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Patients often present with severe fatty liver (FL) due to insulin deficiency at the onset of diabetic ketoacidosis (DKA). On the other hand, glycogenic hepatopathy (GH) is a possible cause of liver dysfunction in patients with DKA. We herein report a case of type 1 diabetes mellitus with severe FL at the onset of DKA, who demonstrated subsequent marked liver dysfunction after achieving an improvement of FL. As liver dysfunction persisted even after the FL improved, GH was suspected to be the cause of liver dysfunction. FL and GH have different prognoses and should therefore be differentiated using imaging studies and biopsies.

DOI： 10.2169/internalmedicine.3488-24

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AIMS/INTRODUCTION: We previously showed that glucokinase haploinsufficiency improves the glucose tolerance of db/db mice by preserving pancreatic β-cell mass and function. In the present study, we aimed to determine the effects of glucokinase haploinsufficiency on the β-cell mass and function of long-term high-fat, high-sucrose (HFHS) diet-fed mice. MATERIALS AND METHODS: Four-week-old male glucokinase haploinsufficient (Gck+/-) mice and 4-week-old male wild-type (Gck+/+) mice (controls) were each divided into two groups: an HFHS diet-fed group and a normal chow-fed group, and the four groups were followed until 16, 40 or 60 weeks-of-age. Their glucose tolerance, glucose-stimulated insulin secretion and β-cell mass were evaluated. In addition, islets were isolated from 40-week-old mice, and the expression of key genes was compared. RESULTS: Gck+/-HFHS mice had smaller compensatory increases in β-cell mass and glucose-stimulated insulin secretion than Gck+/+HFHS mice, and their glucose tolerance deteriorated from 16 to 40 weeks-of-age. However, their β-cell mass and glucose-stimulated insulin secretion did not decrease between 40 and 60 weeks-of-age, but rather, tended to increase, and there was no progressive deterioration in glucose tolerance. The expression of Aldh1a3 in pancreatic islets, which is high in several models of diabetes and is associated with an impairment in β-cell function, was high in Gck+/+HFHS mice, but not in Gck+/-HFHS mice. CONCLUSIONS: Glucokinase haploinsufficiency prevents the progressive deterioration of pancreatic β-cell mass/function and glucose tolerance in long-term HFHS diet-fed mice.

DOI： 10.1111/jdi.14307

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AIMS/INTRODUCTION: Sodium-glucose cotransporter 2 (SGLT2) inhibitors effectively and safely reduce fasting and postprandial hyperglycemia while promoting weight loss. However, their unique mechanism of action contributes to concerns regarding their safety. We therefore carried out a large-scale, non-commercial, investigator-initiated study on the safety and effectiveness of the SGLT2 inhibitor tofogliflozin. MATERIALS AND METHODS: This multicenter, open-label, uncontrolled, prospective observational study was carried out at hospitals and clinics across Japan in participants aged ≥20 years who were SGLT2 inhibitor-naïve and had an established diagnosis of type 2 diabetes. The primary endpoint was adverse drug reactions (ADRs) of special interest. Secondary endpoints included all other ADRs and adverse events, glycated hemoglobin (HbA1c), and weight loss. RESULTS: The study, carried out from June 2014 through February 2020, enrolled 11,480 participants from 1,103 medical institutions; 6,967 participants completed the 104-week follow up. The most common ADRs of special interest were urinary and genital tract infections (1.53%), followed by volume depletion (1.25%). Hypoglycemia occurred in 27 participants (0.24%), adverse events in 1,054 (9.18%) and ADRs in 645 (5.62%). HbA1c decreased by 0.85% (95% confidence interval 0.82%-0.88%) and bodyweight decreased by 3.05 kg (95% confidence interval 2.94-3.17 kg). The HbA1c target was achieved by 51.70% of participants for target HbA1c <7.0%, 85.3% for <8.0% and 5.4% for <6.0% at week 104. CONCLUSIONS: Tofogliflozin was associated with only mild or moderate ADRs characteristic of SGLT2 inhibitors, with no unpredictable, new, serious, or high-incidence adverse events or ADRs. This independent study confirmed the safety and effectiveness of tofogliflozin in adult type 2 diabetes patients.

DOI： 10.1111/jdi.14287

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

ABSTRACT

Aims/Introduction

PIONEER REAL Japan was a non‐interventional prospective study of oral semaglutide in adults with type 2 diabetes in Japanese clinical practice.

Materials and Methods

Adults naïve to injectable glucose‐lowering therapies initiated oral semaglutide in routine clinical practice and were followed for 34–44 weeks. The primary endpoint was change in glycated hemoglobin (HbA_1c) from baseline to end of study; the co‐primary endpoint was number of adverse events (AEs). Secondary endpoints included change in bodyweight from baseline to end of study. Analyses were also carried out for subgroups aged &lt;75 and ≥75 years.

Results

A total of 624 participants initiated oral semaglutide; 578 completed the study. Mean baseline HbA_1c and bodyweight were 7.7% and 72.4 kg, respectively. At end of study, estimated change (95% confidence interval [CI]) in HbA_1c from baseline was −0.7 percentage points (−0.77, −0.61) overall, −0.8 percentage points (−0.86, −0.67) in the &lt;75 years subgroup and −0.5 percentage points (−0.68, −0.41) in the ≥75 years subgroup (all P &lt; 0.0001). Estimated change (95% CI) in bodyweight was −2.8 (−3.19, −2.50) kg overall, −2.9 (−3.38, −2.49) kg in the &lt;75 years subgroup and − 2.7 (−3.18, −2.14) kg in the ≥75 years subgroup (all P &lt; 0.0001). AEs occurred in 161 (25.8%) participants: 99 of 423 (23.4%) and 62 of 201 (30.8%) participants in the &lt;75 and ≥75 years subgroups, respectively. Gastrointestinal AEs were the AEs most frequently leading to oral semaglutide discontinuation.

Conclusions

In routine clinical practice, HbA_1c and bodyweight were significantly reduced from baseline in adults initiating oral semaglutide, including those aged ≥75 years, with no new safety concerns.

DOI： 10.1111/jdi.14291

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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AIMS: This randomized, open-label, parallel-group, controlled trial compared the effects of dulaglutide and trelagliptin on beta-cell function in patients with type 2 diabetes. MATERIALS AND METHODS: For 24 weeks, participants received dulaglutide (0.75 mg/week) or trelagliptin (100 mg/week), after which beta-cell function was evaluated using a glucagon stimulation test-based disposition index. The primary endpoint was the change in disposition index over the 24-week treatment period. RESULTS: Fifty patients with type 2 diabetes who received metformin with or without basal insulin were randomized to receive dulaglutide or trelagliptin. Forty-eight patients completed the 24-week dulaglutide (n = 23) or trelagliptin (n = 25) treatment. The dulaglutide group reduced HbA1c levels more than the trelagliptin group (dulaglutide: - 0.77% ± 0.07% vs. trelagliptin: - 0.57% ± 0.07%; p = 0.04). Change in disposition index during the 24 weeks did not differ between the groups (dulaglutide: - 0.07 ± 1.08 vs. trelagliptin: + 0.59 ± 1.04; p = 0.66), but the dulaglutide group increased HOMA2-%β levels more than the trelagliptin group (dulaglutide: + 26.2 ± 4.3% vs. trelagliptin: + 5.4 ± 4.1%; p = 0.001). The dulaglutide group showed greater body fat mass reduction than the trelagliptin group (dulaglutide: - 1.2 ± 0.3 kg vs. trelagliptin: - 0.3 ± 0.2 kg; p = 0.02) without skeletal muscle mass loss. CONCLUSION: Dulaglutide and trelagliptin had similar effects on beta-cell function according to the glucagon stimulation test-based disposition index. However, dulaglutide promoted improved HOMA2-%β levels compared to trelagliptin and body fat mass was reduced without loss of skeletal muscle mass (UMIN-CTR 000024164). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13340-024-00717-6.

DOI： 10.1007/s13340-024-00717-6

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DOI： 10.1038/s41746-024-01158-w

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We evaluated the effectiveness of a mobile health (mHealth) intervention for diabetic kidney disease patients by conducting a 12-month randomized controlled trial among 126 type 2 diabetes mellitus patients with moderately increased albuminuria (urinary albumin-to-creatinine ratio (UACR): 30-299 mg/g creatinine) recruited from eight clinical sites in Japan. Using a Theory of Planned Behavior (TPB) behavior change theory framework, the intervention provides patients detailed information in order to improve patient control over exercise and dietary behaviors. In addition to standard care, the intervention group received DialBetesPlus, a self-management support system allowing patients to monitor exercise, blood glucose, diet, blood pressure, and body weight via a smartphone application. The primary outcome, change in UACR after 12 months (used as a surrogate measure of renal function), was 28.8% better than the control group's change (P = 0.029). Secondary outcomes also improved in the intervention group, including a 0.32-point better change in HbA1c percentage (P = 0.041). These improvements persisted when models were adjusted to account for the impacts of coadministration of drugs targeting albuminuria (GLP-1 receptor agonists, SGLT-2 inhibitors, ACE inhibitors, and ARBs) (UACR: -32.3% [95% CI: -49.2%, -9.8%] between-group difference in change, P = 0.008). Exploratory multivariate regression analysis suggests that the improvements were primarily due to levels of exercise. This is the first trial to show that a lifestyle intervention via mHealth achieved a clinically-significant improvement in moderately increased albuminuria.

DOI： 10.1038/s41746-024-01114-8

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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INTRODUCTION: As treatment agents for diabetes, liraglutide is a long-acting glucagon-like peptide 1 receptor agonist, and dipeptidyl peptidase 4 (DPP4) inhibitors are widely used because of their safety and tolerability. Regular treatment with liraglutide has been reported to significantly reduce blood glucose levels, but the impact of low-dose (0.3 mg) liraglutide on blood glucose levels immediately after treatment switching from a DPP4 inhibitor remains unknown. METHODS: We conducted a single-arm, retrospective, observational study in 55 inpatients with type 2 diabetes (T2D) to investigate the changes (Δ) in their blood glucose levels at six time points (6-point) from the day before (day -1) to the day after (day 1) by switching the antidiabetic treatment from a DPP4 inhibitor to liraglutide 0.3 mg (low-dose liraglutide) once daily. We also attempted to identify factors associated with the blood glucose-lowering effects of liraglutide. RESULTS: The median values of the changes in fasting, preprandial, and postprandial blood glucose levels and the fluctuations in the blood glucose levels expressed as the standard deviation of the 6-point blood glucose levels were significantly lower on day 1 than on day -1 (P < 0.05, P < 0.0001, P < 0.0001, P < 0.01, respectively); there were no cases of severe hypoglycemia. The Δ blood glucose levels were not associated with the baseline serum hemoglobin A1c values or with any markers of the insulin secreting capacity. There were no associations between the previously used blood glucose-lowering drug and the Δ blood glucose levels. CONCLUSION: Switching from a DPP4 inhibitor to low-dose (0.3 mg) liraglutide once daily significantly reduced the blood glucose levels and excursions of the blood glucose levels even from the very day after the treatment switch, with no serious adverse events.

DOI： 10.1007/s13300-024-01557-y

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INTRODUCTION: The real-world SPARTA Japan study confirmed the effectiveness and safety of the fixed-ratio combination of insulin glargine 100 U/mL plus lixisenatide (iGlarLixi) once daily over 6 months in Japanese people with type 2 diabetes (T2D). This post hoc analysis examined the impact of participant characteristics on the achievement of age-defined glycaemic targets with iGlarLixi therapy. METHODS: The retrospective, observational SPARTA Japan study included adults with T2D who initiated iGlarLixi. In this analysis, data from insulin-naïve and insulin-experienced participants were separately assessed to compare glycated haemoglobin (HbA1c), body weight and safety outcomes between those who achieved ('achieved' group) and those who did not achieve ('not-achieved' group) age-defined glycaemic targets after 6 months of iGlarLixi. The not-achieved group was further stratified by whether or not their iGlarLixi dose was increased during treatment. RESULTS: In total, 418 participants were included in this analysis (138 insulin naïve and 280 insulin experienced). Among both insulin-naïve and insulin-experienced participants, those in the achieved group were older and had lower baseline HbA1c than those in the not-achieved group. Compared with the not-achieved group, the achieved group showed significantly greater HbA1c reductions from baseline (in both insulin-naïve and insulin-experienced participants) and significantly greater body weight reductions (in insulin-naïve participants), despite some participants in the not-achieved group receiving significantly higher insulin glargine doses than those in the achieved group. In both insulin-naïve and insulin-experienced participants, the incidence of hypoglycaemia and gastrointestinal-related adverse events was similar in the achieved and not-achieved groups. In a multivariate analysis, glycaemic target achievement was significantly more likely in older individuals and those who lost weight during iGlarLixi treatment. CONCLUSIONS: Achievement of age-defined glycaemic targets with iGlarLixi treatment for 6 months was significantly affected by increased age and body weight loss, regardless of prior insulin exposure. TRIAL REGISTRATION: UMIN-CTR Trials Registry, UMIN000044126; registered 10 May 2021.

DOI： 10.1007/s13300-024-01531-8

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BACKGROUND: Increasing physical activity improves glycemic control in patients with type 2 diabetes (T2D). Mobile health (mHealth) interventions have been proven to increase exercise, but engagement often fades with time. As the use of health behavior theory in mHealth design can increase effectiveness, we developed StepAdd, an mHealth intervention based on the constructs of social cognitive theory (SCT). StepAdd improves exercise behavior self-efficacy and self-regulation through the use of goal-setting, barrier-identifying, and barrier-coping strategies, as well as automatic feedback functions. A single-arm pilot study of StepAdd among 33 patients with T2D showed a large increase in step count (mean change of 4714, SD 3638 daily steps or +86.7%), along with strong improvements in BMI (mean change of -0.3 kg/m2) and hemoglobin A1c level (mean change of -0.79 percentage points). OBJECTIVE: In this study, we aim to investigate the efficacy and safety of StepAdd, an mHealth exercise support system for patients with T2D, via a large, long, and controlled follow-up to the pilot study. METHODS: This is a randomized, open-label, multicenter study targeting 160 patients with T2D from 5 institutions in Japan with a 24-week intervention. The intervention group will record daily step counts, body weight, and blood pressure using the SCT-based mobile app, StepAdd, and receive feedback about these measurements. In addition, they will set weekly step count goals, identify personal barriers to walking, and define strategies to overcome these barriers. The control group will record daily step counts, body weight, and blood pressure using a non-SCT-based placebo app. Both groups will receive monthly consultations with a physician who will advise patients regarding lifestyle modifications and use of the app. The 24-week intervention period will be followed by a 12-week observational period to investigate the sustainability of the intervention's effects. The primary outcome is between-group difference in the change in hemoglobin A1c values at 24 weeks. The secondary outcomes include other health measures, measurements of steps, measurements of other behavior changes, and assessments of app use. The trial began in January 2023 and is intended to be completed in December 2025. RESULTS: As of September 5, 2023, we had recruited 44 patients. We expect the trial to be completed by October 8, 2025, with the follow-up observation period being completed by December 31, 2025. CONCLUSIONS: This trial will provide important evidence about the efficacy of an SCT-based mHealth intervention in improving physical activities and glycemic control in patients with T2D. If this study proves the intervention to be effective and safe, it could be a key step toward the integration of mHealth as part of the standard treatment received by patients with T2D in Japan. TRIAL REGISTRATION: Japan Registry of Clinical Trials (JRCT) jRCT2032220603; https://rctportal.niph.go.jp/en/detail?trial_id=jRCT2032220603. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/53514.

DOI： 10.2196/53514

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AIMS: This study aimed to clarify the renal influence of glucagon-like peptide 1 receptor agonists (GLP1Ras) with or without sodium-glucose co-transporter 2 inhibitors (SGLT2is) on Japanese patients with type 2 diabetes mellitus (T2DM). METHODS: We retrospectively extracted 547 patients with T2DM who visited the clinics of members of Kanagawa Physicians Association. The progression of albuminuria status and/or a ≥ 15% decrease in the estimated glomerular filtration rate (eGFR) per year was set as the renal composite outcome. Propensity score matching was performed to compare GLP1Ra-treated patients with and without SGLT2i. RESULTS: After matching, 186 patients in each group were compared. There was no significant difference of the incidence of the renal composite outcomes (17% vs. 20%, P = 0.50); however, the annual decrease in the eGFR was significantly smaller and the decrease in the urine albumin-to-creatinine ratio was larger in GLP1Ra-treated patients with the concomitant use of SGLT2is than in those without it (-1.1 ± 5.0 vs. -2.8 ± 5.1 mL/min/1.73 m2, P = 0.001; and -0.08 ± 0.61 vs. 0.05 ± 0.52, P = 0.03, respectively). CONCLUSION: The concomitant use of SGLT2i with GLP1Ra improved the annual decrease in the eGFR and the urine albumin-to-creatinine ratio in Japanese patients with T2DM.

