論文

• Lipotoxicity Induces β-cell Small Extracellular Vesicle-Mediated β-cell Dysfunction in Male Mice.
  Abhishek Roy, Alexandra Hoff, Tracy K Her, Gallage Ariyaratne, Roberto-León Gutiérrez, M H D Noor Tahawi, Kamalnath Sankaran Rajagopalan, Matthew R Brown, Kazuno Omori, Sean Lewis-Brinkman, Thanh Nguyen, Alondra Soto-González, Quinn P Peterson, Aleksey V Matveyenko, Naureen Javeed
  Endocrinology, 166, 5, 2025年03月24日, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, Chronically elevated circulating excess free fatty acids (ie, lipotoxicity) is a pathological process implicated in several metabolic disorders, including obesity-driven type 2 diabetes (T2D). Lipotoxicity exerts detrimental effects on pancreatic islet β-cells by reducing glucose-stimulated insulin secretion (GSIS), altering β-cell transcriptional identity, and promoting apoptosis. While β-cell-derived small extracellular vesicles (sEV) have been shown to contribute to β-cell failure in T2D, their specific role in lipotoxicity-mediated β-cell failure remains to be elucidated. In this work, we demonstrate that lipotoxicity enhances the release of sEVs from β-cells, which exhibit altered proteomic and lipidomic profiles. These palmitate (PAL)-exposed extracellular vesicles (EVs) induce β-cell dysfunction in healthy mouse and human islets and trigger significant islet transcriptional changes, including the upregulation of genes associated with the TGFβ/Smad3 pathway, as noted by RNA sequencing. Importantly, pharmacological inhibition of the TGFβI/II receptor improved PAL EV-induced β-cell dysfunction, underscoring their involvement in activating the TGFβ/Smad3 pathway during this process. We have comprehensively characterized lipotoxic β-cell sEVs and implicated their role in inducing β-cell functional failure in T2D. These findings highlight potential avenues for therapeutic interventions targeting sEV-mediated pathways to preserve β-cell health in metabolic disorders.
• Switching from Conventional Fibrates to Pemafibrate Has Beneficial Effects on the Renal Function of Diabetic Subjects with Chronic Kidney Disease.
  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, 48, 3, 473, 481, 2024年05月, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, BACKGRUOUND: 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.
• Effects of pemafibrate on lipid metabolism in patients with type 2 diabetes and hypertriglyceridemia: A multi-center prospective observational study, the PARM-T2D study.
  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, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, AIMS: Pemafibrate, a novel selective peroxisome proliferator-activated receptor modulator, was shown to ameliorate lipid abnormalities in a phase III clinical trial of patients with type 2 diabetes mellitus (T2DM). However, its efficacy has not been demonstrated in real-world clinical practice in patients with T2DM. METHODS: We performed a multi-center prospective observational study of the use of pemafibrate in patients with T2DM and hypertriglyceridemia versus conventional therapy, with or without a fibrate. The primary outcomes were the changes from baseline in fasting serum triglyceride (TG) and high-density lipoprotein-cholesterol (HDL-C) concentrations at week 52. RESULTS: We recruited 650 patients, and data from 504 (252 per group) were analyzed after propensity score matching. In the pemafibrate group, both TG and HDL-C showed significant improvements (p < 0.001), and several indices reflecting TG-rich lipoproteins, low-density lipoprotein-cholesterol particle size, and liver enzyme elevations were significantly ameliorated compared with the control group, but there was no difference in glycemic control markers. One of the key secondary endpoints showed that switching from conventional fibrates to pemafibrate improved eGFR but increased uric acid concentration. CONCLUSIONS: In patients with T2DM, pemafibrate has superior effects on lipid profile as well as liver and renal dysfunction to conventional fibrates.
• The agreement between measured HbA1c and optimized target HbA1c based on the Dementia Assessment Sheet for Community-based Integrated Care System 8-items (DASC-8): A cross-sectional study of elderly patients with diabetes.
  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08月, ［査読有り］, ［国内誌］
  英語, 研究論文（学術雑誌）, 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; 22: 560-567.
• Luseogliflozin preserves the pancreatic beta-cell mass and function in db/db mice by improving mitochondrial function.
  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, 9740, 9740, 2022年06月13日, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• Glucokinase activation leads to an unsustained hypoglycaemic effect with hepatic triglyceride accumulation in db/db mice.
  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, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• Glucokinase activation or inactivation: Which will lead to the treatment of type 2 diabetes?
