 山本 知穂, 一山 芽衣, 北尾 直之, 山本 浩平, 三次 有奈, 野本 博司, 中村 昭伸, 三好 秀明, 渥美 達也, 亀田 啓
    北海道医学雑誌 89 2 159 - 160 北海道医学会 2014年11月
  • Nakamura Akinobu, Yoneda Masato, Sumida Yoshio, Miyoshi Hideaki, Nakajima Atsushi, Atsumi Tatsuya, Terauchi Yasuo
    Journal of Gastrointestinal & Digestive System 4 5 221 - 221 OMICS International 2014年10月 
    Japanese patients with nonalcoholic fatty liver disease (NAFLD) according to the presence/absence of obesity. Methods: A total of 141 Japanese patients with liver-biopsy-confirmed NAFLD were enrolled. All patients were classified as having nonalcoholic fatty liver (NAFL) or nonalcoholic steatohepatitis (NASH) on the basis of Matteoni's classification. Obesity was defined as a body mass index of ≥25. To evaluate the overall accuracy of the NAFIC and modified NAFIC scoring systems, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of these scoring systems for the diagnosis of NASH were calculated. Results: In the obese group, the sensitivity, specificity, PPV and NPV of the NAFIC scoring system for the diagnosis of NASH were 67.3%, 76.2%, 77.8% and 65.3%, respectively, while the corresponding values for the modified NAFIC scoring systems were 78.8%, 69.0%, 75.9% and 72.5%. On the other hand, in the nonobese group, the sensitivity, specificity, PPV and NPV of the NAFIC scoring system were 47.1%, 86.7%, 66.7% and 74.3%, respectively, while those of the modified NAFIC scoring system were 58.8%, 83.3%, 66.7% and 78.1%, respectively. When the patients were divided by sex, the sensitivity of the NAFIC and modified NAFIC scoring systems in the female nonobese group were 53.8% and 69.2%, respectively. However, surprisingly, in the male nonobese group, the sensitivity of both the scoring systems was only 25.0%. Conclusion: The sensitivity of both the NAFIC and modified NAFIC scoring systems for the diagnosis of NASH was lower in the male nonobese group than in all the other groups. These findings suggest that caution should be exercised in the use of the NAFIC scoring system as a diagnostic screening tool for NASH in Japanese patients with NAFLD, especially male nonobese patients.
  • 宮 愛香, 橋本 玲奈, 高橋 清彦, 菅原 基, 一山 芽衣, 山本 知穂, 北尾 直之, 山本 浩平, 野本 博司, 亀田 啓, 中村 昭伸, 三好 秀明, 菅野 宏美, 三橋 智子, 渥美 達也
    日本内分泌学会雑誌 90 3 946 - 946 (一社)日本内分泌学会 2014年10月
  • 澤谷 亮佑, 高橋 清彦, 菅原 基, 橋本 玲奈, 北尾 直之, 一山 芽衣, 宮 愛香, 山本 浩平, 山本 知穂, 野本 博司, 中村 昭伸, 三好 秀明, 清水 力, 渥美 達也
    日本内分泌学会雑誌 90 3 985 - 985 (一社)日本内分泌学会 2014年10月
  • 宮 愛香, 三好 秀明, 山本 知穂, 野本 博司, 中村 昭伸, 渥美 達也
    肥満研究 20 Suppl. 206 - 206 (一社)日本肥満学会 2014年10月
  • 短期高脂肪食負荷と長期高脂肪食負荷による膵β細胞増殖機構の差異
    中村 昭伸, 北尾 直之, 野本 博司, 三好 秀明, 寺内 康夫, 渥美 達也
    糖尿病合併症 28 Suppl.1 135 - 135 (一社)日本糖尿病合併症学会 2014年09月
  • 野本 博司, 北尾 直之, 高野 善成, 一山 芽衣, 小梁川 直秀, 宮 愛香, 三次 有奈, 山本 浩平, 山本 知穂, 亀田 啓, 中村 昭伸, 永井 聡, 近藤 琢磨, 三好 秀明, 清水 力, 渥美 達也
    日本内分泌学会雑誌 90 Suppl.Update 39 - 41 (一社)日本内分泌学会 2014年09月 
    62歳女。38歳時にクローン病を発症し、複数回の小腸切除を受け、近年はアダリムマブ投与にて症状安定していた。また、経過中に鉄欠乏性貧血と診断され含糖酸化鉄注射液の間歇投与を受けていた。今回、手足のしびれが出現し、低Ca血症にてCa製剤投与を受けるも改善ないため当科紹介となった。初診時の採血で低Ca血症に加え低P血症、更に低Mg血症の併存が明らかとなり、FGF23の測定を行った。入院後に各種内服薬ならびにグルコン酸Caの投与を一旦中止し、電解質の推移を確認したところ、血清Ca・血清Pの経時的な減少を認めたため、速やかに服薬を再開し精査を行った。低Mg血症はMg製剤の経静脈的な補充にて血清濃度が正常域に回復したため、経口剤に切り替え再発は認めなかった。後日、初診時にFGF23が高値であったことが判明し、前医での含糖酸化鉄投与歴も考慮して、同鉄剤によるFGF23上昇が病態に関与していると考えた。同鉄剤中止後にFGF23の経時的な低下ならびに正常化を認め、それに伴い血清Pも正常化した。最終的に含糖酸化鉄の中止と活性型ビタミンD製剤、経口Ca製剤、Mg製剤の経口投与のみで多彩な電解質異常は是正され、軽快退院した。
  • Yuri Ono, Hikaru Kamoshima, Akinobu Nakamura, Hiroshi Nomoto
    EXPERT OPINION ON PHARMACOTHERAPY 15 13 1785 - 1795 2014年09月 [査読有り][通常論文]
     
    Background: The effects of the mitiglinide/voglibose fixed-dose combination on postprandial glycemic/metabolic responses in patients with type 2 diabetes mellitus (T2DM) treated with dipeptidyl peptidase-4 (DPP-4) inhibitors are unknown. Methods: Twelve T2DM patients treated with a DPP-4 inhibitor underwent identical meal tolerance tests (MTTs) at breakfast, lunch and dinner, before and 2 - 3 weeks after treatment with a fixed-dose combination of mitiglinide 10 mg and voglibose 0.2 mg (combination). Patients were randomized in a cross-over fashion to administer the combination either three-times-daily before each meal or twice-daily before breakfast and dinner. Glycemic/metabolic responses were evaluated at 0, 30, 60 and 120 min in each MTT. Results: Three-times-daily administration of the combination significantly suppressed postprandial hyperglycemia after each meal, particularly after lunch and dinner. Active glucagon-like peptide-1 levels increased significantly after each meal, as did early-phase insulin secretion without excessive insulin secretion. Postprandial hyperglycemia after lunch was significantly greater after twice-daily than three-times-daily administration, but there were no clinically relevant differences in other metabolic responses. Conclusion: This study revealed that adding the mitiglinide/voglibose combination to a DPP-4 inhibitor elicited additive improvements in postprandial glycemic/metabolic responses assessed using MTTs at breakfast, lunch and dinner with identical meal compositions.
  • Hiraku Kameda, Hideaki Miyoshi, Chikara Shimizu, So Nagai, Akinobu Nakamura, Takuma Kondo, Dai Chida, Tatsuya Atsumi
    ENDOCRINOLOGY 155 7 2492 - 2499 2014年07月 [査読有り][通常論文]
     
    The hypothalamic-pituitary-adrenal (HPA) axis is a major part of the neuroendocrine system that controls responses to stress, and has an important function in the regulation of various body processes. We previously created a mouse line deficient in the melanocortin 2 receptor (MC2R). MC2R-deficient mice (MC2R(-/-) mice) have high adrenocorticotropic hormone (ACTH) levels because of undetectable corticosterone levels. Increased neuromedin B (NMB) expression was recently reported in the pituitary gland of adrenalectomized mice, a model for acute adrenal insufficiency. To investigate gene expression in the pituitary gland under chronic adrenal deficiency, we examined the pituitary gland of MC2R(-/-) mice, a model of chronic adrenal insufficiency. To understand the molecular background of pituitary cells under chronic adrenal deficiency, we first performed DNA microarray analyses using the pituitary glands of the MC2R(-/-) mice. The DNA microarray analysis and real-time polymerase chain reaction showed that NMB expression was higher in the MC2R(-/-) than in the wild-type (WT) mice. We detected NMB expression in the MC2R(-/-) pituitary corticotrophs by immunohistochemistry using the specific antibodies for ACTH and NMB. In addition, the plasma NMB concentration was significantly higher in the MC2R(-/-) mice than in the WT mice. Subcutaneous implantation of a sustained-release corticosterone pellet decreased the expression of NMB mRNA as well as pituitary proopiomelanocortin mRNA. In isolated anterior pituitary cells, NMB mRNA expression was increased by the administration of corticotropin-releasing hormone (CRH) and was suppressed by dexamethasone treatment. In this study, we first demonstrate NMB expression in corticotrophs and its regulation by CRH and glucocorticoids. Furthermore, corticotrophs seemed to secrete NMB into the systemic circulation.
  • Masahiro Takihata, Akinobu Nakamura, Kazutaka Aoki, Mari Kimura, Yusuke Sekino, Masahiko Inamori, Shin Maeda, Eiji Gotoh, Atsushi Nakajima, Yasuo Terauchi
    OBESITY RESEARCH & CLINICAL PRACTICE 8 4 E331 - E338 2014年07月 [査読有り][通常論文]
     