DOI： 10.1097/XCE.0000000000000292

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AIMS/INTRODUCTION: This study evaluated the effects of the Medtronic MiniMed 770G hybrid closed-loop system on glycemic control and psychological aspects in persons with type 1 diabetes mellitus. MATERIALS AND METHODS: This 3-month prospective observational study included 22 participants with type 1 diabetes mellitus who used the Medtronic MiniMed 640G predictive low-glucose suspend system and were switched to the 770G system. Time in the range of 70-180 mg/dL and glycated hemoglobin levels were evaluated; satisfaction, emotional distress and quality of life were assessed using self-reported questionnaires, including the Diabetes Treatment Satisfaction Questionnaire Status, Problem Area in Diabetes and Diabetes Therapy-Related Quality of Life. RESULTS: Time in the range of 70-180 mg/dL increased (63.5 ± 13.4 to 73.0 ± 10.9% [mean ± standard deviation], P = 0.0010), and time above the range of 181-250 mg/dL decreased (26.9 ± 8.9 to 19.6 ± 7.1%, P < 0.0005). Glycated hemoglobin levels decreased (7.7 ± 1.0 to 7.2 ± 0.8%, P = 0.0021). The percentage of participants with time below the range of 54-69 mg/dL <4% of readings increased from 91% to 100% (P < 0.0005). No significant changes were detected in the satisfaction, emotional distress and quality of life levels, but increased sensor calibration might be related to worsened emotional distress and quality of life. CONCLUSIONS: The hybrid closed-loop system decreased hyperglycemia and minimized hypoglycemia, but did not improve psychological aspects compared with the predictive low-glucose suspend system, probably because sensor calibration was increased.

DOI： 10.1111/jdi.14103

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Sodium-glucose cotransporter 2 inhibitor (SGLT2-I) shows excellent antihypertensive effects in addition to its hypoglycemic effects. However, whether body mass index (BMI) affects the antihypertensive effect of SGLT2-I remains unknown. We investigated the impact of baseline BMI on the achievement of target blood pressure (BP) with SGLT2-I treatment in Japanese patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). We retrospectively evaluated 447 Japanese patients with T2DM and CKD treated with SGLT2-I for at least 1 year. The primary outcome was achieving the target BP (<130/80 mmHg) after SGLT2-I treatment. Patients were divided into two groups according to a baseline BMI of 29.1 determined by receiver operating characteristic analysis and analyzed in a cohort model with propensity score matching. In each group, 130 patients were compared by propensity score matching. The target BP achievement rate was significantly higher in the BMI < 29.1 group than in the BMI ≥ 29.1 group (34% and 21%, respectively, p = 0.03). The odds ratio for achieving the target BP in the BMI ≥ 29.1 group was 0.50 (95% confidence interval, 0.28-0.90, p = 0.02). The BMI < 29.1 group had significantly lower systolic and diastolic BPs after SGLT2-I treatment than the BMI ≥ 29.1 group. Only the BMI < 29.1 group was showed a significant decrease in the logarithmic albumin-to-creatinine ratio from baseline after SGLT2-I treatment. In patients with T2DM and CKD, baseline BMI was associated with the antihypertensive effects of SGLT2-I. Patients in the lower baseline BMI group were more likely to achieve the target BP after SGLT2-I treatment. Pretreatment BMI affects the antihypertensice effect of SGLT2 inhibirors in patients with T2DM and CKD.

DOI： 10.1038/s41440-023-01464-y

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Language：Japanese   Publisher：(一社)日本糖尿病・妊娠学会  

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Language：Japanese   Publisher：(一社)日本糖尿病・妊娠学会  

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Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes are interacting comorbidities of obesity, and increased hepatic de novo lipogenesis (DNL), driven by hyperinsulinemia and carbohydrate overload, contributes to their pathogenesis. Fatty acid synthase (FASN), a key enzyme of hepatic DNL, is upregulated in association with insulin resistance. However, the therapeutic potential of targeting FASN in hepatocytes for obesity-associated metabolic diseases is unknown. Here, we show that hepatic FASN deficiency differentially affects NAFLD and diabetes depending on the etiology of obesity. Hepatocyte-specific ablation of FASN ameliorated NAFLD and diabetes in melanocortin 4 receptor-deficient mice but not in mice with diet-induced obesity. In leptin-deficient mice, FASN ablation alleviated hepatic steatosis and improved glucose tolerance but exacerbated fed hyperglycemia and liver dysfunction. The beneficial effects of hepatic FASN deficiency on NAFLD and glucose metabolism were associated with suppression of DNL and attenuation of gluconeogenesis and fatty acid oxidation, respectively. The exacerbation of fed hyperglycemia by FASN ablation in leptin-deficient mice appeared attributable to impairment of hepatic glucose uptake triggered by glycogen accumulation and citrate-mediated inhibition of glycolysis. Further investigation of the therapeutic potential of hepatic FASN inhibition for NAFLD and diabetes in humans should thus consider the etiology of obesity.

DOI： 10.1172/jci.insight.161282

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DOI： 10.1507/endocrj.EJ23-0186

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AIMS/INTRODUCTION: The Dementia Assessment Sheet for Community-based Integrated Care System 8-items (DASC-8) assesses memory, orientation, instrumental activities of daily living and basic activities of daily living. Category I (DASC-8 score ≤10), category II (11 ≤ DASC-8 score ≤16) and category III (DASC-8 score ≥17) have been defined. Based on these categories, the glycemic targets in diabetes patients aged ≥65 years have been proposed by the Japan Diabetes Society and the Japan Geriatrics Society Joint Committee. DASC-8 is difficult to apply to patients without family members or supportive persons. We propose a verbal fluency test as the screening tool. MATERIALS AND METHODS: We enrolled 69 inpatients aged ≥65 years with type 2 diabetes, who were administered the DASC-8 and VF tests, which included recalling animal names and common nouns starting with a specified letter in 1 min. The relationship between DASC-8 and verbal fluency test scores was investigated. RESULTS: Animal fluency correlated with DASC-8 scores after adjustment for patient characteristics. Animal scores correlated with orientation, instrumental activities of daily living and basic activities of daily living scores of DASC-8, and tended to show a relationship with DASC-8 memory scores. An animal score ≥8 predicted category I with a sensitivity of 89% and a specificity of 57%. An animal score ≤6 predicted category III with a sensitivity of 85% and a specificity of 67%. CONCLUSIONS: Animal scores would be useful in predicting the categories of DASC-8. Animal fluency could be a screening tool of DASC-8 when a patient's family member or supportive person is absent.

DOI： 10.1111/jdi.14040

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We investigated the pathophysiology of the dawn phenomenon by examining the effects of changes in blood glucose levels from late night to early morning on various hormones in a group taking glargine BS and a group taking Lantus XR, with the goal of achieving better glycemic control. Patients with types 1 and 2 diabetes scheduled for inpatient education were divided into BS and XR groups. Blood glucose levels were tracked from 0:00 to 7:00, while blood samples were extracted at 3:00 and 7:00 to measure glucose levels and hormones related to the dawn phenomenon. Overall, we analyzed blood sample and intermittently scanned Continuous Glucose Monitoring data of 43 and 40 patients, respectively. From 0:00 to 7:00, the mean blood glucose was significantly lower in the BS group, although the fluctuation was similar (p < 0.0001). The BS group also exhibited significantly higher ∆ACTH (p = 0.0215) and ∆ cortisol (p = 0.0430) than the XR group. In the BS group, ∆Glu exhibited a significant negative correlation with ∆ACTH and ∆cortisol (p = 0.0491). Similar findings were not observed in the XR group. These results suggest that XR may be a better choice for long-acting insulin since it is less likely to induce cortisol secretion. Further, analysis of the dawn phenomenon and non-dawn phenomenon groups showed the mean CPR levels at 3:00 and 7:00 were significantly higher in the latter (p = 0.0135). This supports the conventional belief that appropriate basal insulin replacement therapy is a beneficial treatment for the dawn phenomenon.

DOI： 10.1507/endocrj.EJ22-0562

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BACKGROUND: This ANAFIE Registry sub-analysis investigated 2-year outcomes and oral anticoagulant (OAC) use stratified by glycated hemoglobin (HbA1c) levels among Japanese patients aged ≥ 75 years with non-valvular atrial fibrillation (NVAF) with and without clinical diagnosis of diabetes mellitus (DM). METHODS: The ANAFIE Registry was a large-scale multicenter, observational study conducted in Japan; this sub-analysis included patients with baseline HbA1c data at baseline. The main endpoints evaluated (stroke/systemic embolic events [SEE], major bleeding, intracranial hemorrhage, cardiovascular death, all-cause death, and net clinical outcome [a composite of stroke/SEE, major bleeding, and all-cause death]) were stratified by HbA1c levels (< 6.0%; 6.0% to < 7.0%; 7.0% to < 8.0%; and ≥ 8.0%). RESULTS: Of 17,526 patients with baseline HbA1c values, 8725 (49.8%) patients had HbA1c < 6.0%, 6700 (38.2%) had 6.0% to < 7.0%, 1548 (8.8%) had 7.0% to < 8.0%, and 553 (3.2%) had ≥ 8.0%. Compared with other subgroups, patients with HbA1c ≥ 8.0% were more likely to have lower renal function, higher CHA2DS2-VASc and HAS-BLED scores, higher prevalence of non-paroxysmal AF, and lower direct OAC (DOAC) administration, but higher warfarin administration. The HbA1c ≥ 8.0% subgroup had higher event rates for all-cause death (log-rank P = 0.003) and net clinical outcome (log-rank P = 0.007). Similar trends were observed for stroke/SEE. In multivariate analysis, risk of all-cause death (adjusted hazard ratio [aHR]: 1.46 [95% confidence interval 1.11-1.93]) and net clinical outcome (aHR 1.33 [1.05-1.68]) were significantly higher in the HbA1c ≥ 8.0% subgroup. No significant differences were observed in risks of major bleeding or other outcomes in this and other subgroups. No interaction was observed between HbA1c and OACs. Use/non-use of antidiabetic drugs was not associated with risk reduction; event risks did not differ with/without injectable antidiabetic drugs. CONCLUSIONS: Among elderly Japanese patients with NVAF, only HbA1c ≥ 8.0% was associated with increased all-cause death and net clinical outcome risks; risks of the events did not increase in other HbA1c subgroups. Relative event risks between patients treated with DOACs and warfarin were not modified by HbA1c level. TRIAL REGISTRATION: UMIN000024006; date of registration: September 12, 2016.

DOI： 10.1186/s12933-023-01915-3

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Imeglimin and metformin act in metabolic organs, including β-cells, via different mechanisms. In the present study, we investigated the impacts of imeglimin, metformin, or their combination (Imeg + Met) on β-cells, the liver, and adipose tissues in db/db mice. Imeglimin, metformin, or Imeg + Met treatment had no significant effects on glucose tolerance, insulin sensitivity, respiratory exchange ratio, or locomotor activity in db/db mice. The responsiveness of insulin secretion to glucose was recovered by Imeg + Met treatment. Furthermore, Imeg + Met treatment increased β-cell mass by enhancing β-cell proliferation and ameliorating β-cell apoptosis in db/db mice. Hepatic steatosis, the morphology of adipocytes, adiposity assessed by computed tomography, and the expression of genes related to glucose or lipid metabolism and inflammation in the liver and fat tissues showed no notable differences in db/db mice. Global gene expression analysis of isolated islets indicated that the genes related to regulation of cell population proliferation and negative regulation of cell death were enriched by Imeg + Met treatment in db/db islets. In vitro culture experiments confirmed the protective effects of Imeg + Met against β-cell apoptosis. The expression of Snai1, Tnfrsf18, Pdcd1, Mmp9, Ccr7, Egr3, and Cxcl12, some of which have been linked to apoptosis, in db/db islets was attenuated by Imeg + Met. Treatment of a β-cell line with Imeg + Met prevented apoptosis induced by hydrogen peroxide or palmitate. Thus, the combination of imeglimin and metformin is beneficial for the maintenance of β-cell mass in db/db mice, probably through direct action on β-cells, suggesting a potential strategy for protecting β-cells in the treatment of type 2 diabetes.

DOI： 10.1210/endocr/bqad095

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BACKGROUND: Antithyroid drugs (ATDs) are frequently used to achieve euthyroidism in patients with hyperthyroidism. ATDs cause characteristic common and rare adverse events; however, comprehensive comparisons between methimazole (MMI) and propylthiouracil (PTU) in terms of adverse events are limited. METHODS: In this study, we thoroughly explored adverse events in association with MMI and PTU use with a disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database and evaluated the prevalence of MMI and PTU prescriptions using the National Database of Health Insurance Claims and Specific Health Checkups (NDB) Open Data Japan. We analyzed 3271 cases of MMI use and 1029 cases of PTU use with respect to 9789 preferred terms (PTs) for adverse events registered in the JADER database by calculating and comparing reporting odds ratios (RORs). RESULTS: We found that 8 PTs, including agranulocytosis (p < 0.0001, 4.01-fold), aplasia cutis congenita (p < 0.0001, 123.22-fold), and exomphalos (p = 0.0002, 22.17-fold), demonstrated significantly higher RORs (more than 4-fold) for MMI use than for PTU use. Nineteen PTs, including anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (p < 0.0001, 29.84), rapidly progressive glomerulonephritis (p < 0.0001, 6.44), and pulmonary alveolar hemorrhage (p < 0.0001, 7.77), had RORs for PTU use more than four times those for MMI use. NDB Open Data Japan showed more frequent PTU prescriptions than MMI prescriptions for women of reproductive age. CONCLUSIONS: This large-scale study confirmed that a variety of congenital malformations were identified as having significantly high RORs for MMI use, while diseases related to ANCA-associated vasculitis were specific to PTU.

DOI： 10.1089/thy.2023.0030

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DOI： 10.2188/jea.JE20220329

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INTRODUCTION: iGlarLixi, a fixed-ratio combination of insulin glargine 100 U/mL and the glucagon-like peptide 1 receptor agonist (GLP-1 RA) lixisenatide, is one option for treatment intensification in individuals with type 2 diabetes (T2D) who are unable to achieve targeted glycaemic control with their current glucose-lowering agent. Real-world data on the impact of prior treatment on the effectiveness and safety of iGlarLixi may be useful to guide individualised treatment decisions. METHODS: This analysis of the 6-month, retrospective, observational SPARTA Japan study compared glycated haemoglobin (HbA1c), body weight and safety for pre-specified subgroups defined by prior treatment: post oral antidiabetic agent (OAD), GLP-1 RA, basal insulin (BI) + OADs (BOT), GLP-1 RA + BI or multiple daily injections (MDI). The post BOT and MDI subgroups were further divided on the basis of prior dipeptidyl peptidase 4 inhibitor (DPP-4i) use, and the post MDI group was divided on the basis of whether participants continued bolus insulin. RESULTS: Of the 432 participants in the full analysis set (FAS), 337 were included in this subgroup analysis. Across subgroups, mean baseline HbA1c ranged from 8.49% to 9.18%. iGlarLixi significantly (p < 0.05) reduced mean HbA1c from baseline in all but the post GLP-1 RA + BI group. At 6 months, these significant reductions ranged from 0.47% to 1.27%. Prior DPP-4i exposure had no impact on the HbA1c-lowering effect of iGlarLixi. Mean body weight decreased significantly in the FAS (0.5 kg) and the post BOT (1.2 kg) and MDI (1.5 and 1.9 kg) subgroups but increased in the post GLP-1 RA subgroup (1.3 kg). iGlarLixi treatment was generally well tolerated, with very few participants discontinuing because of hypoglycaemia or gastrointestinal events. CONCLUSION: In participants with suboptimal glycaemic control on various regimens, 6 months of iGlarLixi treatment improved HbA1c in all but one prior treatment subgroup (GLP-1 RA + BI), and was generally well tolerated. TRIAL REGISTRATION: UMIN-CTR Trials Registry, UMIN000044126; registered 10 May 2021.

DOI： 10.1007/s13300-023-01373-w

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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INTRODUCTION: Few studies have examined the effects of glucagon-like peptide-1 receptor agonist switching, particularly in Japanese patients. Therefore, we aimed to investigate the effects of switching from liraglutide to semaglutide or dulaglutide on blood glucose, body weight, and the occurrence of adverse effects in clinical practice. MATERIALS AND METHODS: This was an open-label, prospective, randomized, parallel-group controlled trial. Patients with type 2 diabetes treated with liraglutide (0.6 or 0.9 mg) at Yokosuka Kyosai Hospital in Japan were recruited from September 2020 to March 2022 and, after obtaining informed consent, randomly assigned to the semaglutide or dulaglutide group (1:1). Changes in the glycated hemoglobin level from baseline to weeks 8, 16, and 26 were evaluated post-treatment. RESULTS: Initially, 32 participants were enrolled, of whom 30 completed the study. Glycemic control was significantly better in the semaglutide group than in the dulaglutide group (-0.42 ± 0.49% vs -0.00 ± 0.34%, P = 0.0120). Body weight significantly decreased in the semaglutide group (-2.6 ± 3.6 kg, P = 0.0153), whereas no change was observed in the dulaglutide group (-0.1 ± 2.7 kg, P = 0.8432). We found a significant difference in body weight between the groups (P = 0.0469). The proportion of participants who reported adverse events was 75.0% and 18.8% in the semaglutide and dulaglutide groups, respectively. One patient in the semaglutide group had difficulty continuing treatment due to severe vomiting and weight loss. CONCLUSIONS: Switching from once-daily liraglutide to once-weekly semaglutide 0.5 mg significantly improved glycemic control and body weight compared with switching to once-weekly dulaglutide 0.75 mg.

