Background: Accumulation of epicardial fat (EF) is associated with increased cardio-metabolic risks and coronary events, independently of traditional cardiovascular risk factors. Therefore, the reduction of EF volume (EFV) may be associated with reduced cardio-metabolic risks and future cardiovascular events. Sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce body fat including visceral fat and cardiovascular events in patients with type 2 diabetes. However, it has still been unknown whether SGLT2 inhibitors can reduce EFV. Methods: Type 2 diabetic patients with HbA1c 6.5–9.0% and body mass index (BMI, kg/m²) ≥25.0 were enrolled in this single arm pilot study. Participants were administered luseogliflozin 2.5 mg daily and the dosage was tolerated to be increased up to 5.0 mg daily. EFV [median (interquartile range), cm³] was measured by magnetic resonance imaging. Primary endpoint was the decrease in EFV at 12 weeks. Visceral fat area (VFA, cm²) and liver attenuation index (LAI) measured by the abdominal computed tomography, and skeletal muscle index (SMI) and body fat (%) measured by the whole body dual-energy X-ray absorptiometry were also determined at baseline and at 12 weeks. Results: Nineteen patients (mean age: 55 ± 12 years; 26% female) completed this study. Luseogliflozin treatment significantly reduced EFV at 12 weeks [117 (96–136) to 111 (88–134), p = 0.048]. The body weight, BMI, systolic and diastolic blood pressure, HbA1c, fasting plasma glucose, insulin, homeostasis model assessment-insulin resistance (HOMA-IR), triglycerides, SMI, and body fat were significantly reduced by luseogliflozin at 12 weeks. The reduction of EFV was significantly correlated with the reduction of C-reactive protein (r = 0.493, p = 0.019). Neither VFA nor LAI were significantly reduced by the luseogliflozin treatment. No severe adverse events were observed. Conclusions: Our data suggest that luseogliflozin could reduce the EFV in parallel with the improvement of systemic micro-inflammation and the reduction of body weight in Japanese patients with type 2 diabetes. The reduction of muscle mass after the administration of SGLT2 inhibitors may require a particular attention. Trial registration umin.ac.jp, UMIN000019072

Sarcopenic obesity, defined as reduced skeletal muscle mass and power with increased adiposity, was reported to be associated with cardiovascular disease risks in previous cross-sectional studies. Whole body dual-energy X-ray absorptiometry (DXA) can simultaneously evaluate both fat and muscle mass, therefore, whole body DXA may be suitable for the diagnosis of sarcopenic obesity. However, little is known regarding whether sarcopenic obesity determined using whole body DXA could predict incident cardiovascular disease (CVD). The aim of this study was to investigate the impact of sarcopenic obesity on incident CVD in patients with type 2 diabetes. A total of 716 Japanese patients (mean age 65 ± 13 years; 47.0% female) were enrolled. Android fat mass (kg), gynoid fat mass (kg), and skeletal muscle index (SMI) calculated as appendicular non-fat mass (kg) divided by height squared (m2), were measured using whole body DXA. Sarcopenic obesity was defined as the coexistence of low SMI and obesity determined by four patterns of obesity as follows: android to gynoid ratio (A/G ratio), android fat mass or percentage of body fat (%BF) was higher than the sex-specific median, or body mass index (BMI) was equal to or greater than 25 kg/m2. The study endpoint was the first occurrence or recurrence of CVD. Over a median follow up of 2.6 years (IQR 2.1–3.2 years), 53 patients reached the endpoint. Sarcopenic obesity was significantly associated with incident CVD even after adjustment for the confounding variables, when using A/G ratio [hazard ratio (HR) 2.63, 95% CI 1.10–6.28, p = 0.030] and android fat mass (HR 2.57, 95% CI 1.01–6.54, p = 0.048) to define obesity, but not %BF (HR 1.67, 95% CI 0.69–4.02, p = 0.252), and BMI (HR 1.55, 95% CI 0.44–5.49, p = 0.496). The present data suggest that the whole body DXA is valuable in the diagnosis of sarcopenic obesity (high A/G ratio or android fat mass with low SMI) to determine the risk of CVD events in patients with type 2 diabetes. Meanwhile, sarcopenic obesity classified with low SMI, and high %BF or BMI was not associated with incident CVD.

