PATHOPHYSIOLOGY OF INSULIN-RESISTANCE IN HUMAN-DISEASE

The ability of insulin to stimulate glucose uptake varies widely horn person to person, and these differences, as well as how the individual attempts to compensate for them, are of fundamental importance in the development and clinical course of what are often designated as disea ses of Western civilization. Evidence is presented that non-insulin-de pendent diabetes mellitus (NIDDM) results from a failure on the part o f pancreatic beta-cells to compensate adequately for the defect in ins ulin action in insulin-resistant individuals. In addition, a coherent formulation of the physiological changes that lead from the defect in cellular insulin action to the loss in glucose homeostasis is presente d. However, the ability to maintain the degree of compensatory hyperin sulinemia necessary to prevent loss of glucose tolerance in insulin-re sistant individuals does not represent an unqualified homeostatic vict ory. In contrast, evidence is presented supporting the view that the c ombination of insulin resistance and compensatory hyperinsulinemia pre disposes to the development of a cluster of abnormalities, including s ome degree of glucose intolerance, an increase in plasma triglyceride and a decrease in high-density lipoprotein cholesterol concentrations, high blood pressure, hyperuricemia, smaller denser low-density lipopr otein particles, and higher circulating levels of plaminogen activator inhibitor 1. The cluster of changes associated with insulin resistanc e has been said to comprise syndrome X, and all of the manifestations of syndrome X have been shown to increase risk of coronary heart disea se. Thus it is concluded that insulin resistance and its associated ab normalities are of utmost importance in the pathogenesis of NIDDM, hyp ertension, and coronary heart disease.