DOI： 10.1111/jdi.14000

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AIMS/INTRODUCTION: We carried out a cross-sectional study of people with type 2 diabetes mellitus to elucidate the association between sleep duration and food intake. MATERIALS AND METHODS: Overall, 2,887 participants with type 2 diabetes mellitus (mean age 63.0 years; 61.1% men; mean glycated hemoglobin level 7.5%) were included in this study. The participants' self-reported dietary habits and sleep duration were evaluated using a brief self-administered dietary history questionnaire and Pittsburgh Sleep Quality Index, respectively. The participants were categorized into the following four groups based on sleep duration: <6, 6-6.9, 7-7.9 (reference) and ≥8 h. RESULTS: No significant differences were observed between the groups regarding energy intake (kcal/day), absolute intake (g/day) or relative intake (% energy) of carbohydrates, total fat, proteins and fibers. However, confectionery intake was higher in the <6 h group and lower in the ≥8 h group than in the reference group after adjustment for confounding factors. In multivariate analysis, sleep durations <6 h and ≥8 h significantly correlated with increased (95% confidence interval 0.55 to 3.6; P = 0.0078) and decreased (95% confidence interval -4.0 to -0.32; P = 0.021) confectionery intake, respectively. Confectionery intake was positively correlated with female sex, glycated hemoglobin level and dyslipidemia, whereas it was negatively correlated with alcohol consumption and current smoking status. CONCLUSIONS: Short sleep duration is associated with high confectionery intake in people with type 2 diabetes mellitus; this might disturb their glycemic control. Therefore, short sleepers with type 2 diabetes mellitus could improve their glycemic control by avoiding confectionery intake and maintaining adequate sleep duration.

DOI： 10.1111/jdi.13987

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Metformin monotherapy as first-line treatment for patients with type 2 diabetes (T2D) has been shown to effectively improve blood glucose levels and motivation to undergo treatment and prevent complications. However, no studies have reported its effect when combined with other drugs or compared the effect based on administration time. This study aimed to investigate the effect of metformin administration in Japanese patients with T2D, examine how the introduction line impacts the effect of metformin, and examine the characteristics of patients demonstrating improved blood glucose levels. Data on characteristics of patients who were newly prescribed metformin with no shifting of hypoglycemic agents in the subsequent 24-week observation period, and their age [mean, 56.8 years], body mass index [mean, 27.5 kg/m2], glycated hemoglobin [HbA1c] [mean, 8.1%], and duration of diabetes [mean, 3.0 years] were obtained from the medical records of 201 patients. The changes in HbA1c by introduction line after 24 weeks were -1.59%, -0.91%, -0.89%, and -0.65% in the first, second, third, and fourth induction lines, respectively; earlier introduction more significantly improved blood glucose. The factors significantly associated with HbA1c changes were early introduction, high baseline HbA1c, high estimated glomerular filtration rate, decreased insulin secretion, short estimated duration of diabetes, and increased metformin dose. Furthermore, factors contributing to the largest HbA1c improvement by metformin were high baseline HbA1c and early administration. Metformin is expected to lower blood glucose levels in Japanese patients with T2D, even in those with decreased insulin secretion, due to its early introduction as a first-line drug.

DOI： 10.1507/endocrj.EJ22-0330

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OBJECTIVE: The study aimed to evaluate the long-term effects of combination therapy comprising dulaglutide and long-acting insulin, on glycemic control in patients with type 2 diabetes. METHODS: This retrospective observational study included 20 patients with type 2 diabetes who underwent blood glucose management with intensive insulin therapy for a limited period. All patients were switched from intensive insulin therapy to combination therapy comprising dulaglutide and long-acting insulin. Hemoglobin A1c was evaluated before and 4, 12, and 24 weeks after starting combination therapy. Continuous glucose monitoring was conducted before and 1 and 24 weeks after starting combination therapy. RESULTS: Hemoglobin A1c levels were significantly reduced after 4, 12, and 24 weeks of combination therapy (- 2.2% ± 0.4%, P < 0.0001; - 3.7% ± 0.8%, P = 0.0003; and - 3.6% ± 0.8%, P = 0.0005, respectively). Glycemic variability (% coefficient of variation) was significantly decreased after 1 and 24 weeks of combination therapy (- 5.7% ± 2.1%, P = 0.011; and - 8.7% ± 2.4%, P = 0.003, respectively) and the percentage of readings and time > 250 mg/dL at 24 weeks was significantly improved (- 2.2% ± 0.8%, P = 0.019). CONCLUSION: Combination therapy with dulaglutide and long-acting insulin resulted in better blood glucose control than intensive insulin therapy, which persisted for 24 weeks. Combination therapy also reduced blood glucose fluctuations and the number of self-injections needed. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13340-022-00592-z.

DOI： 10.1007/s13340-022-00592-z

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INTRODUCTION: Many individuals with type 2 diabetes (T2D) experience suboptimal glycemic control. Treatment intensification options include fixed-ratio combination products containing a basal insulin and a glucagon-like peptide-1 receptor agonist, such as iGlarLixi (insulin glargine 100 U/mL and lixisenatide). This study aimed to provide real-world evidence of the effect of iGlarLixi in Japanese clinical practice. METHODS: SPARTA Japan was a non-comparative, observational study conducted at 27 institutions in Japan. Anonymized individual-level data from adults with T2D receiving iGlarLixi in routine clinical practice were retrospectively collected. The primary study objective was to assess the impact of iGlarLixi on the change in glycated hemoglobin (HbA1c) at 6 months' post-treatment initiation, with preplanned subanalyses to determine the influence of baseline characteristics. Secondary and exploratory endpoints included assessment of the proportion of individuals achieving HbA1c targets, change in body weight, and incidence and severity of hypoglycemia and gastrointestinal events. RESULTS: The full analysis set included 432 individuals, with data available at 6 months for 426. Of the 432 individuals, the mean (SD) age at baseline was 61.6 (12.8) years and the majority had a T2D duration of ≥ 10 years [mean (SD) 13.3 (10.4) years]. At 6 months, HbA1c had significantly decreased versus baseline ( -0.85%; P < 0.0001), with a greater decrease in those aged < 65 years, with a shorter duration of T2D and higher baseline HbA1c. A significant increase in the proportion of participants achieving age-specific HbA1c versus baseline was observed. Mean body weight decreased by 0.5 kg (P = 0.0034 versus baseline). There were few hypoglycemia and gastrointestinal events (in individuals with HbA1c data); no severe hypoglycemic events were reported. CONCLUSIONS: The results of this real-world study indicate that iGlarLixi may improve glycemic control without serious adverse events in Japanese individuals with T2D who have suboptimal glycemic control on current treatment regimens and switch to iGlarLixi. TRIAL REGISTRATION: UMIN-CTR Trials Registry, UMIN000044126; registered 10 May 2021.

DOI： 10.1007/s13300-022-01333-w

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Obesity and diabetes are independent risk factors for death during sepsis. S100A8, an alarmin, is related to inflammation, obesity, and diabetes. Here, we examine the role of S100A8 in sepsis of obesity and diabetes models. Injection of S100A8 prolongs the survival of septic mice induced by lethal endotoxemia, Escherichia coli injection, or cecal ligation and puncture. S100A8 decrease the LPS-induced expression of proinflammatory cytokines in peritoneal macrophages by inhibiting TLR4-mediated signals in an autocrine manner. db/db, ob/ob, and western diet-fed mice demonstrate reduced upregulation of S100A8 induced by LPS treatment in both serum and peritoneal cells. These mice also show shorter survival after LPS injection, and S100A8 supplementation prolonged the survival. While myelomonocytic cells-specific S100A8-deficient mice (Lyz2 cre :S100A8 floxed/floxed ) exhibit shorter survival after LPS treatment, S100A8 supplementation prolonged the survival. Thus, myelomonocytic cell-derived S100A8 is crucial for protection from sepsis, and S100A8 supplementation improves sepsis, particularly in mice with obesity and diabetes.

DOI： 10.1016/j.isci.2022.105662

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INTRODUCTION: We aimed to assess the efficacy and safety of lixisenatide and basal insulin (BI) according to timing of treatment initiation, treatment compliance, and number of concomitant daily injections in Japanese individuals with type 2 diabetes (T2D). METHODS: Each substudy analyzed subgroup data from the 3-year post-marketing surveillance PRANDIAL study. Endpoints included glycated hemoglobin (HbA1c), postprandial glucose, treatment response (HbA1c < 7.0% at week 24 and 156), and safety. Changes in HbA1c levels were analyzed using paired t tests; between-group comparisons were made using analysis of variance (ANOVA). RESULTS: Of 2679 participants, 46.5% initiated BI before lixisenatide, 12.0% the same day, 2.7% between 1 and 90 days, and 2.8% at 91 or more days after lixisenatide; 36.0% did not receive BI. Overall, 85.4% of patients were compliant with lixisenatide treatment. The majority of patients (52.4%) received two injections/day (one was lixisenatide). Compared with other subgroups taking BI and lixisenatide, the subgroup starting them simultaneously had a mean change in HbA1c of - 0.69% [8 mmol/mol] (vs + 0.07% [0.8 mmol/mol] to - 0.79% [9 mmol/mol]) and numerically higher treatment response (21.0% vs 8.3-18.7%), but more hypoglycemia (8.1% vs 2.3-2.8%). CONCLUSIONS: Japanese people with T2D achieved better glycemic control by simultaneous as opposed to sequential initiation of lixisenatide and BI.

DOI： 10.1007/s12325-022-02311-1

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DOI： 10.1038/s41598-022-13888-6

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Other Link： https://www.nature.com/articles/s41598-022-13888-6

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Singleton pregnant women with gestational diabetes mellitus (GDM) are at an increased risk of adverse maternal and neonatal outcomes. Multiple pregnancies are associated with increased risks of perinatal complications; however, the impact of GDM on maternal and neonatal outcomes in multiple pregnancies is unknown, and there are currently few reports on GDM status in twin pregnancies. This study aimed to compare the background and perinatal outcomes between Japanese twin pregnancies with and without GDM at a perinatal center in Japan. Additionally, the clinical course of GDM was investigated. In this retrospective cohort study, women with twin pregnancies underwent GDM screening at Yokohama City University Medical Center from January 2011 to December 2016. Overall, 307 twin pregnancies were divided into GDM (47 cases, 15.3%) and non-GDM (260 cases, 84.7%) groups. GDM-associated pregnancy complications, GDM status, and pregnancy outcomes were ascertained. Women with GDM were older and had a higher pre-pregnancy body mass index than those without GDM. Glycemic control was good in all patients, and there was no difference in delivery outcomes between the two groups. Gestational weight gain was lower in pregnant women with GDM (+8.0 kg) than in those without GDM (+11.8 kg), suggesting the impact of strict nutritional guidance on twin pregnancies with GDM. In conclusion, twin pregnancies with GDM did not have different delivery outcomes compared to those without GDM. To manage twin pregnancies with GDM, this study suggests that it is important to monitor patients' weight and blood glucose levels.

DOI： 10.1507/endocrj.EJ21-0537

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AIMS/INTRODUCTION: This study was designed and carried out to investigate the association of dipeptidyl peptidase-4 inhibitor (DPP-4i) use with pancreatic cancer (PC) in individuals with diabetes in Japan. MATERIALS AND METHODS: The JMDC Claims Database, which contains the medical and prescription information of Japanese employment-based health insurance programs, was used. The primary outcome was duration to the first occurrence of PC (International Classification of Diseases 10th Revision code C25), both all and hospitalized, from prescription of DPP-4is or other oral glucose-lowering agents (GLAs). RESULTS: Individuals with diabetes who received DPP-4is (n = 61,430) or other oral GLAs (n = 83,304) were analyzed. Follow-up periods (median [interquartile range]) were 17 months (8-33) for DPP-4is and 14 months (7-28) for other oral GLAs. Kaplan-Meier curve analysis to determine the duration of first use of DPP4i or other oral GLA to diagnosis of PC disclosed no differences between the two groups in duration to all or hospitalized PC (log-rank test: all, P = 0.7140; hospitalized, P = 0.3446). Cox proportional hazards models showed that use of DPP-4is did not affect the PC risk adjusted for medications, age, sex and risk comorbidities (all, hazard ratio 1.1, 95% confidence interval 0.8-1.3, P = 0.6518; hospitalized, hazard ratio 1.1, 95% confidence interval 0.8-1.4, P = 0.6662). Similar results were obtained when individuals with ≥2 years oral GLA treatment and those with medical checkup data (e.g., smoking or drinking habit) available were analyzed. CONCLUSION: This database study shows that there is not a significant PC risk due to DPP-4i treatment in individuals with diabetes in Japan, but larger studies with longer follow up are required to confirm these findings.

DOI： 10.1111/jdi.13921

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Prevention or amelioration of declining β cell mass is a potential strategy to cure diabetes. Here, we report the pathways utilized by β cells to robustly replicate in response to acute insulin resistance induced by S961, a pharmacological insulin receptor antagonist. Interestingly, pathways that include CENP-A and the transcription factor E2F1 that are independent of insulin signaling and its substrates appeared to mediate S961-induced β cell multiplication. Consistently, pharmacological inhibition of E2F1 blocks β-cell proliferation in S961-injected mice. Serum from S961-treated mice recapitulates replication of β cells in mouse and human islets in an E2F1-dependent manner. Co-culture of islets with adipocytes isolated from S961-treated mice enables β cells to duplicate, while E2F1 inhibition limits their growth even in the presence of adipocytes. These data suggest insulin resistance-induced proliferative signals from adipocytes activate E2F1, a potential therapeutic target, to promote β cell compensation.

DOI： 10.1016/j.celrep.2022.111436

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DOI： 10.1016/j.jjcc.2022.06.008

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The cardiovascular and renal protective effects of sodium-glucose cotransporter 2 inhibitors (SGLT-2is) and glucagon-like peptide 1 receptor agonists (GLP-1Ras) are enhanced by low/controlled blood pressure (BP). However, the BP-lowering efficacy of SGLT-2is and GLP-1Ras have not been compared directly. We compared the rates of achieving target BP with SGLT-2i and GLP-1Ra treatments in Japanese patients with type 2 diabetes mellitus (T2DM). This retrospective study included 384 SGLT-2i- and 160 GLP-1Ra-treated patients with BP > 130/80 mmHg before treatment. Inverse probability weighting methods using propensity scores were used in this study. The integrated odds ratios (OR) for BP control rates were calculated and clinical changes were analyzed using a generalized linear model. SGLT-2i treatment resulted in significantly higher BP control rates than that in the GLP-1Ra treatment (integrated OR = 2.09 [1.80, 2.43]). Compared with GLP-1Ra, SGLT-2i treatment demonstrated significantly larger decreases in diastolic BP, mean arterial pressure, and body weight (- 3.8 mmHg, P = 0.006; - 4.1 mmHg, P = 0.01; and - 1.5 kg, P = 0.008, respectively) and increased annual estimated glomerular filtration rate (eGFR; 1.5 mL/min/1.73 m2/year, P = 0.04). In T2DM patients with poorly controlled BP, compared with GLP-1Ra, SGLT-2i treatment significantly improved BP management and increased eGFR.

DOI： 10.1038/s41598-022-20313-5

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Previous reports indicated the therapeutic effect of chronic continuous positive airway pressure (CPAP) therapy on cardiac hypertrophy due to sleep apnea syndrome. However, little is known for cases involving diabetic complications. This retrospective observational study examined the effects of CPAP therapy on left ventricular hypertrophy (LVH) in patients with obstructive sleep apnea syndrome (OSAS) and type 2 diabetes mellitus (T2DM). For all cases, the observation period was 3 years from the time when the patient was introduced to CPAP therapy. Overall, 123 patients were divided into a good CPAP group (CPAP ≥4 h/day, n = 63) and non-adherence group (CPAP <4 h/day, n = 60). The mean CPAP usage times were 5.58 ± 1.23 and 1.03 ± 1.17 h/day in the good CPAP and non-adherence groups, respectively. Regression tendencies of the thickness of the left ventricular posterior (-0.30 ± 1.19 mm) and interventricular septal walls (-0.48 ± 1.22 mm) were observed in the good CPAP group. Hypertrophic tendencies of the left ventricular posterior wall (+0.59 ± 1.44 mm) and interventricular septal wall thickness (+0.59 ± 1.43) were observed in the non-adherence group. Left ventricular posterior wall thickness (odds ratio, (coefficient: -0.254, p = 0.0376) and interventricular septal wall thickness (coefficient: -0.426, p = 0.0006) were more likely to be greater in the non-adherence group than in the good CPAP group. Patients in the non-adherence group with an apnea hypopnea index ≥30 had increased left ventricular posterior wall thickness (coefficient: -0.263, p = 0.0673) and interventricular septal wall thickness (coefficient: -0.450, p = 0.0011). In conclusion, appropriate CPAP therapy is an effective treatment for LVH in patients with T2DM and OSAS, especially for severe cases.

DOI： 10.1507/endocrj.EJ22-0308

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DOI： 10.1007/s13300-022-01292-2

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Uncoupling protein 2 (UCP2), a mitochondrial protein, is known to be upregulated in pancreatic islets of patients with type 2 diabetes (T2DM); however, the pathological significance of this increase in UCP2 expression is unclear. In this study, we highlight the molecular link between the increase in UCP2 expression in β-cells and β-cell failure by using genetically engineered mice and human islets. β-cell-specific UCP2-overexpressing transgenic mice (βUCP2Tg) exhibited glucose intolerance and a reduction in insulin secretion. Decreased mitochondrial function and increased aldolase B (AldB) expression through oxidative-stress-mediated pathway were observed in βUCP2Tg islets. AldB, a glycolytic enzyme, was associated with reduced insulin secretion via mitochondrial dysfunction and impaired calcium release from the endoplasmic reticulum (ER). Taken together, our findings provide a new mechanism of β-cell dysfunction by UCP2 and AldB. Targeting the UCP2/AldB axis is a promising approach for the recovery of β-cell function.

