Hypoglycemia and vascular disease.

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 speculative answer is that severe hypoglycemia overcame the benefits of improved glycemic control per se and caused increased macrovascular complications. Hypoglycemia triggers an array of counterregulatory responses that function to return blood glucose to nonpathologic levels. Glucagon, epinephrine, norepinephrine, cortisol, pancreatic polypeptide, growth hormone, corticotropin, and the autonomic nervous system are all activated in response to hypoglycemia. The magnitude of the counterregulatory drive is directly proportional to the depth of hypoglycemia. In fact, the magnitude of counterregulatory responses doubles with each approximately 0.6-mmol/L (10-mg/ dL) reduction in the plasma glucose concentration below approximately 3.9 mmol/L (70 mg/dL). Hypoglycemia is associated with considerable morbidity and even mortality. Case reports have linked hypoglycemia to acute severe myocardial and cerebrovascular events; however, the mechanisms responsible for hypoglycemia causing serious macrovascular events have not been fully elucidated. More recently, additional studies have established associations between hypoglycemia and the development of cardiac and cerebral ischemia and cardiac arrhythmias (3 ). Furthermore, studies have identified several inflammatory, thrombotic, fibrinolytic, and oxidative-stress biomarkers that show significant, acute responses to hypoglycemia (3–5 ). Such changes, especially in the presence of a compromised vasculature (3 ), may further contribute to atherosclerotic processes. Two very recent studies from independent laboratories add valuable evidence to support the theory that hypoglycemia, in addition to hyperglycemia and insulin resistance, can have adverse vascular effects (4, 5 ). Joy et al. and Wright et al. studied both patients with type 1 diabetes [mean (SE) hemoglobin A1c, 7.7% (0.2%) and 7.9% (0.9%), respectively] and nondiabetic control individuals. The hyperinsulinemic glucose clamp was used in both studies to establish euglycemia and hypoglycemia on separate occasions [5.2 mmol/L (94 mg/dL) and 4.5 mmol/L (81 mg/dL), respectively, during euglycemic clamps, and 2.9 mmol/L (52 mg/ dL) and 2.5 mmol/L (45 mg/dL), respectively, during hypoglycemic clamps]. Samples were collected under baseline and experimental conditions, which lasted in the 2 studies for 120 minutes and 60 minutes, respecDepartment of Medicine, University of Maryland School of Medicine, Baltimore, MD. * Address correspondence to this author at: Department of Medicine, University of Maryland School of Medicine, 22 S. Greene St., Rm. N3W42, Baltimore, MD 21201. Fax 410-328-8688; e-mail [email protected]. Received August 4, 2010; accepted September 27, 2010. Previously published online at DOI: 10.1373/clinchem.2010.148247 Clinical Chemistry 57:2 258–260 (2011) Opinions