The role of insulin resistance and hyperinsulinemia in coronary heart disease
Authors: Gerald M. Reaven
Journal: Metabolism (1992)

Patients with impaired glucose tolerance (IGT) and non-insulin-dependent diabetes mellitus (NIDDM) are more resistant to insulin-stimulated glucose uptake than are individuals with normal glucose tolerance. Evidence has also been published showing that first-degree relatives of patients with NIDDM are insulin resistant when compared with a matched group of relatives of subjects with normal glucose tolerance. In addition, the ability of insulin to stimulate glucose uptake varies approximately fourfold in individuals with normal glucose tolerance, and insulin resistance of a degree comparable to that seen in patients with IGT or with Type II diabetes is present in a significant portion of the normal population. Given a defect in insulin-stimulated glucose uptake, glucose tolerance can only be maintained if insulin-resistant individuals continue to secrete greater than normal amounts of insulin. As a corollary, glucose homeostasis will decompensate when the insulin secretory response begins to decrease, and the greater the decline in insulin secretion, the larger the increase in plasma glucose concentration. Resistance to insulin-stimulated glucose uptake and compensatory hyperinsulinemia seems to represent the basic defect in patients with NIDDM, with failure of β-cell function and subsequent development of fasting hyperglycemia only occurring later. This general formulation has received considerable support from longitudinal studies of the natural history of NIDDM. The fact that an increase in ambient insulin concentration can prevent gross decompensation of glucose tolerance in an insulin-resistant individual does not mean that this compensatory response is benign. It now appears that resistance to insulin-stimulated glucose uptake and compensatory hyperinsulinemia are associated not only with states of IGT, but are also seen in individuals with high blood pressure, hypertriglyceridemia, and low plasma concentrations of high-density lipoprotein (HDL) cholesterol. All of these events have been identified as increasing the risk of coronary heart disease (CHD), and there is increasing evidence that they tend to cluster in the same individual. As a consequence, it has been suggested that this constellation of abnormalities constitutes a syndrome (X) that plays an important role in the etiology of CHD. Indeed, in some populations it can be argued that Syndrome X is involved in the etiology of CHD to a greater degree than is an increase in plasma low-density lipoprotein (LDL) cholesterol concentration. In summary, resistance to insulin-stimulated glucose uptake seems to be a relatively common phenomenon, and is present in the majority of patients with IGT or NIDDM. The normal physiologic response to this defect in insulin action is to secrete more insulin in an effort to minimize the degree of IGT. If this compensatory response fails, glucose tolerance decompensates. Unfortunately, even if the hyperinsulinemia can be maintained, such individuals appear to be at increased risk of CHD, either directly as a result of the hyperinsulinemia, or secondary to the increase in blood pressure and the dyslipidemia shown to be associated with resistance to insulin-stimulated glucose uptake and elevation of plasma insulin concentration. As a result of these considerations, it seems possible that insulin resistance plays a major role in several important human diseases.