DOI： 10.1016/j.isci.2022.104603

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AIMS/INTRODUCTION: This study aimed to clarify the nature of the relationship between the abdominal aortic calcification (AAC) grade and the presence of cardiovascular diseases, and determine factors related to AAC grade in people with type 2 diabetes mellitus. MATERIALS AND METHODS: This retrospective cross-sectional study enrolled 264 inpatients with type 2 diabetes mellitus. The AAC score and length were measured using the lateral abdominal radiographs. Logistic regression models were used to assess the associations between AAC scores/lengths and the presence of coronary artery disease (CAD), cerebral infarction (CI) and peripheral artery disease (PAD). The correlation between AAC scores/lengths and other clinical factors were evaluated using linear regression models. RESULTS: The AAC score was significantly correlated with prevalent CAD and CI independent of age and smoking, but not with the prevalence of PAD. AAC length was not significantly correlated with the presence of CAD, CI or PAD; however, the sample size was insufficient to conclude, probably due to low prevalence. Both the AAC score and length were correlated inversely with body mass index (BMI) and, with the Fibrosis-4 (Fib-4) index >2.67; these correlations were significant after adjusting for cardiovascular risk factors and BMI, although AAC was not associated with ultrasonography-diagnosed fatty liver. There was a significant interaction between BMI and Fib-4 index; lower BMI and Fib-4 index >2.67 showed a synergistic association with high AAC grade. CONCLUSIONS: AAC score is associated with CAD and CI morbidity in participants with type 2 diabetes mellitus. Low BMI and Fib-4 index >2.67 can be valuable indicators of AAC in people with type 2 diabetes mellitus.

DOI： 10.1111/jdi.13883

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This study aimed to evaluate the diagnostic accuracy of home sleep apnea testing using peripheral arterial tonometry for sleep apnea as an alternative to polysomnography. We conducted a systematic review and meta-analysis of observational studies, randomized controlled trials, and diagnostic case-control studies examining the diagnostic accuracy of peripheral arterial tonometry by searching the CENTRAL, MEDLINE, EMBASE, ICTRP and ClinicalTrials.gov databases on 5 October 2021. We assessed the risk of bias of the included studies using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. A bivariate random-effects model was generated to derive the summary point estimates of sensitivity and specificity with 95% confidence intervals at different apnea-hypopnea index cutoffs. This meta-analysis included 13 studies (1227 participants, median prevalence of sleep apnea with apnea-hypopnea index ≥ 5 events per hr: 85%). The risk of bias in the included studies was low to moderate. The pooled sensitivity and specificity estimates were 96% (95% confidence interval: 93%-97%) and 44% (95% confidence interval: 32%-56%) at apnea-hypopnea index ≥ 5 events per hr, 88% (85%-91%) and 74% (63%-83%) at apnea-hypopnea index ≧ 15 events per hr, and 80% (66%-89%) and 90% (83%-95%) at apnea-hypopnea index ≧ 30 events per hr, respectively. Peripheral arterial tonometry resulted in a significant number of false negatives and false positives at any apnea-hypopnea index cutoff when applied to the median prevalence setting of the included studies. The inadequate sensitivity and specificity of peripheral arterial tonometry render it an unsuitable alternative to polysomnography for detecting sleep apnea for apnea-hypopnea index ≧ 5, 15 and 30 events per hr.

DOI： 10.1111/jsr.13682

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INTRODUCTION: Real-world evidence on lixisenatide in Japanese people with type 2 diabetes (T2D) is lacking. Therefore, the 3-year post-marketing PRANDIAL study was conducted to evaluate the safety (primary objective) and effectiveness (secondary objective) of lixisenatide in Japanese people with T2D during routine clinical practice. METHODS: This prospective, observational, multicenter, open-label study was conducted in Japanese individuals with T2D who initiated lixisenatide treatment between March 2014 and June 2017. Using electronic case report forms, investigators collected baseline demographic and clinical information and data on medications, safety and effectiveness up to 3 years after initiation of lixisenatide. RESULTS: Overall, 3046 participants were analyzed; their mean ± standard deviation (SD) age was 58.9 ± 13.1 years, and 53.7% were male. Mean ± SD duration of T2D was 12.8 ± 8.6 years, and baseline glycated hemoglobin (HbA1c) was 8.7% ± 1.7%. Most participants (93.9%) were receiving concomitant antidiabetic medications when they initiated lixisenatide. Median (range) lixisenatide treatment duration was 382 (1-1096) days. Adverse drug reactions (ADRs) were reported in 604 participants (19.8%) and serious ADRs in 22 (0.7%). The most common ADR was nausea (9.0%). Of ADRs of special interest, hypoglycemia occurred in 2.9% of participants, injection site reactions in 0.9%, and hypoglycemic unconsciousness in 0.03%. Baseline characteristics associated with an increased risk of ADRs (p < 0.05) were history of treatment for cardiovascular disease, hepatic dysfunction, and other complications. Effectiveness was analyzed in 2675 participants; HbA1c, fasting plasma glucose, postprandial glucose, and body weight all decreased significantly at last observation (all p < 0.0001 vs. baseline). CONCLUSIONS: Lixisenatide was well tolerated, with no unexpected ADRs or new safety signals identified, and showed effective glycemic control and weight reduction up to 3 years, supporting the use of lixisenatide as a safe and effective treatment option for T2D in routine clinical practice in Japan.

DOI： 10.1007/s12325-022-02121-5

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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AIMS/INTRODUCTION: The present trial compared the efficacy and safety of once-daily liraglutide 1.8 mg with liraglutide 0.9 mg in Japanese patients with type 2 diabetes to assess the incremental effects of liraglutide 1.8 mg in those who exhibited an inadequate response to 0.9 mg. MATERIALS AND METHODS: This 26-week randomized trial (NCT02505334) enrolled Japanese adults with type 2 diabetes across 47 sites in Japan. Participants with glycated hemoglobin (HbA1c ) 7.5-10.0% were included and those on insulin treatment were excluded. Participants discontinued pre-trial oral antidiabetic drug and initiated liraglutide 0.9 mg for a 12-week run-in period, after which those with HbA1c ≥7.0% (466) were randomized (1:1) to two treatment arms: continuing liraglutide 0.9 mg or dose escalation to 1.8 mg. The change from baseline in HbA1c (primary endpoint) and treatment-emergent adverse events (secondary endpoint) were measured at the end of 26 weeks. RESULTS: After 26 weeks of treatment, liraglutide 1.8 mg was more effective compared with 0.9 mg in lowering HbA1c levels, with an estimated treatment difference of -0.40% (95% confidence interval [CI] -0.55, -0.24; P < 0.0001). Liraglutide 1.8 mg was associated with significantly greater odds of participants reaching HbA1c <7.0% (estimated odds ratio [EOR] 3.87; 95% CI 2.12, 7.08; P < 0.0001) and ≤6.5% (EOR 3.78; 95% CI 1.36, 10.54; P = 0.0109) compared with 0.9 mg. Both doses were well tolerated. CONCLUSIONS: Liraglutide 1.8 mg had better efficacy in improving HbA1c levels after 26 weeks treatment vs 0.9 mg in Japanese patients, with both doses well tolerated.

DOI： 10.1111/jdi.13789

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OBJECTIVES: This study aimed to investigate the efficacy of providing education on injection technique to patients with diabetes with lipohypertrophy (LH). DESIGN: We conducted a systematic review and meta-analysis. METHODS: We included patients with diabetes who use insulin and have LH, and excluded patients without LH. We performed a literature search on CENTRAL, MEDLINE, EMBASE, ICTRP and ClinicalTrials.gov in November 2021 for randomised controlled trials (RCTs). We used the revised Cochrane Risk of Bias 2 tool to evaluate the risk of bias in each outcome in each study. We then pooled the data using a random-effects model and evaluated the certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluation approach. OUTCOME MEASURES: The primary endpoints were change in total daily dose (TDD) of insulin, change in HbA1c levels and prevalence of hypoglycaemia. RESULTS: We screened 580 records and included three RCTs (637 participants) in the meta-analysis. Education on injection technique may slightly increase the change of TDD of insulin (three studies, 637 participants: mean difference (MD) -6.26; 95% CI -9.42 to -3.10; p<0.001; I2=38%; low certainty of evidence) and may have little to no effect on change in HbA1c but the evidence is very uncertain compared with that in the control group (three studies, 637 participants: MD -0.59; 95% CI -1.71 to 0.54; p=0.31; I2=98%; very low certainty of evidence). Providing education about injection technique may have little to no effect on the prevalence of hypoglycaemia (three studies, 637 participants: risk ratio 0.44; 95% CI 0.06 to 3.13; p=0.41; I2=90%; very low certainty of evidence). CONCLUSIONS: The present meta-analysis suggests that injection technique education may result in a slight reduction in the TDD of insulin. However, the effect of education on HbA1c, hypoglycaemia and cured LH is uncertain. PROTOCOL REGISTRATION: DOI: dx.doi.org/10.17504/protocols.io.btiinkce.

DOI： 10.1136/bmjopen-2021-055529

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The effects of imeglimin, a novel antidiabetes agent, on β-cell function remain unclear. Here, we unveiled the impact of imeglimin on β-cell survival. Treatment with imeglimin augmented mitochondrial function, enhanced insulin secretion, promoted β-cell proliferation, and improved β-cell survival in mouse islets. Imeglimin upregulated the expression of endoplasmic reticulum (ER)-related molecules, including Chop (Ddit3), Gadd34 (Ppp1r15a), Atf3, and Sdf2l1, and decreased eIF2α phosphorylation after treatment with thapsigargin and restored global protein synthesis in β-cells under ER stress. Imeglimin failed to protect against ER stress-induced β-cell apoptosis in CHOP-deficient islets or in the presence of GADD34 inhibitor. Treatment with imeglimin showed a significant decrease in the number of apoptotic β-cells and increased β-cell mass in Akita mice. Imeglimin also protected against β-cell apoptosis in both human islets and human pluripotent stem cell-derived β-like cells. Taken together, imeglimin modulates the ER homeostasis pathway, which results in the prevention of β-cell apoptosis both in vitro and in vivo.

DOI： 10.2337/db21-0123

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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.

DOI： 10.1111/dom.14586

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AIMS: This study aimed to clarify the differences in how sodium glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP1Ra) influence kidney function in Japanese patients with type 2 diabetes mellitus (T2DM). METHODS: We retrospectively built two databases of patients with T2DM who visited the clinics of members of Kanagawa Physicians Association. We defined the renal composite outcome as either progression of albuminuria status and/or > 15% deterioration in estimated glomerular filtration rate (eGFR) per year. We used propensity score matching to compare patient outcomes after SGLT2i and GLP1Ra treatments. RESULTS: The incidence of renal composite outcomes was significantly lower in SGLT2i-treated patients than in GLP1Ra-treated patients (n = 15[11%] and n = 27[20%], respectively, P = 0.001). Annual eGFR changes (mL/min/1.73 m2/year) between the two groups differed significantly (-1.8 [95 %CI, -2.7, -0.9] in SGLT2i-treated patients and - 3.4 [95 %CI, -4.6, -2.2] in GLP1Ra-treated patients, P = 0.0049). The urine albumin-to-creatinine ratio changed owing to a significant interaction between the presence or absence of a decrease in systolic blood pressure and the difference in treatments (P < 0.04). CONCLUSION: Renal composite outcome incidence was lower in SGLT2i-treated patients than in GLP1Ra-treated patients.

DOI： 10.1016/j.diabres.2022.109231

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DOI： 10.1111/jdi.13764

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DOI： 10.1111/jdi.13650

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Background: We assessed the effect of supervised, combined aerobic and resistance exercise on diabetic parameters in Japanese patients with type 2 diabetes mellitus (T2DM). Methods: This 12-week, multicenter (17 medical institutions), open-label, parallel-group study (clinicaltrials.jp; JapicCTI-184002), randomized (1:1) Japanese patients aged 20-75 years with T2DM and hemoglobin A1c (HbA1c) of 7.0-10.0% to supervised exercise (n = 113) or standard therapy (n = 115). The supervised exercise group undertook supervised aerobic (30 min) and resistance exercise 3 times/week (20 designated gyms). Primary endpoint was change in HbA1c from baseline at week 13. Secondary endpoints were change in fasting blood glucose (FBG), glycoalbumin, fasting insulin, homeostatic model assessment of insulin resistance (HOMA-IR), and HOMA-β at week 13. Results: Of 228 randomized patients, 97 (85.8%) in the supervised exercise group and 108 (93.9%) in the standard therapy group completed the study. Supervised exercise significantly lowered HbA1c at week 13 versus standard therapy (estimated difference in change from baseline [95% confidence interval]: - 0.44% [- 0.61, - 0.28], p < 0.001). Supervised exercise also significantly decreased FBG (estimated difference: - 13.0 [- 19.2, - 6.7] mg/dL) and glycoalbumin (estimated difference:  - 1.52% [- 2.10, - 0.93]) compared with standard therapy. Fasting insulin (- 0.5 µIU/mL) and HOMA-IR (- 0.3) decreased with supervised exercise, but group differences were not significant. Treatment-emergent adverse events were more frequent in the supervised exercise group (42.5%) than in the standard therapy group (29.6%); however, no major safety concerns were identified. Conclusions: A structured, supervised, aerobic and resistance exercise program improved HbA1c and was well accepted among patients with T2DM. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-021-00506-5.

DOI： 10.1007/s13340-021-00506-5

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Plasma and liver SerpinB1 levels are elevated in mice with insulin resistance and promote β-cell proliferation in human islets. We measured serum SerpinB1 levels in Japanese subjects with or without type 2 diabetes (T2DM). We enrolled 12 normal glucose tolerance (NGT) and 51 T2DM subjects. There was no difference in serum SerpinB1 levels between the 2 groups (T2DM, 1.3 ± 0.9 ng/mL vs. NGT, 1.8 ± 1.7 ng/mL; P = 0.146). After adjusting for age and sex, the serum SerpinB1 levels were positively correlated with HOMA2-%S (β = 0.319, P = 0.036), and negatively correlated with fasting blood glucose (β = -0.365, P = 0.010), total cholesterol (β = -0.396, P = 0.006), low-density lipoprotein (LDL) cholesterol (β = -0.411, P = 0.004), triglycerides (β = -0.321, P = 0.026), and γGTP (β = -0.322, P = 0.026) in subjects with T2DM. Thus, circulating SerpinB1 is possibly associated with insulin sensitivity and better blood glucose level in Japanese subjects with T2DM. Trial registration: UMIN Clinical Trials Registry, UMIN000020453.

DOI： 10.1371/journal.pone.0276915

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Patients with type 2 diabetes who have cardiovascular disease and are receiving empagliflozin have a lower rate of primary composite cardiovascular outcomes. In contrast, glimepiride increases cardiovascular hospitalization when combined with metformin. Here, we assessed the effects of empagliflozin and glimepiride on endothelial function using flow-mediated dilation (FMD). In this prospective, open-label, randomized, parallel-group study, 63 patients with type 2 diabetes received metformin and insulin glargine U100 for 12 weeks. This was followed by additional treatment with empagliflozin or glimepiride for 12 weeks. The primary outcome was the change in the FMD measurement (ΔFMDs) at 24 weeks of additional treatment. Secondary outcomes comprised changes in metabolic markers and body composition. The empagliflozin group (n = 33) and glimepiride group (n = 30) showed no significant differences in ΔFMDs (empagliflozin, -0.11 [95%CI: -1.02, 0.80]%; glimepiride, -0.34 [95%CI: -1.28, 0.60]%; P = 0.73). Additionally, changes in glycated hemoglobin were similar between the two groups. However, a significant difference in body weight change was observed (empagliflozin, -0.58 [95%CI: -1.60, 0.43] kg; glimepiride, 1.20 [95%CI: 0.15, 2.26] kg; P = 0.02). Moreover, a body composition analysis revealed that body fluid volume significantly decreased after empagliflozin treatment (baseline, 35.8 ± 6.8 L; after 12 weeks, -0.33 ± 0.72 L; P = 0.03). Hence, although empagliflozin did not improve endothelial function compared with glimepiride for patients with type 2 diabetes, it did decrease body fluid volumes. Thus, the coronary-protective effect of empagliflozin is not derived from endothelial function protection, but rather from heart failure risk reduction. Trial registration: This trial was registered on September 13, 2016; UMIN000024001.