Dedifferentiation has been implicated in β cell dysfunction and loss in rodent diabetes. However, the pathophysiological significance in humans remains unclear. To elucidate this, we analyzed surgically resected pancreatic tissues of 26 Japanese subjects with diabetes and 11 nondiabetic subjects, who had been overweight during adulthood but had no family history of diabetes. The diabetic subjects were subclassified into 3 disease stage categories, early, advanced, and intermediate. Despite no numerical changes in endocrine cells immunoreactive for chromogranin A (ChgA), diabetic islets showed profound β cell loss, with an increase in α cells without an increase in insulin and glucagon double-positive cells. The proportion of dedifferentiated cells that retain ChgA immunoreactivity without 4 major islet hormones was strikingly increased in diabetic islets and rose substantially during disease progression. The increased dedifferentiated cell ratio was inversely correlated with declining C-peptide index. Moreover, a subset of islet cells converted into exocrine-like cells during disease progression. These results indicate that islet remodeling with dedifferentiation is the underlying cause of β cell failure during the course of diabetes progression in humans.

Sarcopenia is defined as an age-related loss of skeletal muscle mass and strength, and is a major cause of disability and mobility limitations. Recent studies have demonstrated that type 2 diabetes and insulin signaling deficiencies contribute to the progression of sarcopenia, suggesting that a sufficient supply of insulin to the skeletal muscles may be important for the maintenance of muscle function; however, little has been reported regarding whether insulin treatment can protect against sarcopenia. We conducted a retrospective observational study to examine the impact of insulin treatment on the muscle mass of patients with type 2 diabetes. A total of 312 patients (mean age: 64 ± 11 years; 40.8% female; 27.6% treated with insulin) were studied in this retrospective observational study. Skeletal muscle index (SMI) and grip strength (kg) were used to assess sarcopenia. The prevalence of sarcopenia was 18.0%. Insulin treatment was shown to be protective against the annual decline of SMI (standardized β 0.195; p = 0.025) even after adjusting for covariates, including age, gender, duration of diabetes, and body mass index. In a cohort matched by propensity scores, insulin treatment significantly increased the 1-year change in SMI (mean ± SE) compared with non-insulin-treated group (2.40 ± 0.98% vs. −0.43 ± 0.98%; p = 0.050). Our data suggest that insulin treatment could attenuate the progression of sarcopenia in patients with type 2 diabetes.

To investigate the association of both latent autoimmune diabetes in adults (LADA) and type 2 diabetes (T2DM) with muscle mass and function (sarcopenia). Japanese patients with LADA (N=20), T2DM (N=208), and control subjects (N=41) were included in this cross-sectional study. The definition of LADA was based on age of onset (≥30), positive glutamic acid decarboxylase autoantibodies, and insulin requirement within the first 6months after diagnosis. Sarcopenia was diagnosed by the criteria for Asians, using skeletal muscle index (male <7.0 and female <5.4) and grip strength (male <26.0kg and female <18.0kg). The odds ratio (OR) with a 95% confidence interval (CI) was estimated using logistic regression. The prevalence of sarcopenia was higher in LADA (35.0%) than in either T2DM (13.3%) or control subjects (9.8%). LADA was significantly associated with an increased risk for sarcopenia in a multivariate model in which age and body mass index were incorporated (OR: 9.57, 95% CI: 1.86-49.27). In contrast, T2DM tended to be associated with an increased risk for sarcopenia (OR: 2.99, 95% CI: 0.83-10.80). This study provides evidence that patients with LADA are at a high risk for sarcopenia compared to those with T2DM or to control subjects.

Objective To predict fatty liver disease (FLD), including nonalcoholic FLD (NAFLD) and metabolic dysfunction-associated FLD (MAFLD), from blood tests and anthropometric measurements, the fatty liver index (FLI) and triglyceride glucose-body mass index (TyG-BMI) have been reported as promising indicators. We evaluated the predictive ability of several indices, including the waist circumference, BMI, FLI and TyG-BMI, that might predict FLD in non-obese individuals undergoing health checkups. Methods This retrospective observational study enrolled non-obese subjects who underwent abdominal ultrasonography between May 1, 2015, and June 30, 2021. Obesity was defined as a BMI <25 kg/m2. FLD was diagnosed by abdominal ultrasonography. Using a receiver operating characteristic analysis, we examined the predictive validity of indices for NAFLD and MAFLD by calculating the area under the curve (AUC). Results Of the 24,825 subjects (mean age 44.3±10.0 years old; 54% men) enrolled in this examination of the association of indices, including FLI and TyG-BMI, with NAFLD, NAFLD was diagnosed in 3,619 (27%) men and 733 (6%) women. In both men and women, the FLI and TyG-BMI had significantly higher AUC values for NAFLD prediction than the other indicators (FLI: 0.786 for men and 0.875 for women, TyG-BMI: 0.783 for men and 0.868 for women). In analyses of subjects with a BMI <23 kg/m2, the superiority of the FLI and TyG-BMI remained unchanged. The FLI and TyG-BMI also had significantly higher AUC values for MAFLD prediction than the other indicators. Conclusion The FLI and TyG-BMI had a particularly high predictive ability for NAFLD and MAFLD in non-obese subjects.