    This study compared the impacts of intragastric balloon (IGB) therapy and intensive lifestyle modification therapy on abdominal fat distribution. Sixteen extremely obese Japanese patients were assigned to an intensive lifestyle modification therapy group with educational hospitalisation (8 patients) or an IGB therapy group (8 patients) and were followed up for 6 months. The main outcome measures were the differences at 6 months, relative to the baseline values, in the visceral fat area (VFA), subcutaneous fat area (SFA), and liver volume as measured using computed tomography. At 0 month, the body weights (BWs) were 121.3 +/- 19.0 kg and 127.1 +/- 24.4 kg and the VFAs were 299 +/- 55 cm(2) and 257 +/- 56 cm(2) in the intensive lifestyle modification therapy group and the IGB therapy group, respectively. No statistically significant differences in the baseline characteristics were observed between these two groups. At 6 months, no difference in the changes in BW from the baseline value (-11.5 [-16.4, -6.6] kg vs. -11.2 [-18.9, -3.4] kg) was seen between the two groups. However, a statistically significant difference in the change in the VFA (-66 [-87, -44] cm(2) vs. -22 [-70, 26] cm(2) [P = 0.027]) was observed; no significant changes in the SFA or liver volume were seen. In conclusion, IGB therapy was as effective as intensive lifestyle modification therapy for weight reduction but was less effective with respect to the improvement in abdominal visceral fat accumulation and liver steatosis in super-obese Japanese patients. (C) 2013 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.
  • シタグリプチンとグリメピリドの抗動脈硬化作用及び膵β細胞機能改善効果における比較研究Sapporo Athero-Incretin Study(1)
    野本 博司, 三好 秀明, 古本 智夫, 井上 篤, 曹 圭龍, 中村 昭伸, 近藤 琢磨, 渥美 達也, 萬田 直紀, 栗原 義夫, 青木 伸
    日本動脈硬化学会総会プログラム・抄録集 46回 236 - 236 (一社)日本動脈硬化学会 2014年06月
  • リラグルチドとグラルギンの抗動脈硬化作用及び膵β細胞機能改善効果における比較研究Sapporo Athero-Incretin Study(2)
    野本 博司, 三好 秀明, 古本 智夫, 土田 健一, 三次 有奈, 中村 昭伸, 近藤 琢磨, 渥美 達也, 萬田 直紀, 栗原 義夫, 青木 伸
    日本動脈硬化学会総会プログラム・抄録集 46回 237 - 237 (一社)日本動脈硬化学会 2014年06月
  • 1型糖尿病患者における25-(OH)ビタミンDの充足状況に関する検討
    亀田 啓, 三次 有奈, 山本 浩平, 野本 博司, 中村 昭伸, 永井 聡, 近藤 琢磨, 三好 秀明, 南 昭子, 清水 力, 渥美 達也
    日本骨形態計測学会雑誌 24 2 S123 - S123 日本骨形態計測学会 2014年05月
  • Togashi Y, Shirakawa J, Orime K, Kaji M, Sakamoto E, Tajima K, Inoue H, Nakamura A, Tochino Y, Goshima Y, Shimomura I, Terauchi Y
    Endocrinology 155 5 1643 - 52 2014年05月 [査読有り][通常論文]
     
    The glucokinase-induced up-regulation of insulin receptor substrate 2 (IRS-2) plays an important role in β-cell adaptive proliferation in response to high-fat diet-induced insulin resistance. This study aimed to investigate the role of IRS-2 in the proliferation of β-cells after a 60% partial pancreatectomy. IRS-2-deficient (IRS-2(-/-)) mice or wild-type mice were subjected to a pancreatectomy (60% partial pancreatectomy) or a sham operation (Sham). The β-cell proliferation and gene expression profiles of the islets were then assessed. Gene expression in islets from pancreatectomized and Sham C57BL/6J male mice was analyzed using a cDNA microarray analysis. To compare with β-cell proliferation induced by a high-fat diet, Gck(+/-) mice subjected to a pancreatectomy were also analyzed. The IRS-2(-/-) mice exhibited β-cell expansion and a significant increase in β-cell proliferation after the pancreatectomy, compared with the Sham group. Although glucose-stimulated insulin secretion from islets was not impaired, IRS-2(-/-) mice manifested severe hyperglycemia after the pancreatectomy. The expression levels of Aurora kinase B, Cyclin A, and Cyclin B1 in the pancreatectomized islets were also enhanced in the IRS-2(-/-) mice. A gene set enrichment analysis suggested an association between the genes that were up-regulated in the pancreatectomized islets and those involved in M phase progression in the cell cycle. β-Cell proliferation after a pancreatectomy was observed even in the Gck(+/-) mice. In conclusion, IRS-2 was not required for β-cell proliferation but might be needed for functional β-cell mass, after a pancreatectomy. A partial pancreatectomy in mice may be an attractive model for the development of new strategy for exploring the unique nature of β-cell proliferation.
  • 山本 浩平, 亀田 啓, 野本 博司, 中村 昭伸, 永井 聡, 近藤 琢磨, 三好 秀明, 清水 力, 渥美 達也
    日本内分泌学会雑誌 90 1 308 - 308 (一社)日本内分泌学会 2014年04月
  • 高野 善成, 中村 昭伸, 野本 博司, 亀田 啓, 近藤 琢磨, 三好 秀明, 三橋 智子, 清水 力, 寺内 康夫, 渥美 達也
    日本内分泌学会雑誌 90 1 319 - 319 (一社)日本内分泌学会 2014年04月
  • リラグルチドとグラルギンの抗動脈硬化作用及び膵β細胞機能改善効果における比較研究Sapporo Athero-Incretin Study 2
    三好 秀明, 野本 博司, 古本 智夫, 曹 圭龍, 土田 健一, 三次 有奈, 中村 昭伸, 近藤 琢磨, 渥美 達也, 萬田 直樹, 栗原 義夫, 青木 伸
    糖尿病 57 Suppl.1 S - 128 (一社)日本糖尿病学会 2014年04月
  • 短期高脂肪食が膵β細胞増殖に与える影響
    北尾 直之, 中村 昭伸, 高野 善成, 一山 芽衣, 小梁川 直秀, 宮 愛香, 三次 有奈, 山本 浩平, 山本 知穂, 野本 博司, 亀田 啓, 近藤 琢磨, 三好 秀明, 寺内 康夫, 渥美 達也
    糖尿病 57 Suppl.1 S - 141 (一社)日本糖尿病学会 2014年04月
  • インスリンデグルデクのContinuous Glucose Monitoring Systemsによる血糖変動の検討
    山本 知穂, 北尾 直之, 高野 善成, 一山 芽衣, 宮 愛香, 小梁川 直秀, 山本 浩平, 三次 有奈, 野本 博司, 亀田 啓, 中村 昭伸, 近藤 琢磨, 三好 秀明, 渥美 達也
    糖尿病 57 Suppl.1 S - 147 (一社)日本糖尿病学会 2014年04月
  • 膵β細胞におけるsmall Maf転写因子群の意義とインクレチン効果に関する検討
    野本 博司, 近藤 琢磨, 中村 昭伸, 三好 秀明, 渥美 達也
    糖尿病 57 Suppl.1 S - 263 (一社)日本糖尿病学会 2014年04月
  • 2型糖尿病患者におけるインスリンをベースとしたシタグリプチン高用量とビルダグリプチン標準用量の血糖変動におよぼす効果
    小梁川 直秀, 北尾 直之, 高野 善成, 一山 芽衣, 宮 愛香, 三次 有奈, 山本 浩平, 山本 知穂, 野本 博司, 亀田 啓, 中村 昭伸, 近藤 琢磨, 三好 秀明, 渥美 達也
    糖尿病 57 Suppl.1 S - 309 (一社)日本糖尿病学会 2014年04月
  • 2型糖尿病合併骨粗鬆症患者の、ビスホスホネート製剤とSERMによる骨質マーカーへの影響
    三次 有奈, 野本 博司, 亀田 啓, 中村 昭伸, 永井 聡, 近藤 琢磨, 三好 秀明, 渥美 達也
    糖尿病 57 Suppl.1 S - 318 (一社)日本糖尿病学会 2014年04月
  • 高脂肪食負荷期間による膵β細胞増殖メカニズムの差異
    北尾 直之, 中村 昭伸, 野本 博司, 亀田 啓, 近藤 琢磨, 三好 秀明, 寺内 康夫, 渥美 達也
    日本臨床分子医学会学術総会プログラム・抄録集 51回 79 - 79 日本臨床分子医学会 2014年04月
  • インスリノーマ手術症例における臨床・病理学的検討
    高野 善成, 北尾 直之, 宮 愛香, 一山 芽衣, 山本 知穂, 小梁川 直秀, 山本 浩平, 野本 博司, 中村 昭伸, 近藤 琢磨, 三好 秀明
    糖尿病 57 3 211 - 211 (一社)日本糖尿病学会 2014年03月
  • 無症状で発見された1型糖尿病の1例
    北尾 直之, 小梁川 直秀, 山本 浩平, 山本 知穂, 野本 博司, 亀田 啓, 曹 圭龍, 中村 昭伸, 近藤 琢磨, 三好 秀明, 渥美 達也
    糖尿病 57 3 211 - 211 (一社)日本糖尿病学会 2014年03月
  • インスリンデグルデクのContinuous Glucose Monitoring Systemsによる血糖変動の検討
    山本 知穂, 野本 博司, 亀田 啓, 中村 昭伸, 近藤 琢磨, 三好 秀明, 渥美 達也
    糖尿病 57 3 213 - 213 (一社)日本糖尿病学会 2014年03月
  • 糖尿病患者における無症候性心筋虚血罹患率の観察研究
    小梁川 直秀, 三次 有奈, 山本 浩平, 山本 知穂, 野本 博司, 亀田 啓, 曹 圭龍, 中村 昭伸, 近藤 琢磨, 三好 秀明, 渥美 達也
    糖尿病 57 3 215 - 215 (一社)日本糖尿病学会 2014年03月
  • silent somatotroph adenoma術後に耐糖能障害が改善した1例
    宮 愛香, 中村 昭伸, 山本 知穂, 小梁川 直秀, 北尾 直之, 野本 博司, 亀田 啓, 曹 圭龍, 近藤 琢磨, 三好 秀明, 渥美 達也
    糖尿病 57 3 223 - 223 (一社)日本糖尿病学会 2014年03月
  • Yuri Ono, Akinobu Nakamura, Kyu Yong Cho, Hiroshi Nomoto
    Expert opinion on pharmacotherapy 15 3 311 - 24 2014年02月 [査読有り][通常論文]
     