DOI： 10.1371/journal.pone.0262831

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AIMS: To evaluate, through exploratory post hoc subgroup analyses, the efficacy and safety of oral semaglutide versus comparators in Japanese patients enrolled in the global PIONEER 1, 3, 4 and 8 clinical trials. MATERIALS AND METHODS: Patients were randomized to once-daily oral semaglutide 3, 7 or 14 mg or comparator (placebo, sitagliptin 100 mg or liraglutide 1.8 mg). Change from baseline in glycated haemoglobin (HbA1c) and body weight, and proportions of patients attaining HbA1c <7.0% (53 mmol/mol) and body weight loss ≥5%, were analysed at week 26 for all Japanese patients in each trial separately using the treatment policy estimand (regardless of treatment discontinuation or rescue medication use). Adverse events (AEs) were analysed descriptively. RESULTS: Reductions in HbA1c from baseline in Japanese patients were 1.0% to 1.2% (11.3 mmol/mol to 13.3 mmol/mol) and 1.4% to 1.7% (15.7 mmol/mol to 18.3 mmol/mol) for oral semaglutide 7 mg and 14 mg, respectively. HbA1c reductions were similar or greater than with comparators. Body weight reductions were 1.0% to 2.7% and 3.7% to 4.7% for oral semaglutide 7 mg and 14 mg, respectively, and were generally greater with oral semaglutide than comparators. As expected, the main class of AEs was gastrointestinal, and these AEs comprised most commonly mild-to-moderate constipation, nausea and diarrhoea. CONCLUSIONS: Oral semaglutide appears efficacious and well tolerated in Japanese patients across the type 2 diabetes spectrum.

DOI： 10.1111/dom.14536

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AIM: To characterize the long-term changes in body composition associated with sodium-glucose cotransporter-2 (SGLT2) inhibitors. MATERIALS AND METHODS: In this multicentre, single-arm, open-label study, 107 patients with type 2 diabetes were treated with canagliflozin 100 mg, as add-on therapy, for 12 months. Body composition was measured with a body composition analyser (T-SCAN PLUS) using the impedance method to prospectively analyse changes in body components, including percentage of body fat, body fat mass, total body water, muscle mass and mineral mass. Estimated plasma volume (PV) was calculated using the Kaplan formula. RESULTS: Body weight showed a significant decrease from 1 month to 12 months of treatment with canagliflozin, with a higher rate of decrease in body fat in body composition. A significant decrease in mineral mass was also observed, but its rate was low. Following treatment with canagliflozin, changes in total body water did not affect intracellular water, and a significant decrease in extracellular water, including plasma components, was observed early and was sustained up to 12 months. Protein mass, a component of muscle mass, was not affected, with only a slight decrease in water volume observed. CONCLUSIONS: Canagliflozin decreased extracellular fluid and PV in addition to decreasing fat in the body via calorie loss resulting from urinary glucose excretion. This study suggested that SGLT2 inhibitors might reduce body weight by regulating fat mass or water distribution in the body and might have cardiac and renal protective effects by resetting the homeostasis of fluid balance.

DOI： 10.1111/dom.14508

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

<title>Abstract</title>We investigated the impact of basal dietary sodium intake on the dapagliflozin-induced changes in albuminuria and blood pressure (BP) measured at home in patients with diabetic kidney disease (DKD).This was a secondary analysis of the Y-AIDA Study, in which DKD patients with estimated glomerular filtration rate (eGFR) ≥ 45 ml/min/1.73 m² and urinary albumin-to-creatinine ratio (UACR) ≥ 30 mg/g creatinine were administered dapagliflozin for 24 weeks, and dapagliflozin significantly improved albuminuria levels and home BP profiles. The effects on UACR, home-measured BP, and eGFR were compared between high- and low-sodium intake groups (HS and LS groups), which were created using baseline urinary sodium-to-creatinine ratio of 84 participants with available basal sodium-to-creatinine ratios. At baseline, clinic-/home-measured BPs, UACR, and eGFR, were comparable in the two groups. After 24 weeks, the reductions from baseline in ln-UACR were comparable in the two groups. In contrast, the reductions in evening home systolic BP and eGFR from baseline were larger in HS than in LS (BP: − 13 ± 2.08 vs. − 6 ± 1.88, <italic>P</italic> = 0.020; eGFR: − 3.33 ± 1.32 vs. 0.37 ± 1.29, <italic>P</italic> = 0.049). The home BP-lowering effects of dapagliflozin are larger in HS than LS, concomitant with a larger reduction in eGFR, suggesting a dapagliflozin-induced improvement in glomerular relative hyperfiltration in HS.

DOI： 10.1038/s41598-020-79687-z

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Other Link： http://www.nature.com/articles/s41598-020-79687-z

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This study aimed to reveal the relationship between quality of life (QOL) and sleep quality in patients with type 1 diabetes mellitus (T1DM). Overall, 202 patients with T1DM were registered in our study, and 192 were eligible for analysis. Baseline characteristics and laboratory values were determined. Patients completed the Japanese versions of the Pittsburgh Sleep Quality Index (PSQI) and Diabetes Therapy-Related QOL (DTR-QOL) questionnaires. We investigated the relationship between the global PSQI and DTR-QOL total scores by using linear regression analysis. In univariate regression analysis, DTR-QOL total scores were associated with body mass index, alcohol consumption, hypertension, hemoglobin A1c (HbA1c), and global PSQI score (all p-value <0.05) but not with sleep duration. When the association between PSQI subscales and DTR-QOL total scores was examined, DTR-QOL total scores were significantly related to subjective sleep quality and daytime dysfunction. In a multivariate regression analysis, the global PSQI score was negatively related to DTR-QOL total scores. Patients with an HbA1c concentration ≥8.0% had significantly lower DTR-QOL total scores. We revealed a relationship between QOL and sleep quality in T1DM patients and showed that the relationship between QOL and PSQI subscales in T1DM patients may be different from that in patients with type 2 diabetes mellitus. Assessing and managing sleep quality may be necessary for patients with diabetes to improve QOL.

DOI： 10.1507/endocrj.EJ21-0408

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INTRODUCTION: Dulaglutide is a long-acting glucagon-like peptide 1 receptor agonist that is administered once weekly for the treatment of type 2 diabetes. However, the immediate glucose-lowering effect of dulaglutide after the first administration and the factors affecting the efficacy of the drug remain unclear. METHODS: This study was a retrospective and observational study of 80 subjects with type 2 diabetes conducted in a hospitalized setting. The changes (Δ) in the blood glucose (BG) levels at six time points (6-point BG levels) from the baseline (day - 1) to the day after the first administration of 0.75 mg of dulaglutide (day 1) were evaluated. The associations of the Δ 6-point BG levels with the patients' characteristics and laboratory data were also analyzed. RESULTS: Significant reduction of the fasting BG, preprandial BG, postprandial BG, and standard deviation (SD) of the 6-point BG levels was observed on day 1 as compared to day - 1 (P < 0.0001) and the reduced BG levels were maintained throughout the remaining observation period of 5 days. The baseline serum hemoglobin A1c and glycoalbumin levels were positively correlated with the reduction of the fasting BG. The Δ BG levels were not related to the parameters of insulin-secreting capacity. Insulin treatment was positively associated with the reduction of the 6-point BG levels. Patients without cerebrovascular disease and patients without diabetic retinopathy showed greater improvements of the fasting BG and SD of the 6-point BG levels, respectively. Urinary microalbumin level was positively correlated with improvements of the 6-point BG levels. Dulaglutide reduced the BG levels, irrespective of the previously used class of antidiabetic medication(s). CONCLUSION: Dulaglutide achieved reduction in glucose level within 24 h of the first injection. The improvement in the BG levels remained stable for a week in the hospitalized clinical setting.

DOI： 10.1007/s13300-021-01147-2

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IntroductionSodium-glucose cotransporter-2 inhibitors (SGLT2is) are proven to ameliorate kidney and heart failure in patients with type 2 diabetes (T2D), in addition to improving glycemic controls. Canagliflozin is a SGLT2i and has proved beneficial for kidney and heart diseases in addition to decreasing the incidence of the composite outcomes of cardiovascular diseases and stroke.Areas coveredThis paper reviews the development of canagliflozin and its effects on renal dysfunction, heart failure, and vascular diseases.Expert opinionCanagliflozin contributes to the inhibition of renal function, decline progression and, therefore, is effective for T2D patients with chronic kidney dysfunction and albuminuria. The Canagliflozin Cardiovascular Assessment Study (CANVAS) revealed that patients showed increased incidence of amputation via unknown mechanisms, which has not been observed in other studies that used real-world data. Moreover, canagliflozin has been proven effective for anemia-associated outcomes of chronic kidney failure. Meta-analyses have revealed that canagliflozin contributed to lower diastolic blood pressure when compared with other SGLT2is. A subanalysis of CANVAS data proved that canagliflozin reduced the risk of hemorrhagic stroke. Canagliflozin should be used for T2D patients with chronic kidney failure and/or albuminuria and those with vascular diseases, with monitoring for ulcers and/or the pulse on the lower limb.

DOI： 10.1080/14656566.2021.1939675

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AIMS/INTRODUCTION: The diabetes knowledge test (DKT) is unavailable in Japan. In this study, we developed and evaluated a Japanese version of the DKT (J-DKT) for in-patients with type 2 diabetes before and after receiving diabetes education. MATERIALS AND METHODS: The J-DKT contains 12 questions (0-12 points) to assess knowledge regarding diabetes, its complications, and diabetic nutrition therapy. During the median 10 days of hospitalization, 107 patients with type 2 diabetes received diabetes education (20 min private lessons every day from physicians, two nutrition counselling programs from dietitians, and a 2 h group session conducted by physicians, dietitians, and nurses). The J-DKT was administered on admission and before discharge. To confirm the J-DKT's reliability, we assessed the internal consistency using Cronbach's α (≥0.70 was considered acceptable). To evaluate its validity, we investigated changes in the J-DKT total scores after the education programs and examined the differences in the scores among groups classified based on patient characteristics such as age, diabetes-related hospitalization history, and hospitalization duration. RESULTS: The J-DKT total scores increased from 5 to 8 (P ˂ 0.01) after the education programs. The J-DKT before and after the program showed a Cronbach's α of 0.48 and 0.73, respectively. Except for age, baseline characteristics such as history and period of hospitalization for diabetes were not associated with the J-DKT scores after the education program. CONCLUSIONS: The validity and reliability of the J-DKT after the diabetes education program were acceptable in this study.

DOI： 10.1111/jdi.13683

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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.

DOI： 10.1111/jdi.13532

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BACKGROUND: Diabetic kidney disease (DKD) is one of the main complications of type 2 diabetes mellitus (T2DM). DKD is a known risk factor for end-stage renal disease, cardiovascular disease, and all-cause death. Effective intervention for early-stage DKD is vital to slowing down the progression of kidney disease and improve prognoses. Mobile health (mHealth) is reportedly effective in supporting patients' self-care and improving glycemic control, but the impact of mHealth on DKD has yet to be shown. OBJECTIVE: The purpose of this study is to evaluate the efficacy of standard therapy with the addition of a self-management support system, DialBetesPlus, in patients with DKD and microalbuminuria. METHODS: This study is a prospective, randomized, open-label, multicenter clinical trial. The target population consists of 160 patients diagnosed with T2DM accompanied by microalbuminuria. We randomly assigned the patients to 2 groups-the intervention group using DialBetesPlus in addition to conventional therapy and the control group using conventional therapy alone. DialBetesPlus is a smartphone application that supports patients' self-management of T2DM. The study period was 12 months, with a follow-up survey at 18 months. The primary outcome was a change in albuminuria levels at 12 months. Secondary outcomes included changes in physical parameters, blood test results (glycemic control, renal function, and lipid metabolism), lifestyle habits, self-management scores, medication therapy, and quality of life. RESULTS: The study was approved in April 2018. We began recruiting patients in July 2018 and completed recruiting in August 2019. The final 18-month follow-up was conducted in March 2021. We recruited 159 patients and randomly allocated 70 into the intervention group and 61 into the control group, with 28 exclusions due to withdrawal of consent, refusal to continue, or ineligibility. The first results are expected to be available in 2021. CONCLUSIONS: This is the first randomized controlled trial assessing the efficacy of mHealth on early-stage DKD. We expect that albuminuria levels will decrease significantly in the intervention group due to improved glycemic control with ameliorated self-care behaviors. TRIAL REGISTRATION: UMIN-CTR UMIN000033261; https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000037924. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/31061.

DOI： 10.2196/31061

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INTRODUCTION: Sleep disorders and short sleep duration are common symptoms among people with diabetes. However, the evidence is limited about the associations of post-challenge hyperglycemia and sleep quality or quantity with all-cause mortality in the US general population. RESEARCH DESIGN AND METHODS: Our study included 8795 adults from the National Health and Nutrition Examination Survey 2005-2014. Mortality data were ascertained through 2015. Multivariable Cox proportional-hazards models were used to estimate adjusted HRs (aHRs) for all-cause mortality according to 2-hour plasma glucose levels during the 75 g oral glucose tolerance test-normal glucose tolerance (NGT), <140 mg/dL; impaired glucose tolerance (IGT), 140-199 mg/dL; and diabetes, ≥200 mg/dL. We then examined the associations of glucose tolerance status and self-reported physician-diagnosed sleep disorders (yes vs no) or sleep duration (<7 vs ≥7 hours) with all-cause mortality. RESULTS: During follow-up (median, 5.6 years), the diabetes group had a higher risk of all-cause mortality compared with the NGT group (aHR (95% CI)=1.93 (1.41 to 2.64)), but not the IGT group (aHR (95% CI)=1.19 (0.90 to 1.59)). When we categorized participants according to glucose tolerance status and sleep disorders, the IGT group with sleep disorders had a higher risk of all-cause mortality (aHR (95% CI)=2.03 (1.24 to 3.34)) compared with the NGT group without sleep disorders. Both diabetes groups with and without sleep disorders also showed high mortality risks. The results were consistent when we used sleep duration instead of sleep disorders. CONCLUSIONS: Using the most updated US national data, we found a high risk of all-cause mortality among individuals with IGT having sleep disorders or short sleep duration as well as those with diabetes. Future investigations are needed to identify whether and what kind of sleep management is beneficial for people with impaired glucose metabolism to prevent early death.

DOI： 10.1136/bmjdrc-2020-002047

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BACKGROUND: Syndrome of inappropriate antidiuretic hormone secretion can be caused by arginine-vasopressin-producing tumors or enhanced arginine vasopressin secretion from the posterior pituitary gland due to central nervous system disorders and intrathoracic diseases. CASE PRESENTATION: A 53-year-old Asian man was hospitalized with complaints of tremor and hiccups. Laboratory examination revealed findings suggestive of hypotonic hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion. The patient did not complain of headache or photophobia, and showed no signs of meningeal irritation. Positron emission tomography-computed tomography revealed 18F-fluoro-deoxy-glucose accumulation along the cervical spinal cord, based on which the patient was diagnosed as having aseptic meningitis. The hyponatremia was treated successfully by fluid restriction, and optimum plasma sodium concentration was maintained by tolvaptan administration. CONCLUSIONS: This case underscores the need to consider the possibility of mild meningitis as the cause of syndrome of inappropriate antidiuretic hormone secretion in patients without other identifiable cause.

DOI： 10.1186/s13256-021-02956-6

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It has been well established that insulin-like growth factors (IGFs) mainly mediate long-term actions in cell fates, whereas insulin predominantly exerts its role on metabolic activity. Indeed, insulin mediates multiple anabolic biological activities in glucose and amino acid transport, lipid and protein synthesis, the induction of glycogen, the inhibition of gluconeogenesis, lipolysis, and protein degradation. The interactions and differences between insulin receptor signaling and IGF-I receptor signaling in the metabolism and the cell fates are quite complicated. Because of the overlapping actions of IGF-I singling with insulin signaling, it has been difficult to distinguish the role of both signaling mechanisms on the metabolism. Furthermore, comprehensive information on the IGF-I function in respective tissues remains insufficient. Therefore, we need to clarify the precise roles of IGF-I signaling on the metabolism separate from those of insulin signaling. This review focuses on the metabolic roles of IGFs in the respective tissues, especially in terms of comparison with those of insulin, by overviewing the metabolic phenotypes of tissue-specific IGF-I and insulin receptor knockout mice, as well as those in mice treated with the dual insulin receptor/IGF-I receptor inhibitor OSI-906.

DOI： 10.3390/ijms22136817

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Stem cell therapy using islet-like insulin-producing cells derived from human pluripotent stem cells has the potential to allow patients with type 1 diabetes to withdraw from insulin therapy. However, several issues exist regarding the use of stem cell therapy to treat type 1 diabetes. In this review, we will focus on the following topics: (1) autoimmune responses during the autologous transplantation of stem cell-derived islet cells, (2) a comparison of stem cell therapy with insulin injection therapy, (3) the impact of the islet microenvironment on stem cell-derived islet cells, and (4) the cost-effectiveness of stem cell-derived islet cell transplantation. Based on these various viewpoints, we will discuss what is required to perform stem cell therapy for patients with type 1 diabetes.

DOI： 10.3390/cells10071589

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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.

DOI： 10.1111/dom.14459

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DOI： 10.2337/db21-780-P

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Objective We assessed the effect of canagliflozin, an SGLT2 inhibitor, on hepatic steatosis using three imaging modalities: magnetic resonance imaging (MRI), computed tomography, and transient elastography. We further determined factors associated with improving hepatic steatosis by canagliflozin among patients with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). Methods We conducted a six-month prospective single-arm study between August 2015 and June 2017. The primary outcome was the change in hepatic steatosis assessed using the hepatic proton density fat fraction (PDFF) on MRI before and after treatment with canagliflozin. The secondary outcomes were changes in measures of glucose metabolism, including the hepatic glucose uptake on FDG-PET, and the inflammation and volumes of visceral and subcutaneous adipose tissue and skeletal muscle. Patients Nine patients with type 2 diabetes and NAFLD completed this study. All participants received canagliflozin at a dose of 100 mg daily. Results Canagliflozin caused a significant reduction in hepatic PDFF from baseline (median 20.6% [interquartile range 11.7%, 29.8%]) after 6 months (10.6% [5.4%, 22.6%], p=0.008). Canagliflozin also significantly reduced the body weight, glycated hemoglobin, homeostasis model assessment of insulin resistance (HOMA-IR), high sensitivity C-reactive protein (hs-CRP), and volumes of adipose tissue and skeletal muscle (all p<0.05). The reduction in hepatic PDFF was not correlated with changes in the body weight, HOMA-IR, hs-CRP, or volume of adipose tissue and skeletal muscle from baseline after six months. Conclusion Among patients with type 2 diabetes and NAFLD, canagliflozin improved hepatic steatosis. The effect may be independent of reducing adiposity, insulin resistance, inflammation, and skeletal muscle volume.

