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Cardiovascular implications of insulin resistance and non-insulin-dependent diabetes mellitus.

ATIENTS WITH TYPE 2 diabetes mellitus, or non‐insulin-dependent diabetes mellitus (NIDDM), represent 10% to 15% of the population seen by physicians who regularly treat coronary artery disease (CAD). Given an increasing prevalence of NIDDM in developed countries and its association with obesity, high caloric intake, and sedentary lifestyle, 1-3 this percentage is almost certain to rise. In the 1980s, the Framingham study showed that the presence of NIDDM increased cardiovascular mortality 2-fold in men and almost 4-fold in premenopausal women.4 NIDDM adversely affects the natural history of CAD and the therapeutic benefits from percutaneous and surgical coronary revascularization procedures. 5,6 This adverse impact has been documented in all contemporary cardiovascular databases, 7 and the association between macrovascular disease (eg, myocardial infarction and stroke) and NIDDM has become stronger over time.8,9 The pathophysiologic mechanisms responsible for this adverse impact are incompletely understood, however. Despite considerable improvements in pharmacologic and operative treatment of CAD, little improvement in outcome has occurred in these patients. Much of the toll exacted by NIDDM on cardiovascular mortality in the general population can be explained by its well-known acceleration of the atherosclerotic process. 10 NIDDM also dramatically worsens the prognosis of patients with established CAD. Although the reasons for the poor prognosis are incompletely understood, the observation that NIDDM more than doubles mortality 11,12 and the incidence of congestive heart failure13,14 after an index myocardial infarction suggests that at least some of the adverse risk may reflect a primary impairment in myocardial energy metabolism or ischemic tolerance or both. NIDDM is clinically the most extreme example of the phenomenon of impaired tissue insulin sensitivity, or insulin resistance. Longitudinal studies have shown that tissue insulin sensitivity, most commonly quantified as the glucose infusion rate (in mg/kg body weight/min) needed to maintain plasma glucose constant during a standard insulin infusion, 15,16 is impaired 10 to 20 years before the onset of frank NIDDM in diabetes-prone populations 17 and is the best predictor of clinical onset of disease. 18 Impaired tissue insulin sensitivity also accompanies (and may predispose to the development of) such conditions as hypertension, obesity, and atherosclerosis. 19 It is not widely appreciated that nondiabetic patients with CAD exhibit some degree of insulin resistance on formal testing (Fig 1). In addition to its well-known role in glucose homeostasis, insulin is involved in the regulation of such diverse biologic processes as vascular tone, cellular hyperplasia and hypertrophy, vascular and myocardial compliance, leukocyte function, and coagulation. The list of factors that may contribute to the adverse impact of NIDDM and insulin resistance on cardiovascular disease continues to grow. Reducing the impact of NIDDM requires a better understanding of the effects of insulin’s action on fundamental biologic processes in the myocardium and arterial wall. This article reviews perspectives on the cellular and molecular basis of insulin action and insulin resistance at the level of the myocardium and vasculature. Emerging evidence that normalizing metabolic abnormalities associated with the insulinresistant phenotype may ameliorate the adverse impact of NIDDM on cardiovascular disease is presented. It is evident, however, that NIDDM remains a difficult and incompletely understood challenge.