    BACKGROUND: Meal tolerance tests (MTTs) are usually conducted at breakfast after overnight fasting in type 2 diabetes mellitus (T2DM) patients, but differences in postprandial glycemic responses between meals have been reported. OBJECTIVE: We conducted MTTs at breakfast, lunch, and dinner to examine the effects of a fixed combination of 10 mg mitiglinide/0.2 mg voglibose (the combination) on glycemic/metabolic responses to meals during the day in T2DM patients. MTTs with unified meals were conducted in 11 T2DM patients before and after 4 weeks of treatment with the combination administered thrice daily before meals. Glycemic/metabolic profiles measured before and at 30, 60, and 120 min after each meal were compared between each meal and between the baseline and treatment periods. RESULTS AND CONCLUSION: The combination significantly reduced postprandial hyperglycemia after each meal. Postprandial AUC0 - 120 min for insulin significantly decreased after lunch and dinner compared with after breakfast, while insulin levels significantly increased at only 30 min after breakfast and dinner. The combination also significantly increased postprandial C-peptide and active glucagon-like peptide-1 levels, and reduced free fatty acid and triglyceride levels, but did not significantly affect glucagon levels compared with baseline, confirming that treatment with the combination improves postprandial responses in Japanese T2DM patients.
  • A. Nakamura, E. Hagiwara, J. Hamai, M. Taguri, Y. Terauchi
    Diabetic Medicine 31 6 707 - 713 2014年 [査読有り][通常論文]
     
    Aims: We investigated the effects of diabetes and the presence of lung cavities on treatment outcomes in patients with pulmonary tuberculosis. Methods: We conducted a retrospective review of the clinical records of all consecutive patients admitted to the Kanagawa Cardiovascular and Respiratory Centre with the diagnosis of pulmonary tuberculosis. The study outcomes examined were time to sputum culture conversion and percentage of patients with sputum culture conversion by the time 2 months of treatment, and these outcomes were compared between patients with and without diabetes. Results: Of the 260 patients enrolled in the study, 69 were diagnosed as having diabetes mellitus, while the remaining 191 did not have diabetes. The percentage of patients with cavities was higher in the patients with diabetes (71.0%) than in those without (45.5% P = 0.0003). The time to sputum culture conversion was significantly longer in the patients with diabetes than in those without (P = 0.0005), and the percentage of patients with a positive sputum culture at 2 months was higher in the patients with diabetes (43.5%) than in those without (18.8% P = 0.0001). Multivariate analyses revealed that the presence/absence of lung cavities was a more important determinant of treatment outcomes than the presence/absence of diabetes. Conclusions: The presence of lung cavities was found to be a more important determinant of the treatment outcomes than that of diabetes per se in patients with pulmonary tuberculosis. © 2014 The Authors.
  • Khadbaatar Zolzaya, Akinobu Nakamura, Kazuki Tajima, Yasuo Terauchi
    JOURNAL OF DIABETES INVESTIGATION 5 1 27 - 30 2014年01月 [査読有り][通常論文]
     
    We investigated the role of insulin receptor substrate (Irs)-1 for diethylnitrosamine (DEN) plus high-fat (HF) diet-induced hepatic tumorigenesis in mice. We gave DEN by intraperitoneal injection at the dose of 80mg/kg to 18-week-old wild-type (WT) and Irs1-knockout (Irs1(-/-)) mice, which were fed a HF diet from 8weeks-of-age until they were killed (52weeks). The Irs1(-/-) mice showed significantly lower plasma alanine aminotransferase levels, triglyceride contents in the liver and also lower expression levels of the genes encoding inflammatory cytokines than the WT mice. The incidence of DEN plus HF diet-induced hepatic tumors was 71.4% in the WT mice, whereas it was just 14.3% in the Irs1(-/-) mice. The present study showed that Irs1 played an important role in DEN plus HF diet-induced hepatic tumorigenesis.
  • 野本 博司, 北尾 直之, 小梁川 直秀, 宮 愛香, 三次 有奈, 山本 浩平, 山本 知穂, 亀田 啓, 曹 圭龍, 中村 昭伸, 永井 聡, 近藤 琢磨, 三好 秀明, 清水 力, 渥美 達也
    日本内分泌学会雑誌 89 3 956 - 956 (一社)日本内分泌学会 2013年12月
  • 続木 惇, 宮 愛香, 中村 昭伸, 山本 知穂, 小梁川 直秀, 北尾 直之, 高野 善成, 野本 博司, 亀田 啓, 曹 圭龍, 近藤 琢磨, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 89 3 967 - 967 (一社)日本内分泌学会 2013年12月
  • 山本 浩平, 亀田 啓, 野本 博司, 中村 昭伸, 近藤 琢磨, 三好 秀明, 永井 聡, 清水 力, 渥美 達也
    日本内分泌学会雑誌 89 3 982 - 982 (一社)日本内分泌学会 2013年12月
  • 比嘉 逸人, 小梁川 直秀, 山本 千穂, 宮 愛香, 山本 浩平, 三次 有奈, 野本 博司, 亀田 啓, 中村 昭伸, 近藤 琢磨, 三好 秀明, 渥美 達也
    日本内分泌学会雑誌 89 3 1006 - 1006 (一社)日本内分泌学会 2013年12月
  • Akinobu Nakamura, Masato Yoneda, Yoshio Sumida, Yuichiro Eguchi, Hideki Fujii, Hideyuki Hyogo, Masafumi Ono, Yasuaki Suzuki, Takumi Kawaguchi, Noriaki Aoki, Takeshi Okanoue, Atsushi Nakajima, Shin Maeda, Yasuo Terauchi
    JOURNAL OF DIABETES INVESTIGATION 4 6 651 - 658 2013年11月 [査読有り][通常論文]
     
    Aims/IntroductionWe reinvestigated the clinical usefulness of the modified NAFIC scoring system, modified by changing the weightage assigned to the fasting serum insulin level based on the importance of hyperinsulinemia in the pathogenesis of non-alcoholic steatohepatitis (NASH), in Japanese patients with non-alcoholic fatty liver disease (NAFLD) who had undergone liver biopsy. Materials and MethodsThe NAFIC score is conventionally calculated as follows: serum ferritin 200ng/mL (female) or 300ng/mL (male), 1point; serum fasting insulin 10U/mL, 1point; and serum type IV collagen 7s 5.0ng/mL, 2points. A total of 147 patients with NAFLD who had undergone liver biopsies were included in the estimation group. To validate the modified scoring system, 355 patients from nine hepatology centers in Japan were also enrolled. ResultsIn the estimation group, 74 (50.3%) patients were histologically diagnosed as having NASH, whereas the remaining 73 (49.7%) were diagnosed as not having NASH. As the percentage of NASH patients increased not only among participants with serum insulin levels greater than 10U/mL, but also in those with serum levels greater than 15U/mL, we advocated use of the modified NAFIC score, as follows: serum fasting insulin 10-15U/mL, 1point and 15U/mL, 2points. The modified NAFIC score showed improved sensitivity and negative predictive value for the diagnosis of NASH. This finding was also confirmed in the validation group. ConclusionsThe modified NAFIC scoring system could be a clinically useful diagnostic screening tool for NASH.
  • Akinobu Nakamura, Yasuo Terauchi
    International Journal of Molecular Sciences 14 11 21240 - 21257 2013年10月24日 [査読有り][通常論文]
     
    Nonalcoholic fatty liver disease (NAFLD) encompasses a clinicopathologic spectrum of diseases ranging from isolated hepatic steatosis to nonalcoholic steatohepatitis (NASH), the more aggressive form of fatty liver disease that may progress to cirrhosis and cirrhosis-related complications, including hepatocellular carcinoma. The prevalence of NAFLD, including NASH, is also increasing in parallel with the growing epidemics of obesity and diabetes. However, the causal relationships between obesity and/or diabetes and NASH or liver tumorigenesis have not yet been clearly elucidated. Animal models of NAFLD/NASH provide crucial information, not only for elucidating the pathogenesis of NAFLD/NASH, but also for examining therapeutic effects of various agents. A high-fat diet is widely used to produce hepatic steatosis and NASH in experimental animals. Several studies, including our own, have shown that long-term high-fat diet loading, which can induce obesity and insulin resistance, can also induce NASH and liver tumorigenesis in C57BL/6J mice. In this article, we discuss the pathophysiology of and treatment strategies for NAFLD and subsequent NAFLD-related complications such as NASH and liver tumorigenesis, mainly based on lessons learned from mouse models of high-fat diet-induced NAFLD/NASH. © 2013 by the authors licensee MDPI, Basel, Switzerland.
  • K. Tajima, A. Nakamura, J. Shirakawa, Y. Togashi, K. Orime, K. Sato, H. Inoue, M. Kaji, E. Sakamoto, Y. Ito, K. Aoki, Y. Nagashima, T. Atsumi, Y. Terauchi
    AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM 305 8 E987 - E998 2013年10月 [査読有り][通常論文]
     
