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ABSTRACT 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.

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 (HbA1c) 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

ABSTRACT 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

Abstract 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.

Background: This study aimed to develop models to predict the 5-year incidence of type 2 diabetes mellitus (T2DM) in a Japanese population and validate them externally in an independent Japanese population. Methods: Data from 10,986 participants (aged 46–75 years) in the development cohort of the Japan Public Health Center-based Prospective Diabetes Study and 11,345 participants (aged 46–75 years) in the validation cohort of the Japan Epidemiology Collaboration on Occupational Health Study were used to develop and validate the risk scores in logistic regression models. Results: We considered non-invasive (sex, body mass index, family history of diabetes mellitus, and diastolic blood pressure) and invasive (glycated hemoglobin [HbA1c] and fasting plasma glucose [FPG]) predictors to predict the 5-year probability of incident diabetes. The area under the receiver operating characteristic curve was 0.643 for the non-invasive risk model, 0.786 for the invasive risk model with HbA1c but not FPG, and 0.845 for the invasive risk model with HbA1c and FPG. The optimism for the performance of all models was small by internal validation. In the internal-external cross-validation, these models tended to show similar discriminative ability across different areas. The discriminative ability of each model was confirmed using external validation datasets. The invasive risk model with only HbA1c was well-calibrated in the validation cohort. Conclusion: Our invasive risk models are expected to discriminate between high- and low-risk individuals with T2DM in a Japanese population.

Abstract 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

CA19-9 is a tumor marker for pancreatic cancer (PC), and the nondiabetic cut-off level is 37 U/mL. CA19-9 levels are said to rise in patients with tumors like PC and intraductal papillary mucinous neoplasm (IPMN). CA19-9 levels have also been shown to be related to HbA1c levels. We hypothesized that the CA19-9 cut-off levels would differ between patients with poorly controlled diabetes. This real-world trial was designed to test our hypotheses. This was a retrospective cohort study. All inpatients with poorly controlled diabetes had mean HbA1c levels of 10.0% and were divided into three groups: those with pancreatic cancer (PC group, N = 20), those with IPMN (IPMN group, N = 55), and those with neither (NC group, N = 985). Serum CA19-9 levels in the PC group were significantly higher than in the IPMN and NC groups (p < 0.001). CA19-9 levels did not differ statistically between the IPMN and NC groups. According to the receiver operating characteristic (ROC) analysis, serum CA19-9 levels of 98.4 U/mL had the highest sensitivity and specificity to detect PC, when comparing PC to IPMN + NC groups. Using this cut-off, the sensitivity and specificity of CA19-9 for PC were 70.0% and 96.5%, respectively, with a 0.81 area under the ROC curve. CA19-9 levels in two inpatients were >98.4 U/mL, most likely due to hepatocellular carcinoma and esophageal cancer. CA19-9 cut-off levels were thought to be 98.4 U/mL. However, we should keep in mind that the sensitivity and specificity were not 100%.

Abstract 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.

Abstract 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 (

BackgroundIncreasing 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). ObjectiveIn 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. MethodsThis 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. ResultsAs 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. ConclusionsThis 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 RegistrationJapan 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

ABSTRACT 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.

ABSTRACT 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:

ABSTRACT 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.

Abstract 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.

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.

Abstract 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.

ABSTRACT 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

Abstract We aimed to determine the mechanism by which the sodium glucose co-transporter 2 inhibitor, luseogliflozin, preserves pancreatic beta-cell mass and function in db/db mice. Six-week-old db/db mice were fed to standard chow or standard chow containing 0.01% luseogliflozin. After 4 weeks, DNA microarray analysis, real-time PCR analysis, and measurement of mitochondrial respiratory capacity and reactive oxygen species (ROS) generation were performed using isolated islets. Immunohistochemistry and electron microscopic analysis were performed using pancreatic tissues. Metabolites extracted from the islets were measured by capillary electrophoresis mass spectrometry. The expression of genes involved in the tricarboxylic acid (TCA) cycle and electron transport chain was upregulated by luseogliflozin. Luseogliflozin improved the mitochondrial complex II-linked oxidative phosphorylation capacity and reduced ROS generation. Mitochondrial morphology was normally maintained by luseogliflozin. Luseogliflozin increased NK6 homeobox 1 (NKX6.1) expression and TCA cycle metabolites. Relief of glucotoxicity by luseogliflozin may involve lower mitochondrial ROS generation and an improvement in complex II-linked mitochondrial respiration. Reducing ROS generation through preventing complex II damage likely increases NKX6.1 expression and ameliorate glucose metabolism in the TCA cycle, contributing to the protection of pancreatic beta-cells. Protection of complex II in pancreatic beta-cells represents a novel therapeutic target for type 2 diabetes.

