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

Abdominal visceral obesity has been reported to be associated with cardiovascular risks than body mass index, waist circumference, and abdominal subcutaneous fat. On the other hand, there is evidence that subcutaneous fat has a beneficial role against cardio-metabolic risks such as diabetes or dyslipidemia. However, little is known regarding the association between high visceral fat with low subcutaneous fat accumulation and the risk for atherosclerosis. This study was designed to elucidate whether high visceral fat with low subcutaneous fat accumulation enhances the risk for atherosclerosis in patients with type 2 diabetes. This is a cross-sectional study of 148 patients with type 2 diabetes (mean age 65 ± 12 years; 44.5 % female). Visceral fat area (VFA, cm2) and subcutaneous fat area (SFA, cm2) were assessed by abdominal computed tomography. Carotid intima media thickness (CIMT, mm) measured by ultrasonography was used for the assessment of atherosclerosis. Patients were divided into four groups: SFA < 100 cm2 and VFA < 100 cm2 [S(−)V(−)], SFA ≥ 100 cm2 and VFA < 100 cm2 [S(+)V(−)], SFA < 100 cm2 and VFA ≥ 100 cm2 [S(−)V(+)], and SFA ≥ 100 cm2 and VFA ≥ 100 cm2 [S(+)V(+)]. Linear regression analysis with a stepwise procedure was used for the statistical analyses. Among the patients examined, 16.3 % were S(−)V(+). Mean (95 % confidence interval) of CIMT adjusting for age and gender were 0.80 (0.69–0.91), 0.86 (0.72–1.01), 1.28 (1.11–1.44) and 0.83 (0.77–0.88) in patients with S(−)V(−), S(+)V(−), S(−)V(+) and S(+)V(+), respectively (p < 0.001). The S(−)V(+) patients exhibited significantly older than S(−)V(−) patients and those with S(+)V(+) and had a highest VFA-SFA ratio (V/S ratio) among the four groups. S(−)V(+) patients were male predominant (100 % male), and S(+)V(−) patients showed female predominance (82 % female). In multivariate linear regression analysis (Adjusted R2 = 0.549), S(−)V(+) was significantly associated with CIMT (Standardized β 0.423, p < 0.001). Notably, S(+)V(+) was inversely associated with CIMT in the multivariate model. This study provides evidence that high visceral fat with low subcutaneous fat accumulation is an important determinant of carotid atherosclerosis and high subcutaneous fat could be protective against atherosclerosis in patients with type 2 diabetes.

Aldosterone-producing adenomas (APAs) are the commonest curable cause of hypertension. Most have gain-of-function somatic mutations of ion channels or transporters. Herein we report the discovery, replication and phenotype of mutations in the neuronal cell adhesion gene CADM1. Independent whole exome sequencing of 40 and 81 APAs found intramembranous p.Val380Asp or p.Gly379Asp variants in two patients whose hypertension and periodic primary aldosteronism were cured by adrenalectomy. Replication identified two more APAs with each variant (total, n = 6). The most upregulated gene (10- to 25-fold) in human adrenocortical H295R cells transduced with the mutations (compared to wildtype) was CYP11B2 (aldosterone synthase), and biological rhythms were the most differentially expressed process. CADM1 knockdown or mutation inhibited gap junction (GJ)-permeable dye transfer. GJ blockade by Gap27 increased CYP11B2 similarly to CADM1 mutation. Human adrenal zona glomerulosa (ZG) expression of GJA1 (the main GJ protein) was patchy, and annular GJs (sequelae of GJ communication) were less prominent in CYP11B2-positive micronodules than adjacent ZG. Somatic mutations of CADM1 cause reversible hypertension and reveal a role for GJ communication in suppressing physiological aldosterone production.

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.

Objective: Primary aldosteronism (PA) is one of the most frequent causes of secondary hypertension. Although clinical practice guidelines recommend a diagnostic process, details of the steps remain incompletely standardized. Design: In the present SCOT-PA survey, we have investigated the diversity of approaches utilized for each diagnostic step in different expert centers through a survey using Google questionnaires. A total of 33 centers from 3 continents participated. Results: We demonstrated a prominent diversity in the conditions of blood sampling, assay methods for aldosterone and renin, and the methods and diagnostic cutoff for screening and confirmatory tests. The most standard measures were modification of antihypertensive medication and sitting posture for blood sampling, measurement of plasma aldosterone concentration (PAC) and active renin concentration by chemiluminescence enzyme immunoassay, a combination of aldosterone-to-renin ratio with PAC as an index for screening, and saline infusion test in a seated position for confirmatory testing. The cutoff values for screening and confirmatory testing showed significant variation among centers. Conclusions: Diversity of the diagnostic steps may lead to an inconsistent diagnosis of PA among centers and limit comparison of evidence for PA between different centers. We expect the impact of this diversity to be most prominent in patients with mild PA. The survey raises 2 issues: the need for standardization of the diagnostic process and revisiting the concept of mild PA. Further standardization of the diagnostic process/criteria will improve the quality of evidence and management of patients with PA.

Whole body dual-energy X-ray absorptiometry (DXA) can simultaneously measure both regional fat and non-fat mass. Android-to-gynoid (A/G) ratio measured by DXA has been reported to be associated with cardiovascular risks and visceral adiposity; however, little is known regarding its relationship with fatty liver disease and atherosclerosis among patients with diabetes. This study was designed to investigate the association of android and gynoid fat mass measured by DXA with fatty liver disease and atherosclerosis in patients with type 2 diabetes. This is a cross-sectional study of 259 patients with type 2 diabetes (mean age 64 ± 13 years; 40.2 % female). Android and gynoid fat mass (kg) were measured by DXA. Skeletal muscle index (SMI) was calculated as appendicular non-fat mass (kg) divided by height (m2). Visceral fat area (VFA, cm2), subcutaneous fat area (SFA, cm2), and liver attenuation index (LAI) were assessed by abdominal computed tomography. Intima media thickness (IMT, mm) in common carotid arteries was determined by carotid ultrasonography. A/G ratio was significantly correlated with VFA (r = 0.72, p < 0.001), SFA (r = 0.32, p < 0.001) and LAI (r = −0.26, p < 0.001). A/G ratio (standardized β −0.223, p = 0.002) as well as VFA (standardized β −0.226, p = 0.001) were significantly associated with LAI in the univariate model. A/G ratio remained to be significantly associated with LAI (standardized β −0.224, p = 0.005) after adjusting for covariates including body mass index and transaminases. Among patients with low SMI (SMI < 7.0 in male and < 5.4 in female), A/G ratio was significantly associated with carotid IMT in the multivariate model (standardized β 0.408, p = 0.014). DXA can be used to simultaneously estimate the risks for both fatty liver disease and atherosclerosis in patients with type 2 diabetes.