  Akinobu Nakamura, Kazuno Omori, Yasuo Terauchi
  Diabetes, obesity & metabolism, 23, 10, 2199, 2206, 2021年10月, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• Lowering of blood pressure and pulse rate by switching from DPP-4 inhibitor to luseogliflozin in patients with type 2 diabetes complicated with hypertension: A multicenter, prospective, randomized, open-label, parallel-group comparison trial (LUNA study).
  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10月, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• Glucokinase is required for high-starch diet-induced β-cell mass expansion in mice.
  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09月, ［査読有り］, ［国内誌］
  英語, 研究論文（学術雑誌）, AIMS/INTRODUCTION: We aimed to determine whether glucokinase is required for β-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 bodyweight, glucose tolerance, insulin sensitivity, insulin secretion and β-cell mass were assessed. RESULTS: Both HSTD-fed Gck+/+ and Gck+/- mice had significantly higher bodyweight 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-min 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. β-Cell mass was significantly larger in HSTD-fed Gck+/+ mice than that in NC-fed Gck+/+ mice. In contrast, the β-cell mass of the HSTD-fed Gck+/- mice was not different from that of the NC-fed Gck+/- mice. CONCLUSIONS: The results showed that HSTD feeding would increase pancreatic β-cell mass and insulin secretion in Gck+/+ , but not Gck+/- mice. This observation implies that glucokinase in β-cells would be required for the increase in β-cell mass induced by HSTD feeding.
• Impact of endogenous insulin secretion on the improvement of glucose variability in Japanese patients with type 2 diabetes treated with canagliflozin plus teneligliptin.
  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, 2021年08月, ［査読有り］, ［国内誌］
  英語, 研究論文（学術雑誌）, AIMS/INTRODUCTION: To identify the effect of combination therapy with a dipeptidyl peptidase-4 inhibitor and a sodium-glucose cotransporter 2 inhibitor compared with switching from a dipeptidyl peptidase-4 inhibitor to a sodium-glucose cotransporter 2 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 carried out 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.
• Improved time in range and postprandial hyperglycemia with canagliflozin in combination with teneligliptin: Secondary analyses of the CALMER study.
  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08月, ［査読有り］, ［国内誌］
  英語, 研究論文（学術雑誌）, 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.
• Favorable effect of sodium-glucose cotransporter 2 inhibitor, dapagliflozin, on non-alcoholic fatty liver disease compared with pioglitazone.
  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, 2021年07月, ［査読有り］, ［国内誌］
  英語, 研究論文（学術雑誌）, 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.
• Severe infection including disseminated herpes zoster triggered by subclinical Cushing's disease: a case report.
  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, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• Glucokinase Inactivation Paradoxically Ameliorates Glucose Intolerance by Increasing β-Cell Mass in db/db Mice.
  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, ［査読有り］, ［筆頭著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• Favourable effect of the sodium-glucose co-transporter-2 inhibitor canagliflozin plus the dipeptidyl peptidase-4 inhibitor teneligliptin in combination on glycaemic fluctuation: An open-label, prospective, randomized, parallel-group comparison trial (the CALMER study).
  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, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• Effects of switching from a dipeptidyl peptidase-4 inhibitor to luseogliflozin on nocturnal blood pressure in patients with type 2 diabetes: protocol for a multicentre, prospective, randomised, open-label, blinded endpoint parallel-group comparison study.
  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, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• Effects of dapagliflozin and/or insulin glargine on beta cell mass and hepatic steatosis in db/db mice.
  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］, ［筆頭著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• Reduction in glucose fluctuations in elderly patients with type 2 diabetes using repaglinide: A randomized controlled trial of repaglinide vs sulfonylurea.
  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］, ［筆頭著者］, ［国内誌］
  英語, 研究論文（学術雑誌）, 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.
• Effect of switching from pioglitazone to the sodium glucose co-transporter-2 inhibitor dapagliflozin on body weight and metabolism-related factors in patients with type 2 diabetes mellitus: An open-label, prospective, randomized, parallel-group comparison trial.
  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］, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• The role of glucokinase and insulin receptor substrate-2 in the proliferation of pancreatic beta cells induced by short-term high-fat diet feeding in mice.
  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］, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• Effect of the sodium-glucose cotransporter 2 inhibitor luseogliflozin on pancreatic beta cell mass in db/db mice of different ages.
  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］, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• Satisfaction and efficacy of switching from daily dipeptidyl peptidase-4 inhibitors to weekly trelagliptin in patients with type 2 diabetes-Randomized controlled study.
  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］, ［国内誌］
  英語, 研究論文（学術雑誌）, 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.