DOI： 10.2169/internalmedicine.7134-21

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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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.

DOI： 10.2337/db20-0881

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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DOI： 10.1007/s00535-020-01754-z

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Xanthine oxidoreductase (XOR) catalyzes the oxidation of hypoxanthine to xanthine, and of xanthine to uric acid. XOR also enhances the production of reactive oxygen species and causes endothelial dysfunction. In this study, we evaluated the association of XOR and its substrate with the vascular complications in 94 Japanese inpatients with type 2 diabetes (T2DM). The plasma XOR activity and plasma xanthine levels were positively correlated with the body mass index, aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-GTP, fasting plasma insulin, and the homeostasis model of assessment of insulin resistance (HOMA-IR), and negatively correlated with the high density lipoprotein cholesterol. The plasma XOR activity also showed a positive correlation with the serum triglyceride. Multivariate analyses identified AST, ALT, fasting plasma insulin and HOMA-IR as being independently associated with the plasma XOR activity. The plasma XOR activity negatively correlated with the duration of diabetes, and positively correlated with the coefficient of variation of the R-R interval and sensory nerve conduction velocity. Furthermore, the plasma XOR activity was significantly decreased in patients with coronary artery disease. Thus, the plasma XOR activity might be a surrogate marker for the development of vascular complications, as well as liver dysfunction and insulin resistance, in T2DM.Trial registration: This study is registered at the UMIN Clinical Trials Registry (UMIN000029970; https://www.umin.ac.jp/ctr/index-j.htm ). The study was conducted from Nov 15, 2017.

DOI： 10.1038/s41598-021-83234-9

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Serum high-molecular-weight adiponectin (HMWA) has a positive correlation with insulin secretion in the Japanese population. To validate this correlation, we investigated the correlation between serum HMWA and proinsulin, a marker of β-cell dysfunction, in this population. A total of 488 participants (53.9% women) aged 35-79 years not taking 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 showed that the HMWA level was inversely correlated with the proinsulin level in a general Japanese population.

DOI： 10.1111/jdi.13323

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Multiple daily injections of insulin, referred to basal-bolus regimen, are generally essential in achieving glycemic control and preventing ketosis in insulin-dependent diabetes, such as type 1 diabetes (T1D). A 75-year-old man with T1D receiving basal-bolus insulin therapy exhibited symptoms of dementia after hospitalization due to pyelonephritis and failed to continue insulin self-injection. Given that his social and familial circumstances allowed insulin injection once a day during the morning, bolus insulin injections needed to be discontinued. Ketonuria was observed the day following discontinuation of bolus insulin. Although increasing the basal insulin dose (degludec) from 10 to 15 units improved ketonuria, his preprandial glucose levels increased to ≥ 500 mg/dL before lunch and ≥ 400 mg/dL before dinner. Hence, another bolus insulin injection was simultaneously added to the basal insulin dose before breakfast, which, subsequently, decreased his preprandial glucose levels to ≤ 220 mg/dL before lunch and ≤ 350 mg/dL before dinner. For half a year after discharge, ketonuria or hypoglycemia had not been detected. After 6 months, he was able to restart intensive insulin therapy with familial support. Hence, in cases where elderly patients with diabetes exhibit symptoms of dementia and can receive insulin injection once a day due to their social circumstances, short-term one basal plus one bolus insulin injections a day might be considered to prevent life-threatening diabetes complications among those who are insulin-dependent.

DOI： 10.1007/s13340-020-00452-8

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Lipid management, especially with respect to triglyceride (TG) metabolism, in patients with diabetes is not sufficient with current therapeutic agents, and new approaches for improvement are needed. Members of the angiopoietin-like protein (ANGPTL) family, specifically ANGPTL3, 4, and 8, have been reported as factors that inhibit lipoprotein lipase (LPL) activity and affect TGs. The present study investigated the association between lipid and glucose metabolism markers and the mechanism by which these proteins affect lipid metabolism. A total of 84 patients hospitalized for diabetes treatment were evaluated. Lipid and glucose metabolism markers in blood samples collected before breakfast, on the day after hospitalization, were analyzed. ANGPTL8 showed a significant positive correlation with TG values. HDL-C values displayed a significant positive correlation with ANGPTL3 but a negative correlation with ANGPTL4 and ANGPTL8. The results did not indicate a significant correlation among ANGPTL3, 4, and 8 levels. Thus, it is possible that the distribution of these proteins differs among patients. When patients were divided into groups according to the levels of ANGPTL3 and ANGPTL8, those with high levels of both ANGPTL3 and ANGPTL8 also had high levels of TG and small dense LDL-C/LDL-C (%). Multiple regression analysis indicated that low LPL, high ApoC2, high ApoC3, high ApoE, and high ANGPTL8 levels were the determinants of fasting hypertriglyceridemia. By contrast, no clear association was observed between any of the ANGPTLs and glucose metabolism markers, but ANGPTL8 levels were positively correlated with the levels of HOMA2-IR and BMI. Patients with high levels of both ANGPTL3 and ANGPTL8 had the worst lipid profiles. Among ANGPTL3, 4, and 8, ANGPTL8 is more important as a factor determining plasma TG levels. We anticipate that the results of this research will facilitate potential treatments targeting ANGPTL8 in patients with diabetes.

DOI： 10.1371/journal.pone.0255147

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Taylor and Francis Ltd.  

DOI： 10.1080/14656566.2021.1900824

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AIMS: This study investigated the hypoglycemia risk in people with type 2 diabetes (T2D) who initiated or switched to insulin glargine 300 U/mL (Gla-300) by stratifying them by age and renal function. METHODS: We examined data from 4621 people with T2D (1227 insulin-naïve and 3394 insulin-experienced) of the X-STAR study, a prospective, observational, 12-month study conducted from December 2015 to August 2018 in Japan. Participants were stratified by age (<65, 65 to <75, and ≥75 years) and estimated glomerular filtration rate (eGFR) (≥90, 60 to <90, 30 to <60, and <30 mL/min/1.73 m2). Hypoglycemia was defined according to the Ministry of Health, Labour and Welfare manual of Japan. RESULTS: No apparent increase in the proportion of people who experienced hypoglycemia was found in all subgroups. The proportions were 2.9-3.5% and 2.7-5.2% of insulin-naïve and insulin-experienced people, respectively, for age subgroups, and 2.4-4.7% and 4.6-4.8%, respectively, for eGFR subgroups. The result was similar for HbA1c levels below and at or above 7.0% in all age subgroups. CONCLUSIONS: Our study found no apparent increase in the hypoglycemia risk in people with older age and renal impairment who were administered Gla-300. These results would provide reassuring information on Gla-300 use.

DOI： 10.1016/j.diabres.2020.108647

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DOI： 10.2337/db20-0069

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AIMS/INTRODUCTION: Liraglutide and empagliflozin suppress cardiovascular events. However, reports on their long-term combined use with insulin therapy or direct comparisons of these drugs are limited. MATERIALS AND METHODS: This open-label, parallel-group, randomized controlled trial compared the effects of liraglutide and empagliflozin combined with insulin therapy in type 2 diabetes patients. Adult type 2 diabetes outpatients undergoing stable insulin therapy with glycated hemoglobin levels of 7.0-9.5% were enrolled. Participants received 0.9 mg/day liraglutide or 10 mg/day empagliflozin for 24 weeks. The primary end-point was the change in glycated hemoglobin levels from week 0 to 24. Body composition was assessed by dual-energy X-ray absorptiometry. RESULTS: A total of 64 insulin-treated patients were randomized to receive liraglutide or empagliflozin. We analyzed 61 patients (30 liraglutide and 31 empagliflozin) who could be followed up. Liraglutide induced greater changes in glycated hemoglobin and glycated albumin than empagliflozin (glycated hemoglobin -1.24 ± 0.15% vs -0.35 ± 0.11%, P < 0.0001; glycated albumin -4.4 ± 0.6% vs -2.4 ± 0.5%, P < 0.01). Bodyweight (-1.3 ± 0.4 kg vs -1.5 ± 0.3 kg, P = 0.69) or body fat mass/lean tissue mass; urinary albumin excretion (median -5.3 mg/g-creatinine [interquartile range -60.6, 9.9 mg/g-creatinine] vs -12.9 mg/g-creatinine [interquartile range -70.8, -2.0 mg/g-creatinine], P = 0.23); and frequency of hypoglycemia did not differ significantly between the groups over a period of 24 weeks. There were no cases of study discontinuation owing to adverse effects. CONCLUSIONS: Liraglutide addition to ongoing insulin therapy more effectively reduced glycated hemoglobin and glycated albumin levels than empagliflozin in patients with inadequately controlled type 2 diabetes.

DOI： 10.1111/jdi.13270

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Abnormal hepatic insulin signaling is a cause or consequence of hepatic steatosis. DPP-4 inhibitors might be protective against fatty liver. We previously reported that the systemic inhibition of insulin receptor (IR) and IGF-1 receptor (IGF1R) by the administration of OSI-906 (linsitinib), a dual IR/IGF1R inhibitor, induced glucose intolerance, hepatic steatosis, and lipoatrophy in mice. In the present study, we investigated the effects of a DPP-4 inhibitor, linagliptin, on hepatic steatosis in OSI-906-treated mice. Unlike high-fat diet-induced hepatic steatosis, OSI-906-induced hepatic steatosis is not characterized by elevations in inflammatory responses or oxidative stress levels. Linagliptin improved OSI-906-induced hepatic steatosis via an insulin-signaling-independent pathway, without altering glucose levels, free fatty acid levels, gluconeogenic gene expressions in the liver, or visceral fat atrophy. Hepatic quantitative proteomic and phosphoproteomic analyses revealed that perilipin-2 (PLIN2), major urinary protein 20 (MUP20), cytochrome P450 2b10 (CYP2B10), and nicotinamide N-methyltransferase (NNMT) are possibly involved in the process of the amelioration of hepatic steatosis by linagliptin. Thus, linagliptin improved hepatic steatosis induced by IR and IGF1R inhibition via a previously unknown mechanism that did not involve gluconeogenesis, lipogenesis, or inflammation, suggesting the non-canonical actions of DPP-4 inhibitors in the treatment of hepatic steatosis under insulin-resistant conditions.

DOI： 10.3390/ijms21217815

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INTRODUCTION: Saxagliptin, a member of the dipeptidyl peptidase-4 inhibitor (DPP-4i) class of drugs, was approved by the FDA for the treatment of type 2 diabetes (T2D) in 2009, and has been in clinical use for more than a decade. Since the drug was first launched, much real-world evidence has also been accumulated. The efficacy and safety of saxagliptin, especially its cardiovascular safety, are of particular interest. AREAS COVERED: This review provides an overview of the safety and efficacy of saxagliptin based on observational studies, pharmacovigilance, and meta-analyses. In addition, with the findings of recent cardiovascular outcome trials (CVOTs), the authors discuss, herein, the efficacious use of saxagliptin. EXPERT OPINION: Saxagliptin exhibits a moderate glucose-lowering effect and is well tolerated by patients with T2D. SAVOR-TIMI 53, a CVOT of saxagliptin, reported neutral effects of saxagliptin in respect of the cardiovascular outcomes, but did raise a concern about the risk of heart failure. Conversely, recent CVOTs on sodium-glucose co-transporter-2 inhibitors (SGLT2i) have shown a favorably reduced risk of heart failure with these drugs. Also, DPP-4is decrease the serum glucagon level, whereas the SGLT2is increase it. Given the characteristics of the two classes of drugs, combined therapy with the two might be a promising option.

DOI： 10.1080/14656566.2020.1803280

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing  

DOI： 10.1111/jdi.13248

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DOI： 10.1111/dom.14139

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DOI： 10.1111/dom.14036

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BACKGROUND: With limited real-world insulin glargine 300 U/mL (Gla-300) data among Japanese patients with type 1 diabetes mellitus (T1DM) available, the authors describe its effectiveness and safety in Japanese T1DM patients switching to Gla-300. RESEARCH DESIGN AND METHODS: X-STAR was a 12-month prospective, observational, post-marketing study in Japanese patients with diabetes mellitus from 2015 to 2018: insulin-experienced T1DM patients initiating Gla-300 were analyzed. RESULTS: Of 774 patients, mean (±standard deviation) HbA1c (%) and fasting plasma glucose (mg/dL) decreased from 8.27 ± 1.55 to 8.15 ± 1.35 (by -0.12 ± 1.30 [p = 0.013]) and 167.9 ± 92.6 to 153.9 ± 70.9 (by -13.9 ± 103.8 [p = 0.067]) from baseline to month 12, respectively. A total of 16.3% achieved HbA1c <7.0% at month 12. Gla-300 dose increased by 1.13 ± 3.18 U/day (0.02 ± 0.05 U/kg/day) (p < 0.001), with a + 0.22 ± 2.70 (p = 0.037) body-weight change (kg) from baseline 60.83 ± 12.81 to 12-month 61.06 ± 12.89. Adverse drug reactions (ADRs) and serious ADRs occurred in 9.82% and 0.78% of the patients, respectively. Hypoglycemia was the most common ADR (9.30%). In total, 88.9% adhered to Gla-300 administration schedules, whereas <40% adhered to exercise and dietary instructions, respectively. CONCLUSIONS: Gla-300 showed no unprecedented safety concerns for insulin-experienced T1DM patients in Japanese clinical settings. Our results provide insights into strategies for blunted Gla-300 up-titration dose, despite insufficient HbA1c control and lifestyle modification.

DOI： 10.1080/14656566.2020.1810665

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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BACKGROUND: With limited real-world insulin glargine 300 unit/mL (Gla-300) data available, we assessed the effectiveness and safety of Gla-300 in the Japanese type 2 diabetes mellitus (T2DM) population. RESEARCH DESIGN AND METHODS: X-STAR was a prospective, observational, 12-month post-marketing study of Gla-300 from 2015 to 2018. T2DM patients received Gla-300 as the first insulin (insulin-naïve) or after treatment with another type of insulin (insulin-experienced). RESULTS: We identified 1,227 insulin-naïve and 3,394 insulin-experienced patients. Insulin-naïve group increased the Gla-300 starting dose by 2.80 U/day during 12 months (7.49 to 10.29 U/day). Mean HbA1c reduced by 1.99% (9.82 to 7.83%), and 28.4% showed HbA1c < 7.0%. Insulin-experienced group had a baseline insulin dose of 14.86 U/day, which increased by 0.73 U/day. Mean HbA1c reduced by 0.18% (7.99 to 7.81%), and 24.6% showed HbA1c < 7.0%. Adverse drug reactions occurred in 3.42% (insulin-naïve) and 4.45% (insulin-experienced); symptomatic hypoglycemia (2.93% and 3.86%, respectively) was the most common in both groups. CONCLUSIONS: Gla-300, in clinical practice, provides an effective and safe therapy as HbA1c was reduced/maintained in insulin-naïve/experienced Japanese T2DM patients without new safety signal. This study provides insights into the current Japanese clinical practices where insulin use is delayed and conservative despite relatively low HbA1c achievement.

DOI： 10.1080/14656566.2020.1785430

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Language：Japanese   Publisher：神奈川県医師会  

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Language：Japanese   Publisher：日本臨床分子医学会  

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Objective: Patients with type 2 diabetes mellitus (T2DM) show more executive dysfunction than nondiabetics. However, how long poor glycemic control affects executive function remains unclear. Thus, we aimed to investigate the relationships in a cross-sectional study. Methods: We studied 118 T2DM outpatients (age, ≥ 60 years; excluding history of stroke, dementia and severe hypoglycemia). HbA1c values were recorded every ≤ 12 weeks for ≥ 5 years. All patients underwent verbal-fluency tests (reflecting executive function) and Mini-Mental State Examination (MMSE). The correlation between past glycemic control values and both cognitive tests scores was investigated. As markers of past glycemic control, we used average hemoglobin A1c (HbA1c) values and glycemic control variability [coefficient of variation (CV) of HbA1c values (HbA1c-CV)]. Results: Verbal-fluency tests scores correlated with HbA1c-CV, but not with average HbA1c values, after adjusting for age, years of education and sex. Verbal-fluency tests scores correlated with HbA1c-CV for the past 5 years, best compared with HbA1c-CV for past < 5 years. MMSE scores were also related to only HbA1c-CV for the past 3 years in an adjustment model. Conclusions: Five-year HbA1c variability affected executive function in T2DM patients, but not average HbA1c values. Long-term longitudinal studies may be required.

