Hypoglycemia and Vascular Disease

Abstract

Macrovascular and microvascular complications commonly occur in individuals with type 1 and type 2 diabetes. The mechanisms responsible for these complications remain the subjects of intense investigation. With regard to atherosclerosis specifically, there have been great strides in describing the pathophysiological connection between alterations in the diabetic metabolic state and altered endothelial, platelet, and vascular smooth muscle cell functions. Hyperglycemia and insulin resistance independently disrupt nitric oxide synthesis and signaling, induce the production of reactive oxygen species, and up-regulate inflammatory and thrombotic markers and mediators of vasoconstriction (1, 2). Conversely, insulin per se has been shown to actually have vasodilatory and antiinflammatory effects independent of glycemia. Insulin exerts these beneficial effects via increased nitric oxide synthase production (thereby causing increased nitric oxide synthesis) and the suppression of reactive oxygen species, inflammatory mediators, and thrombotic markers (2). To overcome the deleterious effects of hyperglycemia and insulin resistance, clinicians have increasingly used intensive glucose control for both type 1 and type 2 diabetes. Unfortunately, as glycemic control improves, rates of hypoglycemia increase. Multicenter randomized controlled trials to examine the effects of stricter glycemic control in both type 1 and type 2 diabetes have confirmed that not only do the total rates of hypoglycemia increase with improved glycemia, but the incidence of severe disabling hypoglycemia also increases. Two recent large studies on glucose control and complications in type 2 diabetes mellitus [the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial and the Veterans Affairs Diabetes Trial] found no benefit of improved glycemic control on macrovascular complications. In fact, the ACCORD study found an increased mortality rate in the intensive glucose–control arm of the study, which was stopped earlier than planned. A major question that emanated from these studies was why intensive glycemic control did not produce beneficial effects. One …