Vascular actions of insulin in cardiometabolic disease : effects of metformin, physical activity, and intrinsic aerobic fitness

Abstract

Insulin has important vascular and metabolic actions. The vascular effects of insulin typically account for as much as 40-50% of insulin-stimulated glucose disposal. However, the vascular reactivity to insulin is impaired in obesity and type 2 diabetes, in part due to an imbalance in endothelium-derived nitric oxide (NO) and endothelin-1 (ET-1), limiting the perfusion and delivery of glucose and insulin to target tissues. Consequently, aberrations in the vascular actions of insulin contribute to reduced glycemic control and insulin sensitivity. The studies described in this dissertation were designed to test hypotheses that focus on mechanisms and treatments of impaired vascular reactivity to insulin using rodent models of insulin resistance, obesity, and type 2 diabetes. We investigated the efficacy of metformin (Chapter 2), or daily physical activity (Chapter 3) treatments to improve the vasomotor response to insulin in conduit and skeletal muscle resistance arteries of obese, insulin resistant Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Additionally we evaluated the influence of inherited aerobic fitness (Chapter 4), independent of physical activity levels, on the vascular reactivity to insulin in a large conduit artery of rats selectively bred for low or high aerobic running capacity. We present evidence that obesity-related impairments in micro- and macro-vasomotor reactivity to insulin is largely independent of changes in body composition and adiposity. Specifically, metformin does not enhance the microvascular reactivity to insulin, despite reductions in body weight, food consumption, and improvements in glycemic control in OLETF rats. In contrast, daily physical activity in OLETF rats, significantly improved insulin-stimulated vasorelaxation, an effect that was in part mediated by reduced insulin-stimulated ET-1 aortic vasocontraction. Our data also indicate that low intrinsic aerobic fitness is paradoxically associated with greater insulin-mediated vasorelaxation and an exclusive dependence on nitric oxide in aortic vasomotor function. Collectively, our results shed new light on mechanisms underlying the influence of intrinsic aerobic fitness on the vasoreactivity to insulin, and provided strong evidence of physical activity's powerful insulin-sensitizing effects on the vasculature with obesity.