Cardiovascular disease remains the leading cause of death in patients with diabetes. Cardiovascular disease in diabetes is multifactorial, and control of the cardiovascular risk factors leads to substantial reductions in cardiovascular events. The 2015 American Heart Association and American Diabetes Association scientific statement, “Update on Prevention of Cardiovascular Disease in Adults With Type 2 Diabetes Mellitus in Light of Recent Evidence,” highlighted the importance of modifying various risk factors responsible for cardiovascular disease in diabetes. At the time, there was limited evidence to suggest that glucose-lowering medications reduce the risk of cardiovascular events. At present, several large randomized controlled trials with newer antihyperglycemic agents have been completed, demonstrating cardiovascular safety and reduction in cardiovascular outcomes, including cardiovascular death, myocardial infarction, stroke, and heart failure. This AHA scientific statement update focuses on (1) the evidence and clinical utility of newer antihyperglycemic agents in improving glycemic control and reducing cardiovascular events in diabetes; (2) the impact of blood pressure control on cardiovascular events in diabetes; and (3) the role of newer lipid-lowering therapies in comprehensive cardiovascular risk management in adults with diabetes. This scientific statement addresses the continued importance of lifestyle interventions, pharmacological therapy, and surgical interventions to curb the epidemic of obesity and metabolic syndrome, important precursors of prediabetes, diabetes, and comorbid cardiovascular disease. Last, this scientific statement explores the critical importance of the social determinants of health and health equity in the continuum of care in diabetes and cardiovascular disease.

Controversy exists over the role of stress and depression in the pathophysiology of type 2 diabetes mellitus. Depression has been shown to increase the risk for progressive insulin resistance and incident type 2 diabetes mellitus in multiple studies, whereas the association of stress with diabetes is less clear, owing to differences in study designs and in forms and ascertainment of stress. The biological systems involved in adaptation that mediate the link between stress and physiological functions include the hypothalamic–pituitary–adrenal (HPA) axis and the autonomic nervous and immune systems. The HPA axis is a tightly regulated system that represents one of the body's mechanisms for responding to acute and chronic stress. Depression is associated with cross‐sectional and longitudinal alterations in the diurnal cortisol curve, including a blunted cortisol awakening response and flattening of the diurnal cortisol curve. Flattening of the diurnal cortisol curve is also associated with insulin resistance and type 2 diabetes mellitus. In this article, we review and summarize the evidence supporting HPA axis dysregulation as an important biological link between stress, depression, and type 2 diabetes mellitus.

OBJECTIVE: The prognostic value of long-term glycemic variability is incompletely understood. We evaluated the influence of visit-to-visit variability (VVV) of fasting blood glucose (FBG) on incident cardiovascular disease (CVD) and mortality. RESEARCH DESIGN AND METHODS: We conducted a prospective cohort analysis including 4,982 participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) who attended the baseline, 24-month, and 48-month visits. VVV of FBG was defined as the SD or variability independent of the mean (VIM) across FBG measurements obtained at the three visits. Participants free of CVD during the first 48 months of the study were followed for incident CVD (coronary heart disease [CHD], stroke, and heart failure [HF]) and all-cause mortality. RESULTS: Over a median follow-up of 5 years, there were 305 CVD events (189 CHD, 45 stroke, and 81 HF) and 154 deaths. The adjusted hazard ratio (HR) comparing participants in the highest versus lowest quartile of SD of FBG (≥26.4 vs. <5.5 mg/dL) was 1.43 (95% CI 0.93–2.19) for CVD and 2.22 (95% CI 1.22–4.04) for all-cause mortality. HR for VIM was 1.17 (95% CI 0.84–1.62) for CVD and 1.89 (95% CI 1.21–2.93) for all-cause mortality. Among individuals without diabetes, the highest quartile of SD of FBG (HR 2.67 [95% CI 0.14–6.25]) or VIM (HR 2.50 [95% CI 1.40–4.46]) conferred a higher risk of death. CONCLUSIONS: Greater VVV of FBG is associated with increased mortality risk. Our data highlight the importance of achieving normal and consistent glycemic levels for improving clinical outcomes.

The pathophysiology underlying mitochondrial dysfunction in insulin-resistant skeletal muscle is incompletely characterized. To further delineate this we investigated the interaction between insulin signaling, mitochondrial regulation, and function in C2C12 myotubes and in skeletal muscle. In myotubes elevated insulin and glucose disrupt insulin signaling, mitochondrial biogenesis, and mitochondrial bioenergetics. The insulin-sensitizing thiazolidinedione pioglitazone restores these perturbations in parallel with induction of the mitochondrial biogenesis regulator PGC-1α. Overexpression of PGC-1α rescues insulin signaling and mitochondrial bioenergetics, and its silencing concordantly disrupts insulin signaling and mitochondrial bioenergetics. In primary skeletal myoblasts pioglitazone also up-regulates PGC-1α expression and restores the insulin-resistant mitochondrial bioenergetic profile. In parallel, pioglitazone up-regulates PGC-1α in db/db mouse skeletal muscle. Interestingly, the small interfering RNA knockdown of the insulin receptor in C2C12 myotubes down-regulates PGC-1α and attenuates mitochondrial bioenergetics. Concordantly, mitochondrial bioenergetics are blunted in insulin receptor knock-out mouse-derived skeletal myoblasts. Taken together these data demonstrate that elevated glucose and insulin impairs and pioglitazone restores skeletal myotube insulin signaling, mitochondrial regulation, and bioenergetics. Pioglitazone functions in part via the induction of PGC-1α. Moreover, PGC-1α is identified as a bidirectional regulatory link integrating insulin-signaling and mitochondrial homeostasis in skeletal muscle.

Background The association between physical activity (PA), sedentary behavior, and incident diabetes has been assessed in whites but is less well investigated in multiethnic populations. Objective To assess the association between PA, sedentary behavior, and incident diabetes in the Multi-Ethnic Study of Atherosclerosis. Research design and methods Incident diabetes was assessed among adults without prevalent baseline diabetes (2000–2002) at 5 in-person examinations between 2002 and 2012. Baseline PA (moderate, vigorous, and exercise-specific; metabolic equivalents of task-hours/week) and sedentary behaviors (television watching, reading; hours/day) were assessed by questionnaire. HRs were estimated using Cox proportional hazard models. Results Among 5829 adults (mean age 61.8 years, 54% female, 42% white, 12% Chinese-American, 26% African-American, 21% Hispanic-American), there were 655 incident diabetes cases (median follow-up 11.1 years). After adjustment, diabetes risk was lower in those with brisk or striding compared with none or casual walking pace (HR 0.67; 95% CI 0.54 to 0.84), higher levels of exercise PA (HR for highest vs lowest quartile 0.79; 95% CI 0.63 to 0.98), and any compared with no vigorous PA (HR 0.79; 95% CI 0.66 to 0.95). Race/ethnicity influenced the association of walking pace, exercise PA, and any vigorous PA on diabetes risk, which was only significant among whites. Total leisure sedentary behaviors (HR for highest vs lowest quartile 1.65; 95% CI 1.26 to 2.14) and television watching (HR for highest vs lowest quartile 2.68; 95% CI 1.38 to 5.21) were significantly associated with diabetes risk in multiethnic analyses and were influenced by race/ethnicity. Conclusions These results confirm the importance of PA and sedentary behavior on diabetes risk in a multiethnic population and demonstrate potential variations across race/ethnic groups.