DOI： 10.1007/s13340-019-00411-y

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Obesity can initiate and accelerate the progression of kidney diseases. However, it remains unclear how obesity affects renal dysfunction. Here, we show that a newly generated podocyte-specific tubular sclerosis complex 2 (Tsc2) knockout mouse model (Tsc2Δpodocyte) develops proteinuria and dies due to end-stage renal dysfunction by 10 weeks of age. Tsc2Δpodocyte mice exhibit an increased glomerular size and focal segmental glomerulosclerosis, including podocyte foot process effacement, mesangial sclerosis and proteinaceous casts. Podocytes isolated from Tsc2Δpodocyte mice show nuclear factor, erythroid derived 2, like 2-mediated increased oxidative stress response on microarray analysis and their autophagic activity is lowered through the mammalian target of rapamycin (mTOR)-unc-51-like kinase 1 pathway. Rapamycin attenuated podocyte dysfunction and extends survival in Tsc2Δpodocyte mice. Additionally, mTOR complex 1 (mTORC1) activity is increased in podocytes of renal biopsy specimens obtained from obese patients with chronic kidney disease. Our work shows that mTORC1 hyperactivation in podocytes leads to severe renal dysfunction and that inhibition of mTORC1 activity in podocytes could be a key therapeutic target for obesity-related kidney diseases.

DOI： 10.1371/journal.pone.0229397

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Mary Ann Liebert Inc.  

DOI： 10.1089/dia.2019.0372

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AIMS/HYPOTHESIS: Sodium-glucose cotransporter 2 (SGLT2) inhibitors, which prevent the renal reabsorption of glucose, decrease blood glucose levels in an insulin-independent manner. We previously reported creating a mouse model of systemic inhibition of target receptors for both insulin and IGF-1 by treating animals with OSI-906, a dual insulin/IGF-1 receptor inhibitor, for 7 days. The OSI-906-treated mice exhibited an increased beta cell mass, hepatic steatosis and adipose tissue atrophy, accompanied by hyperglycaemia and hyperinsulinaemia. In the present study, we investigated the effects of an SGLT2 inhibitor, luseogliflozin, on these changes in OSI-906-treated mice. METHODS: We treated C57BL/6J male mice either with vehicle, luseogliflozin, OSI-906 or OSI-906 plus luseogliflozin for 7 days, and phenotyping was performed to determine beta cell mass and proliferation. Subsequently, we tested whether serum-derived factors have an effect on beta cell proliferation in genetically engineered beta cells, mouse islets or human islets. RESULTS: SGLT2 inhibition with luseogliflozin significantly ameliorated hyperglycaemia, but not hyperinsulinaemia, in the OSI-906-treated mice. Liver steatosis and adipose tissue atrophy induced by OSI-906 were not altered by treatment with luseogliflozin. Beta cell mass and proliferation were further increased by SGLT2 inhibition with luseogliflozin in the OSI-906-treated mice. Luseogliflozin upregulated gene expression related to the forkhead box M1 (FoxM1)/polo-like kinase 1 (PLK1)/centromere protein A (CENP-A) pathway in the islets of OSI-906-treated mice. The increase in beta cell proliferation was recapitulated in a co-culture of Irs2 knockout and Insr/IR knockout (βIRKO) beta cells with serum from both luseogliflozin- and OSI-906-treated mice, but not after SGLT2 inhibition in beta cells. Circulating factors in both luseogliflozin- and OSI-906-treated mice promoted beta cell proliferation in both mouse islets and cadaveric human islets. CONCLUSIONS/INTERPRETATION: These results suggest that luseogliflozin can increase beta cell proliferation through the activation of the FoxM1/PLK1/CENP-A pathway via humoral factors that act in an insulin/IGF-1 receptor-independent manner.

DOI： 10.1007/s00125-019-05071-w

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Language：Japanese   Publisher：(一社)日本内科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japan Endocrine Society  

DOI： 10.1507/endocrj.EJ19-0464

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Background: Insulin resistance can occur in all metabolic organs including the liver, adipose tissue, and skeletal muscles. Circulating soluble epidermal growth factor receptor (soluble EGFR) and adipsin levels are altered in obese diabetic mice and are possibly correlated with insulin resistance in both mice and humans. Here, we investigated the significance of soluble EGFR and adipsin as biomarkers for insulin resistance in Japanese subjects with type 2 diabetes. Methods: We measured the soluble EGFR and adipsin levels in sera from 47 non-diabetic subjects and 106 subjects with type 2 diabetes using enzyme-linked immunosorbent assays (ELISAs) and analyzed the correlations between the soluble EGFR or adipsin levels and metabolic parameters in type 2 diabetes subjects. We also measured the gene expression levels of Egfr and Cfd (adipsin) in the liver, adipose tissue, and skeletal muscle in mice with/without obesity or diabetes. Results: The soluble EGFR levels were correlated with the fasting blood glucose level (P = 0.010), HOMA-IR (P = 0.035), HbA1c level (P = 0.007), HDL-cholesterol level (P = 0.044), and FIB-4 index (P = 0.017) after adjustments for age, sex, and total cholesterol levels. These factors are known to be related to hepatic insulin resistance. The serum adipsin levels were correlated with BMI (P < 0.001), waist circumference (P < 0.001), fasting serum insulin level (P = 0.001), HOMA-IR (P = 0.009), CPR-index (P = 0.045), and FIB-4 index (P = 0.007) after adjustments for age, sex and eGFR levels. Abdominal adiposity leads to the potentiation of these factors. The expression of Egfr was abundant in the liver, while Cfd was predominantly expressed in adipose tissue in mice. Conclusions: Soluble EGFR, a hepatokine, is correlated with insulin resistance in the liver, while adipsin, an adipokine, is associated with adipose insulin resistance.Trial registration: UMIN Clinical Trials Registry (www.umin.ac.jp), UMIN000020474. Registered 8 January 2016.

DOI： 10.1186/s13098-020-00591-7

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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.

DOI： 10.2169/internalmedicine.3060-19

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DOI： 10.1080/14656566.2019.1656717

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DOI： 10.1111/jdi.13066

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elmer Press  

DOI： 10.14740/jem.v9i5.604

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BACKGROUND: The Y-AIDA study was designed to investigate the renal- and home blood pressure (BP)-modulating effects of add-on dapagliflozin treatment in Japanese individuals with type 2 diabetes mellitus (T2DM) and albuminuria. METHODS: We conducted a prospective, multicenter, single-arm study. Eighty-six patients with T2DM, HbA1c 7.0-10.0%, estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73 m2, and urine albumin-to-creatinine ratio (UACR) ≥ 30 mg/g creatinine (gCr) were enrolled, and 85 of these patients were administered add-on dapagliflozin for 24 weeks. The primary and key secondary endpoints were change from baseline in the natural logarithm of UACR over 24 weeks and change in home BP profile at week 24. RESULTS: Baseline median UACR was 181.5 mg/gCr (interquartile range 47.85, 638.0). Baseline morning, evening, and nocturnal home systolic/diastolic BP was 137.6/82.7 mmHg, 136.1/79.3 mmHg, and 125.4/74.1 mmHg, respectively. After 24 weeks, the logarithm of UACR decreased by 0.37 ± 0.73 (P < 0.001). In addition, changes in morning, evening, and nocturnal home BP from baseline were as follows: morning systolic/diastolic BP - 8.32 ± 11.42/- 4.18 ± 5.91 mmHg (both P < 0.001), evening systolic/diastolic BP - 9.57 ± 12.08/- 4.48 ± 6.45 mmHg (both P < 0.001), and nocturnal systolic/diastolic BP - 2.38 ± 7.82/- 1.17 ± 5.39 mmHg (P = 0.0079 for systolic BP, P = 0.0415 for diastolic BP). Furthermore, the reduction in UACR after 24 weeks significantly correlated with an improvement in home BP profile, but not with changes in other variables, including office BP. Multivariate linear regression analysis also revealed that the change in morning home systolic BP was a significant contributor to the change in log-UACR. CONCLUSIONS: In Japanese patients with T2DM and diabetic nephropathy, dapagliflozin significantly improved albuminuria levels and the home BP profile. Improved morning home systolic BP was associated with albuminuria reduction. Trial registration The study is registered at the UMIN Clinical Trials Registry (UMIN000018930; http://www.umin.ac.jp/ctr/index-j.htm ). The study was conducted from July 1, 2015 to August 1, 2018.

DOI： 10.1186/s12933-019-0912-3

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Some categories of drugs are known for causing hyperglycemia or diabetes such as steroids, antipsychotics, and immunosuppressant. However, there has been little evidence from studies about the proportion of each drug in the context of drug-induced diabetes. In this study, we used data from the Japanese Adverse Drug Event Report (JADER) database, a spontaneous reporting system database maintained at the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan, reported between April 2004 and June 2017. Among 459,250 reports of adverse drug reactions in JADER database, reported instances of the adverse event of hyperglycemia or diabetes were extracted. After the exclusion of anti-diabetes drugs, the drugs frequently implicated in the development of hyperglycemia or diabetes, including prednisolone, tacrolimus, everolimus, ribavirin, quetiapine, aripiprazole, interferon alfa-2b, risperidone, atorvastatin, dexamethasone, ciclosporin, nilotinib, methylprednisolone, or nivolumab, were identified. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, was manifested as the third most frequently associated drug with hyperglycemia or diabetes (340 cases), following prednisolone (694 cases) and tacrolimus (393 cases), and the reporting odds ratio (ROR 8.56, 95% CI 7.65-9.57) of this drug was higher than that of the two aforementioned drugs (ROR 3.96, 95% CI 3.66-4.28 and ROR 3.51, 95% CI 3.17-3.89). These results suggest that there is a potent association of evelolimus with hyperglycemia in clinical practice in Japan.

DOI： 10.1507/endocrj.EJ18-0553

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elmer Press  

DOI： 10.14740/jem570

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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.

DOI： 10.1111/jdi.13106

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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.

DOI： 10.1016/j.metabol.2019.06.006

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DOI： 10.1007/s13300-019-0604-8

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DOI： 10.1507/endocrj.EJ19-0041

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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DOI： 10.1016/j.diabres.2019.01.019

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Language：Japanese   Publisher：(株)日本臨床社  

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DOI： 10.1111/jdi.12903

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Association of Clinical Endocrinologists  

DOI： 10.4158/EP-2018-0200

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DOI： 10.1111/jdi.12849

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japan Diabetes Society  

DOI： 10.11213/tonyobyo.62.649

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DOI： 10.1111/jdi.12846

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DOI： 10.1111/dom.13414

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DOI： 10.14740/jem531w

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DOI： 10.1016/j.jjcc.2018.02.018

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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.

DOI： 10.1016/j.metabol.2018.03.010

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DOI： 10.2337/db18-1138-P

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[This corrects the article DOI: 10.14740/jocmr3281w.].

DOI： 10.14740/jocmr3281wc1

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OBJECTIVE: Diabetes is associated with high risk of cardiovascular (CV) events, particularly in patients with dyslipidemia and diabetic complications. We investigated the incidence of CV events with intensive or standard lipid-lowering therapy in patients with hypercholesterolemia, diabetic retinopathy, and no history of coronary artery disease (treat-to-target approach). RESEARCH DESIGN AND METHODS: In this multicenter, prospective, randomized, open-label, blinded end point study, eligible patients were randomly assigned (1:1) to intensive statin therapy targeting LDL cholesterol (LDL-C) <70 mg/dL (n = 2,518) or standard statin therapy targeting LDL-C 100-120 mg/dL (n = 2,524). RESULTS: Mean follow-up was 37 ± 13 months. LDL-C at 36 months was 76.5 ± 21.6 mg/dL in the intensive group and 104.1 ± 22.1 mg/dL in the standard group (P < 0.001). The primary end point events occurred in 129 intensive group patients and 153 standard group patients (hazard ratio [HR] 0.84 [95% CI 0.67-1.07]; P = 0.15). The relationship between the LDL-C difference in the two groups and the event reduction rate was consistent with primary prevention studies in patients with diabetes. Exploratory findings showed significantly fewer cerebral events in the intensive group (HR 0.52 [95% CI 0.31-0.88]; P = 0.01). Safety did not differ significantly between the two groups. CONCLUSIONS: We found no significant decrease in CV events or CV-associated deaths with intensive therapy, possibly because our between-group difference of LDL-C was lower than expected (27.7 mg/dL at 36 months of treatment). The potential benefit of achieving LDL-C <70 mg/dL in a treat-to-target strategy in high-risk patients deserves further investigation.

DOI： 10.2337/dc17-2224

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing  

DOI： 10.1111/jdi.12732

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DOI： 10.1111/dom.13213

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Chronic low-grade inflammation in the pancreatic islets is observed in individuals with type 2 diabetes, and macrophage levels are elevated in the islets of these individuals. However, the molecular mechanisms underlying the interactions between the pancreatic β cells and macrophages and their involvement in inflammation are not fully understood. Here, we investigated the role of S100 calcium-binding protein A8 (S100A8), a member of the damage-associated molecular pattern molecules (DAMPs), in β-cell inflammation. Co-cultivation of pancreatic islets with unstimulated peritoneal macrophages in the presence of palmitate (to induce lipotoxicity) and high glucose (to induce glucotoxicity) synergistically increased the expression and release of islet-produced S100A8 in a Toll-like receptor 4 (TLR4)-independent manner. Consistently, a significant increase in the expression of the S100a8 gene was observed in the islets of diabetic db/db mice. Furthermore, the islet-derived S100A8 induced TLR4-mediated inflammatory cytokine production by migrating macrophages. When human islet cells were co-cultured with U937 human monocyte cells, the palmitate treatment up-regulated S100A8 expression. This S100A8-mediated interaction between islets and macrophages evoked β-cell apoptosis, which was ameliorated by TLR4 inhibition in the macrophages or S100A8 neutralization in the pancreatic islets. Of note, both glucotoxicity and lipotoxicity triggered S100A8 secretion from the pancreatic islets, which in turn promoted macrophage infiltration of the islets. Taken together, a positive feedback loop between islet-derived S100A8 and macrophages drives β-cell apoptosis and pancreatic islet inflammation. We conclude that developing therapeutic approaches to inhibit S100A8 may serve to prevent β-cell loss in patients with diabetes.

DOI： 10.1074/jbc.M117.809228

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DOI： 10.21037/atm.2018.01.35

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DOI： 10.1111/jgh.14022

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Background: Low-carbohydrate diets have been shown to effectively improve the metabolic status of patients with type 2 diabetes mellitus. However, patients may find it challenging to maintain a strict low-carbohydrate diet. The objective of this study was to determine if a one-meal, low-carbohydrate diet is as effective in improving metabolic status as a conventional, energy-restricted diet among patients with type 2 diabetes mellitus. Methods: In this 12-week randomized controlled study, the primary endpoint was differences in the changes of plasma glycosylated hemoglobin (HbA1c) levels between the two experimental groups. Since the two groups had differences in body weight, body mass index, and waist circumference, propensity score matching was used to assess HbA1c outcomes via cohort pairs according to age, sex, body weight, HbA1c level, and waist circumference. Results: There were no differences in the changes in HbA1c between the two groups (P = 0.95). In addition, there were no differences in the changes in glycated albumin, 1,5-anhydroglucitol, lipid profile, body weight, waist circumference, and fat mass between the two groups. The mini low-carbohydrate diet group had an increased protein intake (P = 0.0085), as compared with the control group. However, neither group showed changes in their Diabetes Treatment Satisfaction Questionnaire score. Conclusion: Either diet would be effective for improving the metabolic status of this study population.

DOI： 10.14740/jocmr3281w

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AIMS: To assess the safety and efficacy of monotherapy with once-weekly subcutaneous (s.c.) semaglutide vs sitagliptin in Japanese people with type 2 diabetes (T2D). METHODS: In this phase IIIa randomized, open-label, parallel-group, active-controlled, multicentre trial, Japanese adults with T2D treated with diet and exercise only or oral antidiabetic drug monotherapy (washed out during the run-in period) received once-weekly s.c. semaglutide (0.5 or 1.0 mg) or once-daily oral sitagliptin 100 mg. The primary endpoint was number of treatment-emergent adverse events (TEAEs) after 30 weeks. RESULTS: Overall, 308 participants were randomized and exposed to treatment, with similar baseline characteristics across the groups. In total, 2.9% of participants in both the semaglutide 0.5 mg and the sitagliptin group prematurely discontinued treatment, compared with 14.7% in the semaglutide 1.0 mg group. The majority of discontinuations in the semaglutide 0.5 and 1.0 mg groups were attributable to adverse events (AEs). More TEAEs were reported in semaglutide- vs sitagliptin-treated participants (74.8%, 71.6% and 66.0% in the semaglutide 0.5 mg, semaglutide 1.0 mg and sitagliptin groups, respectively). AEs were mainly mild to moderate. Gastrointestinal AEs, most frequently reported with semaglutide, diminished in frequency over time. The mean glycated haemoglobin (HbA1c [baseline 8.1%]) decreased by 1.9% and 2.2% with semaglutide 0.5 and 1.0 mg, respectively, vs 0.7% with sitagliptin (estimated treatment difference [ETD] vs sitagliptin -1.13%, 95% confidence interval [CI] -1.32; -0.94, and -1.44%, 95% CI -1.63; -1.24; both P < .0001). Body weight (baseline 69.3 kg) was reduced by 2.2 and 3.9 kg with semaglutide 0.5 and 1.0 mg, respectively (ETD -2.22 kg, 95% CI -3.02; -1.42 and -3.88 kg, 95% CI -4.70; -3.07; both P < .0001). CONCLUSIONS: In Japanese people with T2D, more TEAEs were reported with semaglutide than with sitagliptin; however, the semaglutide safety profile was similar to that of other glucagon-like peptide-1 receptor agonists. Semaglutide significantly reduced HbA1c and body weight compared with sitagliptin.

