New insight in molecular mechanisms regulating SIRT6 expression in diabetes: Hyperglycaemia effects on SIRT6 DNA methylation.

Conflicting data are reported on the relationship between hyperglycaemia, diabetes and SIRT6 expression. To elucidate hyperglycaemia-induced molecular mechanisms regulating SIRT6 expression, the effect of hyperglycaemia on DNA methylation and SIRT6 expression has been evaluated in human aortic endothelial cells exposed to high glucose. DNA methylation of SIRT6 and any potential clinical implication was also evaluated in type 2 diabetic patients and compared with healthy controls. Endothelial cells exposed to high glucose showed lower methylation levels in SIRT6 promoter and increased SIRT6 and TET2 expression. The high glucose-induced epigenetic changes persisted after 48 h of glucose normalization. Diabetic patients showed lower levels of SIRT6 DNA methylation compared with nondiabetic patients. SIRT6 DNA methylation levels inversely correlated with plasma glucose. Our results firstly demonstrate the involvement of epigenetic mechanisms in regulating SIRT6 expression. Further experiments are necessary to clarify metabolic memory mechanisms driving to diabetic complications and how SIRT6 is potentially involved.

Hyperglycemia and Physical Impairment in Frail Hypertensive Older Adults.

Background: Frailty is a multidimensional condition typical of elders. Frail older adults have a high risk of functional decline, hospitalization, and mortality. Hypertension is one of the most common comorbidities in elders. Hyperglycemia (HG) is frequently observed in frail older adults, and represents an independent predictor of worst outcomes, with or without diabetes mellitus (DM). We aimed at investigating the impact of HG on physical impairment in frailty. Methods: We studied consecutive older adults with frailty and hypertension at the ASL (local health unit of the Italian Ministry of Health) of Avellino, Italy, from March 2021 to September 2021. Exclusion criteria were: age <65 years, no frailty, no hypertension, left ventricular ejection fraction <25%, previous myocardial infarction, previous primary percutaneous coronary intervention and/or coronary artery bypass grafting. Blood glucose, Hb1Ac, and creatinine were measured in all patients. Physical frailty was assessed applying the Fried Criteria; we performed a 5-meter gait speed (5mGS) test in all patients. Results: 149 frail hypertensive older adults were enrolled in the study, of which 82 had normoglycemia (NG), and 67 had HG. We observed a significantly slower 5mGS in the HG group compared to the NG group (0.52 ± 0.1 vs. 0.69 ± 0.06; p<0.001). Moreover, we found a strong and significant correlation between 5mGS and glycemia (r: 0.833; p<0.001). A multivariable linear regression analysis using 5mGS as a dependent variable revealed a significant independent association with glycemia (p<0.001) after adjusting for likely confounders. Conclusions: HG drives physical impairment in frail hypertensive older adults independently of DM.

Cognitive Impairment in Frail Hypertensive Elderly Patients: Role of Hyperglycemia.

Endothelial dysfunction is a key hallmark of hypertension, which is a leading risk factor for cognitive decline in older adults with or without frailty. Similarly, hyperglycemia is known to impair endothelial function and is a predictor of severe cardiovascular outcomes, independent of the presence of diabetes. On these grounds, we designed a study to assess the effects of high-glucose and metformin on brain microvascular endothelial cells (ECs) and on cognitive impairment in frail hypertensive patients. We tested the effects of metformin on high-glucose-induced cell death, cell permeability, and generation of reactive oxygen species in vitro, in human brain microvascular ECs. To investigate the consequences of hyperglycemia and metformin in the clinical scenario, we recruited frail hypertensive patients and we evaluated their Montreal Cognitive Assessment (MoCA) scores, comparing them according to the glycemic status (normoglycemic vs. hyperglycemic) and the use of metformin. We enrolled 376 patients, of which 209 successfully completed the study. We observed a significant correlation between MoCA score and glycemia. We found that hyperglycemic patients treated with metformin had a significantly better MoCA score than hyperglycemic patients treated with insulin (18.32 ± 3.9 vs. 14.94 ± 3.8; p < 0.001). Our in vitro assays confirmed the beneficial effects of metformin on human brain microvascular ECs. To our knowledge, this is the first study correlating MoCA score and glycemia in frail and hypertensive older adults, showing that hyperglycemia aggravates cognitive impairment.