    The prevalence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is increasing with the growing epidemics of obesity and diabetes. NAFLD encompasses a clinicopathologic spectrum of disease ranging from isolated hepatic steatosis to NASH, which is a more aggressive form of fatty liver disease, to cirrhosis and, finally, hepatocellular carcinoma (HCC). The exact mechanism behind the development of HCC in NASH remains unclear; however, it has been established that hepatic steatosis is the important risk factor in the development of HCC. Metformin has recently drawn attention because of its potential antitumor effect. Here, we investigated the effects of metformin on high-fat diet (HFD)-induced liver tumorigenesis, using a mouse model of NASH and liver tumor. Metformin prevented long-term HFD-induced liver tumorigenesis in C57Bl/6 mice. Of note, metformin failed to protect against liver tumorigenesis in mice that had already begun to develop NAFLD. Metformin improved short-term HFD-induced fat accumulation in the liver, associated with the suppression of adipose tissue inflammation. Collectively, these results suggest that metformin may prevent liver tumorigenesis via suppression of liver fat accumulation in the early stage, before the onset of NAFLD, which seems to be associated with a delay in the development of inflammation of the adipose tissue.
  • 亀田 啓, 高野 善成, 北尾 直之, 一山 芽衣, 宮 愛香, 三次 有奈, 山本 浩平, 山本 知穂, 小梁川 直秀, 野本 博司, 曹 圭龍, 中村 昭伸, 近藤 琢磨, 三好 秀明, 渥美 達也, 永井 聡, 清水 力
    北海道医学雑誌 88 4-5 171 - 172 北海道医学会 2013年09月
  • 山本 浩平, 亀田 啓, 野本 博司, 曹 圭龍, 中村 昭伸, 近藤 琢磨, 三好 秀明, 渥美 達也, 永井 聡, 清水 力
    北海道医学雑誌 88 4-5 174 - 174 北海道医学会 2013年09月
  • 野本 博司, 三次 有奈, 亀田 啓, 曹 圭龍, 中村 昭伸, 近藤 琢磨, 清水 力, 三好 秀明, 渥美 達也
    肥満研究 19 Suppl. 207 - 207 (一社)日本肥満学会 2013年09月
  • 潜在性甲状腺機能低下症ならびに抗甲状腺ペルオキシダーゼ抗体が糖尿病合併症に与える影響についての検討
    亀田 啓, 高野 善成, 北尾 直之, 一山 芽衣, 宮 愛香, 三次 有奈, 山本 浩平, 山本 知穂, 小梁川 直秀, 野本 博司, 曹 圭龍, 中村 昭伸, 永井 聡, 近藤 琢磨, 三好 秀明, 和田 典男, 柳澤 克之, 渥美 達也
    糖尿病合併症 27 Suppl.1 143 - 143 (一社)日本糖尿病合併症学会 2013年08月
  • 糖尿病教育入院患者における重症慢性歯周病と臨床パラメータの関連性
    三次 有奈, 小梁川 直秀, 山本 浩平, 山本 知穂, 野本 博司, 亀田 啓, 曹 圭龍, 中村 昭伸, 永井 聡, 近藤 琢磨, 三好 秀明, 渥美 達也
    糖尿病合併症 27 Suppl.1 176 - 176 (一社)日本糖尿病合併症学会 2013年08月
  • 内頸動脈剥離術後プラークを用いたマクロファージ炎症バランスとプラークの脆弱性・破綻に関する検討
    曹 圭龍, 三好 秀明, 小梁川 直秀, 山本 知穂, 野本 博司, 亀田 啓, 中村 昭伸, 近藤 琢磨, 渥美 達也
    糖尿病合併症 27 Suppl.1 178 - 178 (一社)日本糖尿病合併症学会 2013年08月
  • M. Takihata, A. Nakamura, K. Tajima, T. Inazumi, Y. Komatsu, H. Tamura, S. Yamazaki, Y. Kondo, M. Yamada, M. Kimura, Y. Terauchi
    DIABETES OBESITY & METABOLISM 15 5 455 - 462 2013年05月 [査読有り][通常論文]
     
    Aims To compare the efficacy and safety of these two agents and the impact on surrogate markers related to diabetic complications in Japanese type 2 diabetic patients. Methods In a multicenter, open-label trial, 130 patients whose diabetes had been inadequately controlled (HbA1c, 6.99.5%) with metformin and/or sulphonylurea were randomly assigned to a sitagliptin group (50mg/day) or a pioglitazone group (15mg/day) and were followed up for 24weeks. At 16weeks, if the patient's HbA1c level was 6.5%, the dose of sitagliptin or pioglitazone was increased up to 100 or 30mg/day, respectively. Main outcome measure was the difference in the mean changes in the HbA1c level from baseline at 24weeks between these two groups. Results Of the 130 patients who were enrolled, 115 subjects (sitagliptin group: 58 patients, pioglitazone group: 57 patients) completed this trial. At 0weeks, the mean HbA1c level was 7.47 +/- 0.66% in the sitagliptin group and 7.40 +/- 0.61% in the pioglitazone group. At 24weeks, the mean changes in the HbA1c level from baseline were 0.86 +/- 0.63% versus 0.58 +/- 0.68% (p=0.024). Hypoglycaemia (2 patients, 3.4% vs. 2 patients, 3.5%), gastrointestinal symptoms (3 patients, 5.2% vs. 1 patient, 1.8%) and pretibial oedema (0 patients, 0% vs. 39 patients, 68.4%, p<0.001) were observed for 24weeks. Conclusions Sitagliptin was not only more tolerable, but also more effective than pioglitazone in Japanese type 2 diabetic patients who had been treated with metformin and/or sulphonylurea.
  • Akinobu Nakamura, Yasuo Terauchi
    ENDOCRINE JOURNAL 60 1 45 - 49 2013年01月 [査読有り][通常論文]
     
    In order to investigate the factors contributing to the glucose-lowering effect of vildagliptin, we analyzed the results of the oral glucose tolerance test together with several clinical parameters in Japanese patients with type 2 diabetes before and after 24 weeks of treatment with vildagliptin. The data of the 13 patients who satisfactorily completed the follow-up examinations were included. After 24 weeks treatment with vildagliptin, the patients were classified into a responder group (69.2%) and a non-responder group (30.8%); the responders consisting of subjects whose HbA1c decreased following 24 weeks treatment with vildagliptin, and the non-responders consisting of subjects who did not show any significant decrease of HbA1c. There were no differences in baseline characteristics between the two groups before administration of vildagliptin. After 24 weeks of treatment, HbA1c was significantly reduced from 7.3 +/- 0.5% to 6.7 +/- 0.5% in the responder group (P = 0.0077), while it tended to rather increased from 7.1 +/- 0.6% to 7.5 +/- 0.7% in the nonresponder group (P = 0.0679). Also, parameters reflecting the glucose-stimulated insulin secretion, such as the insulinogenic index and oral disposition index, were significantly higher in the responder group than in the non-responder group, whereas insulin sensitivity was similar between the two groups. These results suggest that the difference in the degree of improvement of the glucose tolerance between the responder group and non-responder group in this study could be associated with the effect of vildagliptin on the glucose-stimulated insulin secretion, but not on the insulin sensitivity.
  • Orime K, Shirakawa J, Togashi Y, Tajima K, Inoue H, Ito Y, Sato K, Nakamura A, Aoki K, Goshima Y, Terauchi Y
    Endocrinology 154 1 54 - 64 2013年01月 [査読有り][通常論文]
     
    Decreased β-cell mass is a hallmark of type 2 diabetes, and therapeutic approaches to increase the pancreatic β-cell mass have been expected. In recent years, gastrointestinal incretin peptides have been shown to exert a cell-proliferative effect in pancreatic β-cells. Trefoil factor 2 (TFF2), which is predominantly expressed in the surface epithelium of the stomach, plays a role in antiapoptosis, migration, and proliferation. The TFF family is expressed in pancreatic β-cells, whereas the role of TFF2 in pancreatic β-cells has been obscure. In this study, we investigated the mechanism by which TFF2 enhances pancreatic β-cell proliferation. The effects of TFF2 on cell proliferation were evaluated in INS-1 cells, MIN6 cells, and mouse islets using an adenovirus vector containing TFF2 or a recombinant TFF2 peptide. The forced expression of TFF2 led to an increase in bromodeoxyuridine (BrdU) incorporation in both INS-1 cells and islets, without any alteration in insulin secretion. TFF2 significantly increased the mRNA expression of cyclin A2, D1, D2, D3, and E1 in islets. TFF2 peptide increased ERK1/2 phosphorylation and BrdU incorporation in MIN6 cells. A MAPK kinase inhibitor (U0126) abrogated the TFF2 peptide-mediated proliferation of MIN6 cells. A CX-chemokine receptor-4 antagonist also prevented the TFF2 peptide-mediated increase in ERK1/2 phosphorylation and BrdU incorporation in MIN6 cells. These results indicated that TFF2 is involved in β-cell proliferation at least partially via CX-chemokine receptor-4-mediated ERK1/2 phosphorylation, suggesting TFF2 may be a novel target for inducing β-cell proliferation.
  • Kazuki Tajima, Jun Shirakawa, Yu Togashi, Hideaki Inoue, Koichiro Sato, Kazuki Orime, Yuzuru Ito, Mitsuyo Kaji, Eri Sakamoto, Akinobu Nakamura, Kazutaka Aoki, Yoshio Goshima, Tatsuya Atsumi, Yasuo Terauchi
    PloS one 8 5 e64633  2013年 [査読有り][通常論文]
     