Abstract Aims/Introduction To assess the impact of baseline characteristics on the efficacy and safety of oral semaglutide in Japanese patients with type 2 diabetes. Materials and Methods In the Peptide InnOvatioN for Early diabEtes tReatment (PIONEER) 9 and 10 trials, Japanese patients were randomized to once‐daily oral semaglutide (3, 7, or 14 mg) or a comparator (placebo or once‐daily subcutaneous liraglutide 0.9 mg in PIONEER 9; once‐weekly subcutaneous dulaglutide 0.75 mg in PIONEER 10) for 52 weeks, with 5 weeks of follow up. An exploratory analysis grouped patients in each trial according to baseline glycated hemoglobin (HbA1c; ≤8.0, >8.0–≤9.0, or >9.0%), body mass index (

Abstract 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.

Summary: 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.

Background: Subacute thyroiditis (SAT) followed by Graves disease (GD) is a rare condition. We report the case of a patient with recurrent SAT with human leukocyte antigen (HLA)–associated predisposition to GD. Case Report: A 28-year-old Japanese woman presented with neck pain and hyperthyroidism symptoms. We observed elevated C-reactive protein and thyroid hormone levels, along with a high erythrocyte sedimentation rate. Further, anti–thyroid-stimulating hormone receptor antibody was undetected, and thyroid glands were heterogeneous and hypoechoic. These findings confirmed a diagnosis of SAT. The patient was treated with prednisone (starting dose, 30 mg), and clinical and laboratory data suggested an improvement. Six months later, the patient presented with recurrent clinical and biochemical features of hyperthyroidism (thyroid-stimulating hormone level, 0.003 mIU/mL; free thyroxine level, 3.14 ng/dL; and TSH receptor–stimulating autoantibodies, 220%). The patient was diagnosed with GD and was successfully treated with methimazole. Eleven years later, the patient was diagnosed with simultaneous SAT and GD. HLA-typing revealed that the patient possessed characteristic alleles associated with susceptibility to GD, such as HLA-DRB1∗04:03 and ∗15:01, DQB1∗03:02:01 and 06:02:01, and HLA DPB1∗05:01 alleles. Discussion: The occurrence of SAT may trigger thyroid antigen release and lead to the onset of GD in patients who are genetically predisposed to this autoimmune disorder. Conclusion: For certain patients, the diagnosis of GD should be considered in case of recurrent hyperthyroidism and history of resolved SAT.

Abstract 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.

Abstract 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.

Summary: 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.

Abstract 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.

Abstract 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, P = 0.020; eGFR: − 3.33 ± 1.32 vs. 0.37 ± 1.29, P = 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.

Abstract 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

Abstract Aims/Introduction Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long‐term treatments are available. Methods This was an investigator‐initiated multicenter prospective intervention study in which ipragliflozin (50 mg) was administered once daily, and glycemic control, estimated glomerular filtration rate (eGFR) and adverse events were evaluated until 104 weeks after starting research. Results There were 407 patients analyzed. In the eGFR ≥90 group and eGFR ≥60 to 300 group and the eGFR

Abstract 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

Abstract Aims/Introduction We explored the association between fatty liver and pancreatic β‐cell dysfunction in a general population. Materials and Methods This cross‐sectional study included 489 (53.8% women) community‐dwelling Japanese adults. The extent of fatty liver was estimated using the fatty liver index (FLI). After all participants were divided into three groups – low (FLI

Abstract 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

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

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.

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.

BackgroundDiabetic 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. ObjectiveThe 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. MethodsThis 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. ResultsThe 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. ConclusionsThis 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 RegistrationUMIN-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

Abstract We sought to estimate the exact causes of death, mortality rate and life expectancy of diabetes patients by analyzing death records in a diabetes specialist clinic in Japan. Of the 6,140 participants included in our analysis, the average age was 58.1 years and 77% were men. A total of 261 deaths were recorded during the total follow‐up period of 24,079 total person‐years. The leading causes of death were cancer, heart diseases and cerebrovascular diseases. Using a life table prepared from the mortality rates estimated with the exponential distribution model, a life expectancy at 40 years was 39.2 years (95% confidence interval 37.9–40.2 years) for men and 43.6 years (95% confidence interval 41.8–45.3 years) for women. Although the present results must be interpreted with caution, compared with populations with diabetes surveyed during similar periods by the Japan Diabetes Society, our diabetes patients had similar ranking of the causes of death.