DOI： 10.1111/dom.13082

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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.

DOI： 10.1111/jdi.12821

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DOI： 10.1111/jdi.12646

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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.

DOI： 10.1111/jdi.12654

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OBJECTIVES: Excessively short and long sleep durations are associated with type 2 diabetes, but there is limited information about the association between sleep quality and diabetes. Accordingly, the present study was performed to investigate this relationship. MATERIALS AND METHODS: The subjects were 3249 patients with type 2 diabetes aged 20 years or older. Sleep quality was assessed by using the Pittsburgh Sleep Quality Index (PSQI). A higher global PSQI score indicates worse sleep quality, and a global PSQI score >5 differentiates poor sleepers from good sleepers. RESULTS: The mean global PSQI score was 5.94 ± 3.33, and 47.6% of the patients had a score of 6 or higher. Regarding the components of the PSQI, the score was highest for sleep duration, followed by subjective sleep quality and then sleep latency in decreasing order. When the patients were assigned to HbA1c quartiles (≤ 6.5%, 6.6-7.0%, 7.1-7.8%, and ≥ 7.9%), the top quartile had a significantly higher global PSQI score than the other quartiles. The top HbA1c quartile had a sleep duration of only 6.23 ± 1.42 hours, which was significantly shorter than in the other quartiles. Also, sleep latency was 25.3 ± 31.8 minutes in the top quartile, which was significantly longer (by approximately 20 minutes) than in the other quartiles. When analysis was performed with adjustment for age, gender, BMI, smoking, and other confounders, the global PSQI score was still significantly higher and sleep duration was shorter in the top HbA1c quartile (HbA1c ≥ 7.9%). CONCLUSIONS: Japanese patients with type 2 diabetes were found to have poor subjective sleep quality independently of potential confounders, especially those with inadequate glycemic control. Impairment of sleep quality was associated with both increased sleep latency and a shorter duration of sleep.

DOI： 10.1371/journal.pone.0191771

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japan Diabetes Society  

DOI： 10.11213/tonyobyo.61.773

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DOI： 10.1016/bs.vh.2018.01.008

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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.

DOI： 10.3389/fendo.2018.00081

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To identify circulating factors as candidates involved in type 2 diabetes mellitus (T2DM), we conducted two different quantitative proteomic analyses: (1) db/db mouse sera were compared with db/+ mouse sera obtained at 4, 8, 12, and 24 weeks of age, and (2) db/db mouse sera from animals treated with liraglutide were compared with sera from animals without liraglutide treatment. Twenty proteins were differentially expressed in db/db mouse sera in the first experiment and eight proteins were differentially expressed in db/db mouse sera after liraglutide treatment in the second experiment. Soluble epidermal growth factor receptor (sEGFR) was identified as a common factor, and its protein level was significantly affected in both experiments. An enzyme-linked immunosorbent assay confirmed that the relatively low serum sEGFR levels in db/db mice were restored by liraglutide treatment. The serum sEGFR levels were elevated in diabetic mice with impaired insulin secretion and decreased in high-fat diet-fed mice and ob/ob mice. The serum sEGFR levels increased after the administration of a dual inhibitor of IGF-1/insulin receptor or streptozotocin. In humans with normal glucose tolerance or T2DM, the serum sEGFR levels were correlated with the fasting blood glucose, fasting serum insulin, homeostatic model assessment of insulin resistance, HbA1c, total cholesterol, low-density lipoprotein cholesterol, and triglycerides levels. These findings suggest that sEGFR might be a biomarker for evaluating insulin resistance or a therapeutic target of liraglutide.

DOI： 10.1210/en.2017-00339

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Tokyo  

DOI： 10.1007/s13340-017-0328-9

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DOI： 10.1016/j.diabet.2017.03.001

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DOI： 10.1111/dom.12957

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Language：Japanese   Publisher：(一社)日本糖尿病合併症学会  

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Metformin has been widely used for the treatment of type 2 diabetes. However, the effect of metformin on pancreatic β-cells remains controversial. In this study, we investigated the impacts of treatment with metformin on pancreatic β-cells in a mouse model fed a high-fat diet (HFD), which triggers adaptive β-cell replication. An 8-wk treatment with metformin improved insulin resistance and suppressed the compensatory β-cell hyperplasia induced by HFD-feeding. In contrast, the increment in β-cell mass arising from 60 wk of HFD feeding was similar in mice treated with and those treated without metformin. Interestingly, metformin suppressed β-cell proliferation induced by 1 wk of HFD feeding without any changes in insulin resistance. Metformin directly suppressed glucose-induced β-cell proliferation in islets and INS-1 cells in accordance with a reduction in mammalian target of rapamycin phosphorylation. Taken together, metformin suppressed HFD-induced β-cell proliferation independent of the improvement of insulin resistance, partly via direct actions.

DOI： 10.1152/ajpendo.00447.2016

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DOI： 10.1111/dom.12933

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DOI： 10.14740/jocmr3067w

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Growth factor signaling via insulin receptor (IR) and IGF-1 receptor (IGF1R) plays several important roles in the pathogenesis of metabolic syndrome and diabetes. OSI-906 (linsitinib), an anti-tumor drug, is an orally bioavailable dual inhibitor of IR and IGF1R. To investigate the recovery from metabolic changes induced by the acute inhibition of IR and IGF1R in adult mice, mice were treated with OSI-906 or a vehicle for 7 days and the results were analyzed on the last day of injection (Day 7) or after 7 or 21 days of withdrawal (Day 14 or Day 28). On day 7, the visceral white fat mass was significantly reduced in mice treated with OSI-906 accompanied by a reduced expression of leptin and an increased expression of the lipolysis-related genes Lpl and Atgl. Interestingly, the lipoatrophy and the observed changes in gene expression were completely reversed on day 14. Similarly, liver steatosis and β cell proliferation were transiently observed on day 7 but had disappeared by day 14. Taken together, these results suggest that this model for the acute inhibition of systemic IR/IGF1R signaling may be useful for investigating the recovery from metabolic disorders induced by impaired growth factor signaling.

DOI： 10.1038/s41598-017-04304-5

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing Ltd  

DOI： 10.1111/dme.13199

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Language：Japanese   Publisher：日本臨床分子医学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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DOI： 10.1507/endocrj.EJ16-0332

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Tokyo  

DOI： 10.1007/s13340-016-0275-x

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DOI： 10.1007/s13340-016-0271-1

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Glucose- or insulin resistance-mediated β-cell replication serves as a useful physiological model of β-cell mass expansion to study the pathophysiology of type 2 diabetes. Lakshmipathi et al. (2016) report that PKCζ activation is crucial for compensatory β-cell proliferation induced by glucose stimulation or high-fat diet-feeding.

DOI： 10.1111/jdi.12558

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Language：Japanese   Publisher：日本内科学会-関東地方会  

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Language：English   Publishing type：Part of collection (book)   Publisher：Nova Science Publishers, Inc.  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wageningen Academic Publishers  

DOI： 10.3920/BM2016.0230

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：English   Publisher：The Japan Endocrine Society  

This study assessed indicators of the need for insulin therapy and the effect of treatment on pregnancy outcomes in Japanese patients with gestational diabetes mellitus (GDM). All patients diagnosed with GDM were hospitalized for three days. Plasma glucose profiles in patients under strict dietary management and the characteristics of GDM patients with high daily glucose levels were investigated. Patients who failed to achieve glycemic targets were treated with insulin. Indicators of the need for insulin treatment were investigated. Pregnancy outcomes in patients prescribed dietary management and patients prescribed insulin treatment were compared. The study included 112 patients with GDM. GDM patients with high daily glucose levels in the hospital exhibited significantly higher 1-h and 2-h plasma glucose levels in oral glucose tolerance tests (OGTTs) at diagnosis. In our hospital, 102 GDM patients with singleton pregnancies were followed until delivery; 32 (31.3%) were treated with insulin. Univariate analysis identified significant associations of insulin requirement with family history of diabetes and with 1-h and 2-h OGTT values at diagnosis. Multivariate analysis showed that the 1-h OGTT plasma glucose level at diagnosis was an independent predictor of the need for insulin. In perinatal outcomes, insulin treatment was associated with low birth weight.

DOI： 10.1507/endocrj.EJ15-0427

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Other Link： http://search.jamas.or.jp/link/ui/2017035277

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DOI： 10.1038/ncomms12977

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Language：Japanese   Publisher：(一社)日本小児リウマチ学会  

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Language：Japanese   Publisher：日本内科学会-関東地方会  

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DOI： 10.14740/jocmr2686w

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DOI： 10.1080/14656566.2016.1219341

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DOI： 10.1038/srep34707

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BioMed Central Ltd.  

DOI： 10.1186/s12933-016-0438-x

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DOI： 10.1111/jdi.12455

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Public Library of Science  

DOI： 10.1371/journal.pone.0154821

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DOI： 10.1016/j.jsbmb.2016.03.011

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DOI： 10.1038/srep25465

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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DOI： 10.1111/dom.12618

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Language：Japanese   Publisher：日本臨床分子医学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japan Endocrine Society  

DOI： 10.1507/endocrj.EJ15-0500

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DOI： 10.1161/JAHA.115.002875

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DOI： 10.1517/14656566.2016.1145668

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Non-alcoholic fatty liver disease (NAFLD) is associated with various metabolic disorders, and the therapeutic strategies for treating NAFLD and non-alcoholic steatohepatitis (NASH) have not been fully established. In the present study, we examined whether lipid-lowering agents inhibited the progression of NAFLD and tumorigenesis in a non-alcoholic steatohepatitis-derived hepatocellular carcinoma model mouse (STAM mice) generated by streptozotocin injection and a high-fat diet. Seven-week-old STAM mice were divided into groups fed a high-fat diet (Ctl) or a high-fat diet supplemented with ezetimibe (Ez), fenofibrate (Ff), rosuvastatin (Rs), ezetimibe plus fenofibrate (EF), or ezetimibe plus rosuvastatin (ER) for 4 weeks. At the end of the experiments, an oral glucose tolerance test, an insulin tolerance test, biochemical analyses using serum and liver, and a histological analysis of liver were performed in 11-week-old STAM mice. The lipid-lowering agents did not affect the body weight or the casual blood glucose levels in any of the groups. The serum triglyceride level was significantly decreased by Ff, Rs, and EF. Glucose tolerance was improved by Ez and Ff, but none of these agents improved insulin sensitivity. A histochemical analysis revealed that the lipid-lowering agents, with the exception of Rs, significantly inhibited the progression of hepatic steatosis. Nonetheless, no significant changes in the incidence of hepatic tumors were observed in any of the groups. Lipid-lowering agents inhibited the progression of hepatic steatosis without suppressing tumorigenesis in STAM mice. Our data has implications for the mechanism underlying steatosis-independent hepatic tumorigenesis in mice.

DOI： 10.1016/j.ejphar.2015.12.043

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DOI： 10.1016/j.dsx.2015.08.008

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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.

DOI： 10.1507/endocrj.EJ15-0371

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Life Science Publishing Co. Ltd  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japan Diabetes Society  

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DOI： 10.2169/internalmedicine.55.6583

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Language：English   Publisher：The Japan Endocrine Society  

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.

DOI： 10.1507/endocrj.EJ15-0428

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Other Link： http://search.jamas.or.jp/link/ui/2017035285

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DOI： 10.2169/internalmedicine.55.6566

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BACKGROUND: Diabetes therapy that not only lowers glucose levels but also lengthens life spans is required. We previously demonstrated that DPP-4 inhibition ameliorated β cell apoptosis and adipose tissue inflammation in β cell-specific glucokinase haploinsufficient mice fed a diet containing a combination of sucrose and linoleic acid (SL). METHODS: In this study, we investigated the effects of DPP-4 inhibition in obese diabetic db/db mice fed an SL diet or a control diet containing sucrose and oleic acid (SO). We also examined the effects of DPP-4 inhibition in IRS-1-deficient mice fed an SL or SO diet as a model of insulin resistance. RESULTS: DPP-4 inhibition efficiently increases the active GLP-1 levels in db/db mice. Unexpectedly, the SL diet, but not the SO diet, markedly increases mortality in the db/db mice. DPP-4 inhibition reduces the early lethality in SL-fed db/db mice. DPP-4 inhibition improves glucose tolerance, β cell function, and adipose tissue inflammation in db/db mice fed either diet. No significant changes in glycemic control or β cell mass were observed in any of the IRS-1-deficient mouse groups. CONCLUSIONS: A diet containing a combination of sucrose and linoleic acid causes early lethality in obese diabetic db/db mice, but not in lean and insulin resistant IRS-1 knockout mice. DPP-4 inhibition has protective effects against the diet-induced lethality in db/db mice.

DOI： 10.1186/s13098-016-0138-4

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japan Endocrine Society  

DOI： 10.1507/endocrj.EJ15-0401

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DOI： 10.1186/s12876-015-0409-9

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DOI： 10.1007/s10157-015-1110-6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japan Endocrine Society  

DOI： 10.1507/endocrj.EJ15-0206

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Language：Japanese   Publisher：日本内科学会-関東地方会  

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DOI： 10.1111/dom.12507

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DOI： 10.1517/14656566.2015.1057120

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DOI： 10.1002/jcph.483

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DOI： 10.1186/s12902-015-0033-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Ireland Ltd  

DOI： 10.1016/j.diabres.2015.03.008

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DOI： 10.1371/journal.pone.0125519

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DOI： 10.1186/s12876-015-0269-3

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DOI： 10.1007/s12325-015-0198-0

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DOI： 10.1111/jdi.12294

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DOI： 10.1002/jcph.385

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DOI： 10.1177/0300060514534644

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DOI： 10.1507/endocrj.EJ14-0147

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Language：English   Publisher：OMICS International  

DOI： 10.4172/2161-069X.1000221

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Language：Japanese   Publisher：(一社)日本糖尿病合併症学会  

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DOI： 10.1016/j.orcp.2013.07.002

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DOI： 10.1111/jdi.12212

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The IGF-1 receptor has become a therapeutic target for the treatment of cancer. The efficacy of OSI-906 (linstinib), a dual inhibitor of IGF-1 receptor and insulin receptor, for solid cancers has been examined in clinical trials. The effects of OSI-906, however, on the blood glucose levels and pancreatic β-cell functions have not yet been reported. We investigated the impact of OSI-906 on glycemic control, insulin secretion, β-cell mass, and β-cell proliferation in male mice. Oral administration of OSI-906 worsened glucose tolerance in a dose-dependent manner in the wild-type mice. OSI-906 at a dose equivalent to the clinical daily dose (7.5 mg/kg) transiently evoked glucose intolerance and hyperinsulinemia. Insulin receptor substrate (IRS)-2-deficient mice and mice with diet-induced obesity, both models of peripheral insulin resistance, exhibited more severe glucose intolerance after OSI-906 administration than glucokinase-haploinsufficient mice, a model of impaired insulin secretion. Phloridzin improved the hyperglycemia induced by OSI-906 in mice. In vitro, OSI-906 showed no effect on insulin secretion from isolated islets. After daily administration of OSI-906 for a week to mice, the β-cell mass and β-cell proliferation rate were significantly increased. The insulin signals in the β-cells were apparently unaffected in those mice. Taken together, the results suggest that OSI-906 could exacerbate diabetes, especially in patients with insulin resistance. On the other hand, the results suggest that the β-cell mass may expand in response to chemotherapy with this drug.

DOI： 10.1210/en.2013-2032

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DOI： 10.1507/endocrj.EJ13-0450

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DOI： 10.1507/endocrj.EJ13-0460

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DOI： 10.1210/en.2013-1796

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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BACKGROUND: To evaluate the efficacy of switching from insulin to the GLP-1 receptor agonist liraglutide in type 2 diabetes mellitus patients. METHODS: The subjects were 231 outpatients with type 2 diabetes mellitus being treated with liraglutide for the first time. For 161 patients, liraglutide was continued for 24 weeks (continuation group), and for 70 patients, liraglutide was discontinued before 24 weeks (discontinuation group). Fasting and postprandial blood glucose levels, HbA1c, body weight, and insulin dose were evaluated before the switch to liraglutide (baseline) and at 12 and 24 weeks of administration. Trends in HbA1c and weight were compared at 12 and 24 weeks of administration. Multiple regression analyses were conducted to identify clinical factors predicting a successful switch to liraglutide. RESULTS: Multiple regression analysis with ΔHbA1c as the dependent variable in the continuation group indicated that HbA1c at 12 weeks of administration decreased with higher baseline HbA1c and increased with higher baseline daily insulin doses. Multiple regression analysis with Δweight as the dependent variable indicated that Δweight at 24 weeks of liraglutide administration was higher with higher baseline daily insulin doses and longer duration of diabetes. Based on the area under the receiver operating characteristic curve, cut-off values of 19 units for daily insulin dose and nine years for duration of diabetes were identified. CONCLUSIONS: Switching from insulin to liraglutide therapy is possible for carefully selected patients. Daily insulin dosage and duration of insulin therapy appear to be clinically useful indicators for the efficacy of liraglutide therapy.

DOI： 10.14740/jocmr1719w

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DOI： 10.1517/14656566.2014.887680

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DOI： 10.1186/1475-2840-13-65

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DOI： 10.1507/endocrj.ej13-0399