    The precise role of AMP-activated protein kinase (AMPK), a target of metformin, in pancreatic β cells remains controversial, even though metformin was recently shown to enhance the expression of incretin receptors (GLP-1 and GIP receptors) in pancreatic β cells. In this study, we investigated the effect of AMPK in the regulation of incretin receptors expression in pancreatic islets. The phosphorylation of AMPK in the mouse islets was decreased by increasing glucose concentrations. We showed the expression of incretin receptors in bell-shaped response to glucose. Expression of the incretin receptors in the isolated islets showed higher levels under a medium glucose concentration (11.1 mM) than that under a low glucose concentration (2.8 mM), but was suppressed under a high glucose concentration (22.2 mM). Both treatment with an AMPK inhibitor and DN-AMPK expression produced a significant increase of the incretin receptors expression under a low glucose concentration. By contrast, in hyperglycemic db/db islets, the enhancing effect of the AMPK inhibitor on the expression of incretin receptors was diminished under a low glucose concentration. Taken together, AMPK is involved in the regulation of incretin receptors expression in pancreatic islets under a low glucose concentration.
  • A. Nakamura, K. Tajima, K. Zolzaya, K. Sato, R. Inoue, M. Yoneda, K. Fujita, Y. Nozaki, K. C. Kubota, H. Haga, N. Kubota, Y. Nagashima, A. Nakajima, S. Maeda, T. Kadowaki, Y. Terauchi
    DIABETOLOGIA 55 12 3382 - 3391 2012年12月 [査読有り][通常論文]
     
    Epidemiological studies have revealed that obesity and diabetes mellitus are independent risk factors for the development of non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma. However, the debate continues on whether insulin resistance as such is directly associated with NASH and liver tumourigenesis. Here, we investigated the incidence of NASH and liver tumourigenesis in Irs1 (-/-) mice subjected to a long-term high-fat (HF) diet. Our hypothesis was that hepatic steatosis, rather than insulin resistance may be related to the pathophysiology of these conditions. Mice (8 weeks old, C57Bl/6J) were given free access to standard chow (SC) or an HF diet. The development of NASH and liver tumourigenesis was evaluated after mice had been on the above-mentioned diets for 60 weeks. Similarly, Irs1 (-/-) mice were also subjected to an HF diet for 60 weeks. Long-term HF diet loading, which causes obesity and insulin resistance, was sufficient to induce NASH and liver tumourigenesis in the C57Bl/6J mice. Obesity and insulin resistance were reduced by switching mice from the HF diet to SC, which also protected these mice against the development of NASH and liver tumourigenesis. However, compared with wild-type mice fed the HF diet, Irs1 (-/-) mice fed the HF diet were dramatically protected against NASH and liver tumourigenesis despite the presence of severe insulin resistance and marked postprandial hyperglycaemia. IRS-1 inhibition might protect against HF diet-induced NASH and liver tumourigenesis, despite the presence of insulin resistance.
  • A. Nakamura, Y. Togashi, K. Orime, K. Sato, J. Shirakawa, M. Ohsugi, N. Kubota, T. Kadowaki, Y. Terauchi
    DIABETOLOGIA 55 6 1745 - 1754 2012年06月 [査読有り][通常論文]
     
    We investigated changes in the expression of genes involved in beta cell function and proliferation in mouse islets stimulated with glucokinase activator (GKA) in order to elucidate the mechanisms by which GKA stimulates beta cell function and proliferation. Islets isolated from mice were used to investigate changes in the expression of genes related to beta cell function and proliferation stimulated by GKA. In addition, knockout ( (-/-)) mice on a high-fat diet or a high-fat diet containing GKA were used to investigate the effects of GKA on beta cell proliferation in vivo. In wild-type mice, and expression was increased by GKA. In (-/-) mice, GKA administration increased the glucose-stimulated secretion of insulin and expression, but not beta cell proliferation. It was particularly noteworthy that oxidative stress inhibited the upregulation of the and genes induced by GKA. Moreover, whereas neither GKA alone nor exendin-4 alone upregulated the expression of and in the islets of / mice, prior administration of exendin-4 to the mice caused GKA to increase the expression of these genes. GKA-stimulated IRS2 production affected beta cell proliferation but not beta cell function. Oxidative stress diminished the effects of GKA on the changes in expression of genes involved in beta cell function and proliferation. A combination of GKA and an incretin-related agent might therefore be effective in therapy.
  • Sato K, Nakamura A, Shirakawa J, Muraoka T, Togashi Y, Shinoda K, Orime K, Kubota N, Kadowaki T, Terauchi Y
    Endocrinology 153 3 1093 - 102 2012年03月 [査読有り][通常論文]
     
    Type 2 diabetes is characterized by diminished pancreatic β-cell mass and function. Glucagon-like peptide-1 has been reported to increase islet cell proliferation and reduce apoptosis of β-cells in rodents. In this study, we explored the effect of chronic administration of the dipeptidyl peptidase-4 inhibitor vildagliptin on glucose tolerance, β-cell function, and β-cell mass in Irs2-knockout (Irs2(-/-)) mice. Wild-type and Irs2(-/-) mice were fed a high-fat diet for 20 wk, with or without vildagliptin. In both genotypes of mice, vildagliptin significantly decreased the area under the curve (0-120 min) of blood glucose and increased the insulin response to glucose during the oral glucose tolerance test. In the oral glucose tolerance test performed 1 d after discontinuation of vildagliptin administration, the area under the curve (0-120 min) of blood glucose was still significantly decreased and the insulin response to glucose was significantly increased in the Irs2(-/-) mice treated with vildagliptin as compared with the values in the mice not treated with vildagliptin. Histochemical analysis of the pancreatic islets revealed significant increase of the β-cell mass and decrease in the proportion of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive β-cells but no significant increase of the bromodeoxyuridine incorporation in Irs2(-/-) mice treated with vildagliptin. Our results suggest that vildagliptin improved glucose tolerance and increased the β-cell mass by reducing β-cell apoptosis in the Irs2(-/-) mice, and that the reduction of β-cell apoptosis by vildagliptin was independent of the Irs2 expression in the cells.
  • Cheng C, Nakamura A, Minamimoto R, Shinoda K, Tateishi U, Goto A, Kadowaki T, Terauchi Y, Inoue T
    Annals of nuclear medicine 25 10 755 - 761 2011年12月 [査読有り][通常論文]
     
    Insulin resistance (IR) is a physiological condition in which the body produces insulin but does not result in a sufficient biological effect. Insulin resistance is usually asymptomatic but is associated with health problems and is a factor in the metabolic syndrome. The aim of the present study is to clarify organ-specific insulin resistance in normal daily conditions using [F-18]-2-fluoro-2-deoxy-d-glucose ([F-18]-FDG). The biodistribution of [F-18]-FDG was examined in insulin receptor substrate-1 (IRS-1) knockout mice, an animal model of skeletal muscle insulin resistance, and C57BL/6J (wild-type) mice with and without insulin loading. Mice received 0.5 MBq of [F-18]-FDG injected into the tail vein, immediately followed by nothing (control cohorts) or an intraperitoneal injection of 1.5 mU/g body weight of human insulin as an insulin loading test. Blood glucose concentrations for all of the experimental animals were assessed at 0, 20, 40, and 60 min post-injection. The mice were subsequently killed, and tissue was collected for evaluation of [F-18]-FDG biodistribution. The radioactivity of each organ was measured using a gamma counter. In the absence of insulin, the blood glucose concentrations of wild-type mice (132 +/- A 26 mg/dl) and IRS-1 knockout mice (134 +/- A 18 mg/dl) were not significantly different. Blood glucose concentrations decreased following insulin administration, with lower concentrations in wild-type mice than in knockout mice at 20, 40, and 60 min. A statistically significant difference in [F-18]-FDG uptake between wild-type mice and IRS-1 knockout mice was confirmed in the heart, abdominal muscle, and femoral muscle. With insulin loading, [F-18]-FDG uptake in the heart, back muscle, and abdominal muscle was significantly increased compared to without insulin loading in both wild-type mice and knockout mice. Our results showed that IR significantly affected [F-18]-FDG uptake in the heart in normal daily conditions. IR was associated with decreased [F-18]-FDG uptake in the heart and was readily observed in the absence of insulin loading. [F-18]-FDG-positron emission tomography (PET) could be a useful tool for evaluating insulin resistance in images by investigating tissue-specific differences in [F-18]-FDG uptake.
  • Akinobu Nakamura, Masato Yoneda, Koji Fujita, Kazuki Tajima, Kaori Kikuchi, Atsushi Nakajima, Shin Maeda, Yasuo Terauchi
    JOURNAL OF DIABETES INVESTIGATION 2 6 483 - 489 2011年12月 [査読有り][通常論文]
     
    Aims/Introduction: We investigated the relationship between non-alcoholic steatohepatitis (NASH) and different stages of fasting plasma glucose (FPG) concentrations, and the association between factors related to glucose tolerance and severity of NASH.
  • Akinobu Nakamura, Hiroko Shimazaki, Sumika Ohyama, Junichi Eiki, Yasuo Terauchi
    JOURNAL OF DIABETES INVESTIGATION 2 4 276 - 279 2011年08月 [査読有り][通常論文]
     
    We investigated the long-term effect of a glucokinase (GK) activator (GKA) on the changes in hepatic gene expression, glucose metabolism, lipid profiles and hepatic function in wild-type mice and the haploinsufficiency of beta-cell-specific GK mice on a high-fat (HF) diet. Twenty weeks of GKA treatment had no effect on hepatic GK activity or expression of genes related to glucose or lipid metabolism, suggesting that chronic GK activation by GKA showed a sustained reduction of ambient blood glucose levels without causing significant impact on hepatic lipid and glucose metabolisms. Furthermore, GKA exerted glucose-lowering efficacy lasted for up to 40 weeks without increasing bodyweight or exerting adverse effects on lipid metabolism or hepatic function in either genotype on the HF diet. The present results show that GKA is capable of chronically improving glucose metabolism in mice on the HF diet without exerting a harmful influence on their lipid profile or hepatic function. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00104.x, 2011)
  • Tomonori Muraoka, Kazutaka Aoki, Tomoyuki Iwasaki, Kazuaki Shinoda, Akinobu Nakamura, Hiroyuki Aburatani, Shuuichi Mori, Kumpei Tokuyama, Naoto Kubota, Takashi Kadowaki, Yasuo Terauchi
    METABOLISM-CLINICAL AND EXPERIMENTAL 60 5 617 - 628 2011年05月 [査読有り][通常論文]
     
