Background: Type 2 diabetes mellitus (T2DM) is a complex, multifactorial disease with a significant global burden. Although genome-wide association studies (GWAS) have identified many T2DM-associated variants, most lie in non-coding regions, making it difficult to interpret their functional roles. Methods: We aimed to identify genetically regulated Cytosine–phosphate–Guanine (CpG) sites associated with T2DM by conducting a methylome-wide association study (MWAS), followed by Mendelian randomization (MR) and functional validation using human pancreatic cells and mouse models. MWAS was performed using summary statistics from large-scale GWAS and a DNA methylation (DNAm) prediction model to test associations between genetically predicted DNAm and T2DM. Results: We identified 111 CpG sites significantly associated with T2DM in Europeans, including 8 novel sites near genes not previously linked to T2DM. These findings were replicated in independent datasets. Many CpGs also showed associations with cardiometabolic traits, highlighting shared epigenetic mechanisms. Trans-ethnic MR analysis confirmed consistent effects for six CpGs in East Asians. Functional analysis revealed that several CpGs regulate gene expression in human pancreatic α- and β-cells. Among them, 2´-5´-oligoadenylate synthetase like (OASL) expression, regulated by a significant CpG, was differentially expressed in α-cells of T2DM cases compared to controls. Supporting evidence from mouse models suggests a role for OASL in glucose regulation. Conclusion Our study identifies novel genetically regulated CpG sites associated with T2DM risk and highlights OASL as a potential epigenetic regulator of glucose metabolism in α-cells. These findings provide mechanistic insights into the epigenetic architecture of T2DM and suggest potential targets for cross-ethnic biomarker development and therapeutic intervention.

The prevalence of obesity in Asia is of epidemic proportions, with an estimated 1 billion overweight/obese individuals in the region. The majority of patients with type 2 diabetes mellitus (T2DM) are overweight/obese, which increases the risk of cardiorenal outcomes in these patients; hence, sustained reductions in body weight and visceral adiposity are important management goals. However, most of the glucose-lowering therapies such as insulin, sulfonylureas, glinides, and thiazolidinediones induce weight gain, which makes the management of overweight/obese T2DM patients challenging. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are the only oral glucose-lowering agents that have been shown to reduce body weight and visceral adiposity. In addition, SGLT-2 inhibitors therapy reduces ectopic fat deposition and improves adipose tissue function and weight-related quality of life. In this article, we aim to consolidate the existing literature on the effects of SGLT-2 inhibitors in Asian patients with T2DM and to produce clinical recommendations on their use in overweight or obese patients with T2DM. Recommendations from international and regional guidelines, as well as published data from clinical trials in Asian populations and cardiovascular outcomes trials are reviewed. Based on the available data, SGLT-2 inhibitors represent an evidence-based therapeutic option for the management of overweight/obese patients with T2DM.

PURPOSE: Severe hypoglycemia can result in neural damage, impaired cognitive function, coma, seizures, or death. The decision to admit diabetic patients after initial treatment in the emergency department remains unclear. Our purpose is to identify risk factors for developing recurrent hypoglycemia in diabetic patients admitted for severe hypoglycemia. MATERIALS AND METHODS: We reviewed the records of 233 subjects (92 males, 141 females; mean age, 74.1 +/- 9.8 years) with type 2 diabetes treated at a tertiary care teaching hospital and hospitalized for severe hypoglycemia. RESULTS: Seventy-four (31.8%) patients were categorized with recurrent hypoglycemia and 159 (68.2%) with non-recurrent. Multivariate logistic regression analysis revealed that patients with loss of a recent meal, coronary artery disease, infection, and poor renal function (lower estimated glomerular filtration rate) were at risk for recurrent hypoglycemia. The use of calcium-channel blockers appeared to be a protective factor for the development of recurrent hypoglycemia. CONCLUSION: There may be a subset of patients with severe hypoglycemia and certain risk factors for recurrent hypoglycemia that should be admitted.
Aged ; Aged, 80 and over ; Calcium Channel Blockers/adverse effects/therapeutic use ; Coronary Artery Disease/complications ; Diabetes Mellitus, Type 2/complications ; Female ; Glomerular Filtration Rate ; Hospitalization ; Humans ; Hypoglycemia/*etiology/*prevention & control ; Kidney Diseases/complications ; Logistic Models ; Male ; Multivariate Analysis ; Recurrence ; Retrospective Studies ; Risk Factors

The impact the metabolic syndrome (MetS) components on the severity of insulin resistance (IR) has not been reported. We enrolled 564 subjects with MetS and they were divided into quartiles according to the level of each component; and an insulin suppression test was performed to measure IR. In males, steady state plasma glucose (SSPG) levels in the highest quartiles, corresponding to body mass index (BMI) and fasting plasma glucose (FPG), were higher than the other three quartiles and the highest quartiles, corresponding to the diastolic blood pressure and triglycerides, were higher than in the lowest two quartiles. In females, SSPG levels in the highest quartiles, corresponding to the BMI and triglycerides, were higher than in all other quartiles. No significant differences existed between genders, other than the mean SSPG levels in males were greater in the highest quartile corresponding to BMI than that in the highest quartile corresponding to HDL-cholesterol levels. The factor analysis identified two underlying factors (IR and blood pressure factors) among the MetS variables. The clustering of the SSPG, BMI, triglyceride and HDLcholesterol was noted. Our data suggest that adiposity, higher FPG and triglyceride levels have stronger correlation with IR and subjects with the highest BMI have the highest IR.
Waist-Hip Ratio ; Triglycerides/blood ; Middle Aged ; Metabolic Syndrome X/*metabolism ; Male ; *Insulin Resistance ; Humans ; Female ; Fasting/blood ; Cholesterol, HDL/blood ; Body Mass Index ; Blood Glucose/analysis ; Aged ; Adult