Abstract Aims/Introduction Tofogliflozin is a potent and highly selective sodium–glucose cotransporter 2 inhibitor that is currently used to treat patients with type 2 diabetes mellitus. The aim of the present study was to evaluate the safety and efficacy of tofogliflozin add‐on to glucagon‐like peptide‐1 (GLP‐1) receptor agonist monotherapy. Materials and Methods In this 52‐week, prospective, multicenter, single arm, post‐marketing clinical study, Japanese patients who had already been receiving GLP‐1 receptor agonist monotherapy for ≥8 weeks, glycated hemoglobin ≥7.0 and

Abstract 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

Abstract Aims/Introduction The present study investigated the relationship between the macronutrient energy ratio, dietary carbohydrate and glycated hemoglobin levels in Japanese patients with type 2 diabetes, to generate a potential optimal dietary intake of macronutrients for such patients. Materials and Methods In total, 3,032 patients participating in the Sleep and Food Registry in Kanagawa study were evaluated. Their diets were assessed for macronutrient content through a brief self‐administered dietary history questionnaire. Relevant biochemical assays were carried out. Results The mean energy intake (±standard deviation) was 1,711 ± 645 kcal/day. The proportion of energy supplied by protein, fat and carbohydrate were 16.3, 26.8 and 52.3%, respectively. Total fiber intake was 12.6 ± 5.7 g/day. The high glycated hemoglobin (HbA1c) group (HbA1c >8%) had significantly lower protein and higher carbohydrate intake than the low HbA1c group (HbA1c 60%) were most likely to have high HbA1c levels. HbA1c was significantly correlated with carbohydrate (%E) in all age groups and in patients taking one or two antidiabetic drugs. Conclusions The dietary carbohydrate:energy ratio has a positive correlation with HbA1c, suggesting that avoiding excessive carbohydrate intake (>60%) might help foster glycemic control.

Abstract Aims/Introduction Pancreatic β‐cell dysfunction contributes to type 2 diabetes mellitus progression. Drugs that improve insulin secretion might be a valuable treatment approach. The present study aimed to evaluate the effect of the G protein‐coupled receptor 119 agonist DS‐8500a on insulin secretory capacity in Japanese type 2 diabetes mellitus patients. Materials and Methods This single‐center, 4‐week, randomized, double‐blind, cross‐over study enrolled 21 Japanese drug‐naïve type 2 diabetes mellitus patients aged ≥20 years with glycated hemoglobin ≥7.0 and

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),

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.

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.

Abstract To examine the effects of luseogliflozin, a sodium–glucose cotransporter 2 inhibitor, on pancreatic beta cell mass in db/db mice of different ages. db/db mice aged 6, 10, 14 and 24 weeks old were fed either standard chow (control group) or standard chow containing 0.01% luseogliflozin (luseo group). After 4 weeks, immunohistochemistry and gene expression tests were conducted. In 6-week-old db/db mice, immunohistochemistry revealed a significant increase in beta cell mass in the luseo group compared with the control group after 4 weeks of treatment. Gene expression profiling of isolated islets showed upregulation Mafa, Pdx1, Ki67 and Ccnd2 in the luseo group. Beta cell mass decreased with age in db/db mice in the control group. Beta cell mass in the luseo group significantly increased compared with the control group regardless of age, although beta cell mass in the 28-week-old luseo group (4 weeks of treatment in 24-week-old db/db mice) was significantly lower than in the 10-week-old luseo group (4 weeks of treatment in 6-week-old db/db mice). Luseogliflozin preserved beta cell mass in db/db mice. The protective effect was more evident in the earlier phase of diabetes.

Abstract 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.

Abstract Glucokinase-mediated glucose signaling induces insulin secretion, proliferation, and apoptosis in pancreatic β-cells. However, the precise molecular mechanisms underlying these processes are not clearly understood. Here, we demonstrated that glucokinase activation using a glucokinase activator (GKA) significantly upregulated the expression of Fibulin-5 (Fbln5), a matricellular protein involved in matrix-cell signaling, in isolated mouse islets. The islet Fbln5 expression was induced by ambient glucose in a time- and dose-dependent manner and further enhanced by high-fat diet or the deletion of insulin receptor substrate 2 (IRS-2), whereas the GKA-induced increase in Fbln5 expression was diminished in Irs-2-deficient islets. GKA-induced Fbln5 upregulation in the islets was blunted by a glucokinase inhibitor, KATP channel opener, Ca2+ channel blocker and calcineurin inhibitor, while it was augmented by harmine, a dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) 1 A inhibitor. Although deletion of Fbln5 in mice had no significant effects on the glucose tolerance or β-cell functions, adenovirus-mediated Fbln5 overexpression increased glucose-stimulated insulin secretion in INS-1 rat insulinoma cells. Since the islet Fbln5 expression is regulated through a glucokinase/KATP channel/calcineurin/nuclear factor of activated T cells (NFAT) pathway crucial for the maintenance of β-cell functions, further investigation of Fbln5 functions in the islets is warranted.