    Ezetimibe inhibits intestinal cholesterol absorption, thereby reducing serum cholesterol. Recent studies suggest that ezetimibe affects liver steatosis and insulin resistance. We investigated the impact of ezetimibe on insulin sensitivity and glucose metabolism in C57BL/6 mice. We analyzed 4 mouse groups fed the following diets: normal chow (4% fat) for 12 weeks, normal chow for 10 weeks followed by normal chow plus ezetimibe for :2 weeks, high-fat chow (32% fat) for 12 weeks, and high-fat chow for 10 weeks followed by high-fat chow plus ezetimibe for 2 weeks. In the normal chow + ezetimibe group, ezetimibe had no impact on body weight, fat mass, lipid metabolism, liver steatosis, glucose tolerance, or insulin sensitivity. In the high-fat chow + ezetimibe group, ezetimibe had no impact on body weight or fat mass but significantly decreased serum low-density lipoprotein cholesterol, triglyceride, and glutamate pyruvate transaminase levels; liver weight; hepatic triglyceride: content; and hepatic cholesterol content and increased the hepatic total bile acid content. In association with increases in IRS-2 and Akt phosphorylation, ezetimibe ameliorated hepatic insulin resistance in the high-fat chow + ezetimibe group, but had no effect on insulin sensitivity in primary cultured hepatocytes. A DNA microarray and Taqman polymerase chain reaction revealed that ezetimibe up-regulated hepatic SREBP2 and SHP expression and down-regulated hepatic SREBP-c expression. SLIP silencing mainly in the liver worsened insulin resistance, and ezetimibe protected against insulin resistance induced by down-regulation of SUP. Ezetimibe down-regulated SREBP-1c in the liver and reversed hepatic insulin resistance in mice fed a high-fat diet. (C) 2011 Elsevier Inc. All rights reserved.
  • Akinobu Nakamura, Takeshi Osonoi, Yasuo Terauchi
    JOURNAL OF DIABETES INVESTIGATION 1 5 208 - 211 2010年10月 [査読有り][通常論文]
     
    To investigate the factors contributing to pioglitazone-induced edema, we analyzed sodium excretion and several clinical parameters before and after administration of pioglitazone. We analyzed these parameters before and after 8 weeks of administration of pioglitazone to female subjects with type 2 diabetes. When we evaluated whether a significant correlation was found between salt excretion and blood pressure, six patients showed such correlation and 20 patients did not. After 8 weeks of pioglitazone administration, five patients had developed edema, and, surprisingly, such correlation was not found in all five subjects. Salt excretion after administration of pioglitazone was significantly lower in subjects who developed edema and those who showed the correlation, and the hematocrit was significantly lower after administration in the subjects who showed the correlation, but not in the edema group. Pioglitazone-induced edema would be caused not only by fluid retention, but also by other factors, such as vascular permeability. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00046.x, 2010)
  • 菊地 香織, 中村 昭伸, 永倉 穣, 岸田 日帯, 菊地 泰介, 寺内 康夫
    日本内分泌学会雑誌 86 2 281 - 281 (一社)日本内分泌学会 2010年09月
  • Kiyomi Masuda, Kazutaka Aoki, Kaori Kikuchi, Uru Nezu, Tomonori Muraoka, Kazuaki Shinoda, Akinobu Nakamura, Makoto Shibuya, Mayumi Takahashi, Mari Kimura, Yasuo Terauchi
    DIABETES TECHNOLOGY & THERAPEUTICS 12 6 483 - 490 2010年06月 [査読有り][通常論文]
     
    Background: To self-inject insulin, individuals with diabetes must be able to attach the needle to the injector, recognize the appropriate insulin dosage, detach the needle from the injector, and perform a series of operations necessary for the actual injection. These tasks require a grip strength that is strong enough to hold the necessary devices, eyesight, the use of both hands, and at least a minimum intellectual capacity. Subjects who are unable to grasp or handle the devices required for insulin injection often have difficulties with the self-injection of insulin. Methods: We treated four diabetes patients who had trouble grasping objects and using both hands. One patient had lost five fingers in an accident, two patients had suffered from ischemic cerebral infarction resulting in complete one-sided hemiplegia with no movement in one arm, and one patient had limited muscular power in an arm as a result of spinal cord disease. The plasma glucose control was poor, and the initiation of insulin therapy was necessary in each of these patients. In three cases, we used a commercially available self-injection device (HumaHelper (TM); Eli Lilly Japan K. K., Kobe, Japan) to enable self-injection; in the fourth case, we used a newly manufactured device similar to HumaHelper. Results: All the patients were able to inject insulin by themselves using the appropriate supplementary devices. The blood glucose control of all the patients subsequently improved. Conclusion: Existing or newly manufactured supportive devices can enable handicapped subjects to self-inject insulin.
  • Akinobu Nakamura, Chikara Shimizu, So Nagai, Masahiro Yoshida, Kazutaka Aoki, Takuma Kondo, Hideaki Miyoshi, Norio Wada, Toshihiro Tajima, Yasuo Terauchi, Narihito Yoshioka, Takao Koike
    CLINICAL ENDOCRINOLOGY 72 2 272 - 276 2010年02月 [査読有り][通常論文]
     
    Objective Gitelman's syndrome, recognized as a variant of Bartter's syndrome, is characterized by hypokalaemic metabolic alkalosis in combination with hypomagnesaemia and hypocalciuria. Overlapping biochemical features in Gitelman's syndrome and Bartter's syndrome has been observed. Here, we investigated the clinical, biochemical, and genetic characteristics of five, chronic, nonhypertensive and hypokalaemic Japanese patients. Methods Serum and urinary electrolytes, plasma renin activity and plasma aldosterone concentration were measured in five patients (four males and one female) with hypokalaemia. Renal clearance tests were performed and distal fractional chloride reabsorption calculated. Finally, mutational analysis of the thiazide-sensitive Na-Cl co-transporter gene was performed. Results Symptoms in patients varied from mild (muscle weakness and numbness) to severe (tetany and foot paralysis). All patients were normotensive or hypotensive, and all had hypokalaemia, hypocalciuria, and hyperreninaemic hyperaldosteronism. However, two male patients had normomagnesaemia, while the remainder was hypomagnesaemic. Renal clearance tests showed that the administration of furosemide decreased distal fractional chloride reabsorption, while thiazide ingestion failed to decrease it. Genetic analysis identified six thiazide-sensitive Na-Cl co-transporter gene mutations, including two novel ones. Therefore, on the basis of the confirmatory renal clearance tests and mutational analysis, a diagnosis of Gitelman's syndrome was made in these patients. Conclusions Two of the five patients diagnosed with Gitelman's syndrome were normomagnesaemic, which is uncommon in this syndrome. Our study indicates that renal clearance tests and mutation analysis can play an important role in diagnosing Gitelman's syndrome more precisely.
  • Uru Nezu, Akinobu Nakamura, Kazutaka Aoki, Mari Kimura, Yasuo Terauchi
    ENDOCRINE JOURNAL 56 2 193 - 200 2009年04月 [査読有り][通常論文]
     
    To evaluate the efficacy of a multiple-daily injection regimen and a twice-daily injection regimen using biphasic insulin, we performed an observational Study of 56 insulin-naive patients with type 2 diabetes mellitus who began receiving insulin therapy while they were hospitalized. The subjects were divided into two groups: a multiple-daily injection group (n = 33), and a twice-daily injection group (n = 23). At baseline, the demographic and clinical characteristics were comparable between the two groups. The HbA1c levels were 10.0 +/- 1.6% and 9.5 +/- 2.2% (p = 0.36), respectively. At 12 weeks, the HbA1c levels decreased equally in the two groups (7.2 +/- 1.8% in the multiple-daily injection group and 7.3 +/- 1.6%, p = 0.80 in the twice-daily injection group). The baseline HbA1c, the duration of diabetes, and the endogenous insulin secretory capacity did not affect the change in HbA1c in either group. These results suggest that twice-daily insulin regimen using biphasic insulin is as effective and beneficial as multiple-daily injection regimen for the treatment in type 2 diabetic patients with very poor glycerine control and that in order to achieve the targeted glycemic goal, insulin therapy should be initiated at an early stage.
  • Akinobu Nakamura, Yasuo Terauchi, Sumika Ohyama, Junko Kubota, Hiroko Shimazaki, Tadahiro Nambu, Iseki Takamoto, Naoto Kubota, Junichi Eiki, Narihito Yoshioka, Takashi Kadowaki, Takao Koike
    ENDOCRINOLOGY 150 3 1147 - 1154 2009年03月 [査読有り][通常論文]
     
    We investigated the effect of glucokinase activator (GKA) on glucose metabolism and beta-cell mass. We analyzed four mouse groups: wild-type mice and beta-cell-specific haploinsufficiency of glucokinase gene (Gck(+/-)) mice on a high-fat (HF) diet. Each genotype was also treated with GKA mixed in the HF diet. Rodent insulinoma cells and isolated islets were used to evaluate beta-cell proliferation by GKA. After 20 wk on the above diets, there were no differences in body weight, lipid profiles, and liver triglyceride content among the four groups. Glucose tolerance was improved shortly after the GKA treatment in both genotypes of mice. beta-Cell mass increased in wild-type mice compared with Gck(+/-) mice, but a further increase was not observed after the administration of GKA in both genotypes. Interestingly, GKA was able to up-regulate insulin receptor substrate-2 (Irs-2) expression in insulinoma cells and isolated islets. The administration of GKA increased 5-bromo-2-deoxyuridine (BrdU) incorporation in insulinoma cells, and 3 d administration of GKA markedly increased BrdU incorporation in mice treated with GKA in both genotypes, compared with those without GKA. In conclusion, GKA was able to chronically improve glucose metabolism for mice on the HF diet. Although chronic GKA administration failed to cause a further increase in beta-cell mass in vivo, GKA was able to increase beta cell proliferation in vitro and with a 3-d administration in vivo. This apparent discrepancy can be explained by a chronic reduction in ambient blood glucose levels by GKA treatment. (Endocrinology 150: 1147-1154, 2009)
  • Kazutaka Aoki, Toshihiro Tajima, Yasuhiro Yabushita, Akinobu Nakamura, Uru Nezu, Mayumi Takahashi, Mari Kimura, Yasuo Terauchi
    Endocrine Journal 55 3 557 - 560 2008年 [査読有り][通常論文]
     
    We here report a novel mutation of the thiazide-sensitive Na-Cl cotransporter (TSC) (SLC12A3) gene in a Japanese patient with Gitelman's syndrome (GS). GS is characterized by a renal disorder and is associated with hypokalemia, hypomagnesemia, metabolic alkalosis and hypocalciuria arising from the defective tubular reabsorption of magnesium and potassium. This disease is reportedly caused by mutations in the TSC gene. A 52-year-old man was referred to our hospital because of sleeplessness and tinnitus. He exhibited hypokalemia, hypomagnesemia, hypocalciuria, metabolic alkalosis and hyperreninemie hyperaldosteronism. A renal clearance study revealed that the administration of furosemide decreased chloride reabsorption however, the ingestion of thiazide failed to decrease chloride reabsorption. A diagnosis of GS was made based on the clinical features, laboratory data and renal function test results. Sequencing of the patient's genomic DNA revealed an A to T transition at the initial codon of exon 1 of the TSC gene (c1A> T). Knowledge of this novel mutation may be helpful for understanding the pathophysiology of GS and the function of TSC as well as for providing genetic counseling.
  • Kazutaka Aoki, Akinobu Nakamura, Satoshi Ito, Uru Nezu, Tomoyuki Iwasaki, Mayumi Takahashi, Mari Kimura, Yasuo Terauchi
    DIABETES RESEARCH AND CLINICAL PRACTICE 78 1 30 - 33 2007年10月 [査読有り][通常論文]
     
    Miglitol, a pseudomonosaccharide alpha-glucosidase inhibitor (alpha GI), was more effective at reducing blood glucose levels at 30 and 60 min after a meal than voglibose. Speculating that miglitol administered even after the start of a meal may be effective, we evaluated the timing of administration of miglitol on the plasma glucose and serum insulin levels in 13 type 2 diabetic patients. Miglitol was administered in four different intake manners in each patient (control: no mightol; intake 1: just before breakfast; intake 2: 15 min after the beginning of breakfast; intake 3: 30 min after the beginning of breakfast). The area under the curve (AUC) of plasma glucose was significantly decreased under all the intake conditions, as compared with the AUC in the control. The AUC of serum insulin tended to be lower in all the three groups than in the control, although the differences were not statistically significant. Thus, miglitol administered anytime within 30 min after the start of a meal is effective for glycemic control. These results suggest that if patients miss taking miglitol at the beginning of a meal, they can still take the drug until 30 min after starting their meal. (C) 2007 Elsevier Ireland Ltd. All rights reserved.
  • グルコキナーゼヘテロ欠損マウスにおける高脂肪食負荷と妊娠における膵β細胞量調節機構の差異
    中村 昭伸, 高本 偉碩, 窪田 直人, 門脇 孝, 寺内 康夫
    Diabetes Frontier 18 4 426 - 426 (株)メディカルレビュー社 2007年08月
  • 高脂肪食誘導性のインスリン抵抗性に対する膵β細胞過形成の分子メカニズムの解明
    高本 偉碩, 寺内 康夫, 窪田 直人, 鈴木 亮, 橋本 信嗣, 窪田 哲也, 峯山 智佳, 伊藤 晋介, 中村 昭伸, 山内 敏正, 植木 浩二郎, 戸辺 一之, 門脇 孝
    糖尿病 50 Suppl.1 S - 160 (一社)日本糖尿病学会 2007年04月
  • A. Nakamura, C. Shimizu, S. Nagai, S. Taniguchi, M. Umetsu, T. Atsumi, N. Wada, N. Yoshioka, Y. Ono, H. Sasano, T. Koike
    JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION 30 1 65 - 69 2007年01月 [査読有り][招待有り]
     
    A benign virilizing adrenal adenoma is rare among adrenal neoplasms in middle-aged women. A 39-yr-old Japanese woman who presented with hirsutism, obesity, diabetes mellitus and hypertension was admitted. Plasma concentrations of testosterone and DHEAS were high. While the basal level of plasma ACTH was suppressed, serum cortisol level was high and its circadian rhythm was absent. Serum cortisol level was not suppressed with the low- and high-dose overnight dexamethasone suppression test. Abdominal computed tomography showed a left adrenal tumor, and an adrenocortical scintigraphy revealed uptake of the tracer on the left side. Polycystic ovaries were also found and bone mineral density revealed osteoporosis. Histopathological features of resected adrenal tumour were consistent with those of adrenocortical adenoma. Immunoreactivity of all the steroidogenic enzymes was apparent in the tumor cells and particularly dehydroepiandrosterone sulfotransferase (DHEA-ST) immunoreactivity was markedly expressed. Cortical atrophy and reduced expression of DHEA-ST were detected in the cortex of the adjacent nonneoplastic adrenal gland. Plasma testosterone, DHEAS and cortisol levels returned to normal after surgery, concomitantly with the disappearance of polycystic ovaries. This is a very rare case of virilizing adrenocortical adenoma complicated with Cushing's syndrome (CS).
  • Yasuo Terauchi, Iseki Takamoto, Naoto Kubota, Junji Matsui, Ryo Suzuki, Kajuro Komeda, Akemi Hara, Yukiyasu Toyoda, Ichitomo Miwa, Shinichi Aizawa, Shuichi Tsutsumi, Yoshiharu Tsubamoto, Shinji Hashimoto, Kazuhiro Eto, Akinobu Nakamura, Mitsuhiko Noda, Kazuyuki Tobe, Hiroyuki Aburatani, Ryozo Nagai, Takashi Kadowaki
    JOURNAL OF CLINICAL INVESTIGATION 117 1 246 - 257 2007年01月 [査読有り][通常論文]
     
    Glucokinase (Gck) functions as a glucose sensor for insulin secretion, and in mice fed standard chow, haplo-insufficiency of beta cell-specific Gck (Gck(+/-)) causes impaired insulin secretion to glucose, although the animals have a normal beta cell mass. When fed a high-fat (HF) diet, wild-type mice showed marked beta cell hyperplasia, whereas Gck(+/-) mice demonstrated decreased beta cell replication and insufficient beta cell hyperplasia despite showing a similar degree of insulin resistance. DNA chip analysis revealed decreased insulin receptor substrate 2 (Irs2) expression in HF diet-fed Gck(+/-) mouse islets compared with wild-type islets. Western blot analyses confirmed upregulated Irs2 expression in the islets of HF diet-fed wild-type mice compared with those fed standard chow and reduced expression in HF diet-fed Gck(+/-) mice compared with those of HF diet-fed wild-type mice. HF diet-fed Irs2(+/-) mice failed to show a sufficient increase in beta cell mass, and overexpression of Irs2 in beta cells of HF diet-fed Gck(+/-) mice partially prevented diabetes by increasing beta cell mass. These results suggest that Gck and Irs2 are critical requirements for beta cell hyperplasia to occur in response to HF diet-induced insulin resistance.
  • Akinobu Nakamura, Chikara Shimizu, So Nagai, Satoshi Taniguchi, Masaaki Umetsu, Toshiya Atsumi, Norio Wada, Narihito Yoshioka, Yuri Ono, Yukio Tanizawa, Takao Koike
    DIABETES RESEARCH AND CLINICAL PRACTICE 73 2 215 - 217 2006年08月 [査読有り][通常論文]
     
    Wolfram syndrome is a rare, autosomal recessive disorder characterized by early-onset diabetes mellitus, optic atrophy and neurological and endocrinological abnormalities. A 47-year-old Japanese man with frequent severe hypoglycemic episodes was diagnosed as Wolfram syndrome based on clinical features and laboratory data. He had positive glutamic acid decarboxylase (GAD) and insulinoma-associated antigen-2 (IA-2) antibodies, both uncommon in this syndrome. Genetic analysis revealed that WFS1 gene of the patient has a homozygous 5 base pairs (AAGGC) insertion at position 1279 in exon 8, causing a frameshift at codon 371 leading to premature termination at codon 443. (c) 2006 Elsevier Ireland Ltd. All rights reserved.
  • Rena Morita, Kaoru Takeuchi, Akinobu Nakamura, Toshihiro Tajima, Yoshihiko Kuroda
    Internal medicine (Tokyo, Japan) 45 4 211 - 3 2006年 [査読有り][通常論文]
     
    A 56-year-old mentally retarded Japanese woman (intelligence quotient: 49) was admitted to our hospital with the chief complaints of headache, dizziness, vomiting, and lower limb paralysis. Laboratory tests showed severe hypokalemia, metabolic alkalosis, hypomagnesemia, and hypocalciuria. These findings suggested a diagnosis of Gitelman's syndrome (GS). We examined the thiazide-sensitive Na-Cl cotransporter (TSC) gene for the mutations that can be responsible for Gitelman's syndrome, and confirmed the diagnosis. After potassium and magnesium supplementation, her paralysis improved dramatically. The marriage of her parents was consanguineous. She had nine siblings (all with mental retardation), among whom five had died of unknown causes during childhood. Familial mental retardation has never been detected before in Gitelman's syndrome. Here we report a rare case of Gitelman's syndrome with familial mental retardation.
  • 松崎 純子, 中村 昭伸, 小野 百合
    糖尿病 = JOurnal of the Japan Diabetes Society 47 3 233 - 237 THE JAPAN DIABETES SOCIETY 2004年03月30日 
    【目的】糖尿病患者において動脈硬化の危険因子を知るため, 頸動脈エコー検査所見の有無と他の動脈硬化関連因子および糖尿病コントロール, 合併症との関連を検討した.【方法】241名に頸動脈工コー検査を行い, 異常所見を認めたA群, 認めなかったB群に分け, 2群間における各種検査項目, 動脈硬化危険因子との関連を検討した.【結果】脈波伝播速度 (PWV), 内膜中膜壁厚 (IMT), 高血圧症の罹病率, 年齢, 糖尿病罹病期間, 合併症の有無はA, B両群間で有意差を認めた. 糖尿病大血管症発生群 (40名に出現) およびPWV1, 600cm/sec以上群においてもほぼ同様の結果を認めた. PWV, IMT肥厚度, 高血圧症罹病率は頸動脈エコー所見の重症度および糖尿病大血管症発生に伴い元進していた.【結語】動脈硬化の進展は力口齢, 高血圧に依存するところが多く, 糖尿病患者は血糖コントロールのみならず血圧の管理が重要であると考えられた.
  • N Li, K Nakamura, Y Jiang, H Tsurui, S Matsuoka, M Abe, M Ohtsuji, H Nishimura, K Kato, T Kawai, T Atsumi, T Koike, T Shirai, H Ueno, S Hirose
    HUMAN MOLECULAR GENETICS 13 2 171 - 179 2004年01月 [査読有り][通常論文]
     
    Systemic lupus erythematosus (SLE), a complex multigenic disease, is a typical antibody-mediated autoimmune disease characterized by production of autoantibodies against a variety of autoantigens and immune complex-type tissue inflammation, most prominently in the kidney. Evidence suggests that genetic factors predisposing to aberrant proliferation/maturation of self-reactive B cells initiate and propagate the disease. In SLE-prone New Zealand Black (NZB) mice and their F-1 cross with New Zealand White (NZW) mice, B cell abnormalities can be ascribed mainly to self-reactive CD5(+) B1 cells. Our genome-wide scans to search for susceptibility genes for aberrant activation of B1 cells in these mice showed evidence that the gene, Ltk, encoding leukocyte tyrosine kinase (LTK), is a possible candidate. LTK is a receptor-type protein tyrosine kinase, belonging to the insulin receptor superfamily, and is mainly expressed in B lymphocyte precursors and neuronal tissues. Sequence and functional analyses of the gene revealed that NZB has a gain-of-function polymorphism in the LTK kinase domain near YXXM, a binding motif of the p85 subunit of phosphatidylinositol 3-kinase (PI3K). SLE patients also had this type of Ltk polymorphism with a significantly higher frequency compared with the healthy controls. Our findings suggest that these polymorphic LTKs cause up-regulation of the PI3K pathway and possibly form one genetic component of susceptibility to abnormal proliferation of self-reactive B cells in SLE.
  • 中村 昭伸, 小野 百合
    糖尿病 47 4 309 - 311 THE JAPAN DIABETES SOCIETY 2004年 
    糖尿病合併妊娠9例において静脈血漿血糖値 (a) と血糖自己測定値 (b) との差異を検討した. 妊娠初期～中期群ではaとbに有意差を認めなかったのに対し, 妊娠末期群ではbがaに比べ有意に低値を示した. また妊娠末期群では, aの100mg/dl未満群は100mg/dl以上群に比しa, b間の%誤差が大きい傾向を認めた. 妊娠末期にはbは低値の傾向を示し, 正常血糖値であっても低血糖と判断される危険性も高いと考えられた.
  • N Ogata, D Chikazu, N Kubota, Y Terauchi, K Tobe, Y Azuma, T Ohta, T Kadowaki, K Nakamura, H Kawaguchi
    JOURNAL OF CLINICAL INVESTIGATION 105 7 935 - 943 2000年04月 [査読有り][通常論文]
     
    Insulin receptor substrates (IRS-1 and -2) are essential for intracellular signaling by insulin and IGF-I, anabolic regulators of bone metabolism. Mice lacking the IRS-1 gene IRS-1(-/-) showed severe osteopenia with low bone turnover. IRS-1 was expressed in osteoblasts, but not in osteoclasts, of wild-type (WT) mice. IRS-1(-/-) osteoblasts treated with insulin or IGF-I failed to induce tyrosine phosphorylation of cellular proteins, and they showed reduced proliferation and differentiation. Osteoclastogenesis in the coculture of hemopoietic cells and osteoblasts depended on IRS-1 expression in osteoblasts and could not be rescued by IRS-1 expression in hemopoietic cells in the presence of not only IGF-I but also 1,25(OH)(2)D-3. In addition, osteoclast differentiation factor (RANKL/ODF) was not induced by these factors in IRS-1(-/-) osteoblasts. We conclude that IRS-1 deficiency in osteoblasts impairs osteoblast proliferation, differentiation, and support of osteoclastogenesis, resulting in low-turnover osteopenia. Osteoblastic IRS-1 is essential for maintaining bone turnover, because it mediates signaling by IGF-I and insulin and, we propose, also by other factors, such as 1,25(OH)(2)D-3.
  • K. Minakuchi, K. Fujimoto, K. Takada, S. Takashima, K. Nakamura, T. Mitsuhashi
    British Journal of Radiology 64 759 272 - 275 1991年 [査読有り][通常論文]

MISC

所属学協会

  • 日本糖尿病合併症学会   日本臨床分子医学会   日本糖尿病・肥満動物学会   日本病態栄養学会   日本肥満学会   日本内分泌学会   日本糖尿病学会   日本内科学会   

共同研究・競争的資金等の研究課題

  • 日本学術振興会：科学研究費助成事業
    研究期間 : 2012年04月 -2015年03月 
    代表者 : 寺内 康夫, 白川 純, 木村 真理, 中村 昭伸
     
    解糖系の酵素であるグルコキナーゼを介した糖代謝シグナルが、膵β細胞の増殖と関与することを示した。膵β細胞におけるグルコキナーゼの新規標的遺伝子の単離とその機能解析、膵β細胞増殖におけるグルコキナーゼを介したグルコースシグナルの役割の検討、膵β細胞アポトーシスにおけるグルコキナーゼを介したグルコースシグナルの役割を行った。膵切除後膵β細胞増殖機構における責任分子同定のため、IRS-2欠損マウスおよび野生型マウスにおいてSham手術後の膵β細胞量を評価し、膵切除施行後の単離膵島における遺伝子発現マイクロアレイを施行した。
  • 日本学術振興会：科学研究費助成事業
    研究期間 : 2011年 -2013年 
    代表者 : 木村 真理, 寺内 康夫, 中村 昭伸
     
    スクロースとリノール酸とを組み合わせた食事による糖脂肪毒性モデルを確立することに成功し、DPP-4阻害薬は膵島以外にも、脂肪組織および肝臓と多臓器における食事誘導性の糖脂肪毒性に改善作用を持つことを証明した。膵島に対してはGLP-1を介した小胞体ストレスおよびアポトーシスからの保護、肝臓に対してはGLP-1を介した脂肪合成系酵素発現調節による肝臓内脂肪蓄積の抑制、脂肪組織に対してはDPP-4酵素活性阻害によるリンパ球・マクロファージの機能修飾の可能性が示唆された。
  • 地域における系統的糖尿病診療モデルの確立
    日本糖尿病協会研究・教育基金研究助成
  • 糖尿病のデジタルヘルス医療へ向けた包括的代謝疾患マネジメント方針の確立
    鈴木万平糖尿病財団 調査研究助成
  • Beta cell rest を目指した新たな2型糖尿病治療法の確立
    科学研究費補助金基盤C：
  • 膵β細胞内ブドウ糖代謝に着目した新たな2型糖尿病治療法の確立
    武田科学振興財団 医学系研究継続助成：
  • 膵β細胞を標的とした新たな2 型糖尿病治療法および発症予防法の確立
    日本糖尿病協会研究・教育基金研究助成：
  • GCK-MODY（MODY2)の経時的耐糖能悪化抑制メカニズムの解明
    日本糖尿病財団・コストコ研究助成：
  • 新規2型糖尿病治療薬の開発
    寿原記念財団研究助成：
  • 膵β細胞内ブドウ糖代謝に着目した新たな2型糖尿病治療法の確立
    武田科学振興財団医学系研究助成：
  • 2型糖尿病病態における膵β細胞量増加への治療戦略
    秋山記念生命科学振興財団研究助成：
  • インスリン分泌に着目した新規糖尿病治療戦略
    AMED 革新的医療技術創出拠点プロジェクト：
  • グルコキナーゼの制御による膵β細胞量調節メカニズムの解明
    科学研究費補助金基盤C
    代表者 : 中村 昭伸
  • グルコースシグナルに着目した新規2型糖尿病治療薬の開発
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