Insulin resistance means different things to different people. As other Perspectives in this series make clear, insulin resistance can be seen as a molecular and genetic mystery involving defective insulin signaling and glucose transport into cells. To me, on the other hand, insulin resistance represents a major underlying abnormality driving cardiovascular disease, the major cause of morbidity and mortality in much of the world. Because most of the work on insulin resistance has focused on its role in the pathophysiology of type 2 diabetes mellitus, a brief review of the history of the link between cardiovascular disease and insulin resistance is in order.
Margaret Albrink was probably the first investigator to identify a cluster of factors, including obesity and hypertriglyceridemia, that was associated with increased risk for coronary artery disease (CAD) (1). The groundbreaking development of the insulin radioimmunoassay by Berson and Yalow, and the subsequent observation that many diabetics were actually hyperinsulinemic, enabled Albrink and others, including Reaven and Farquhar and their colleagues (2), to begin to define the insulin resistance syndrome and its links to both hypertriglyceridemia and CAD. The next decades brought several prospective cohort studies in which hyperinsulinemia was often associated with CAD, at first in univariate and more recently in multivariate analyses. These efforts culminated recently in the demonstration by investigators in the Insulin Resistance Atherosclerosis Study (IRAS) of a link between a direct measure of insulin resistance itself and atherosclerosis (3). In addition, the 1970s brought a new understanding of protective roles of HDL (4). Together with the characterization of small dense LDLs in the 1980s, this advance led to the identification of a typical dyslipidemic pattern that is a central component of the insulin resistance syndrome. Another important addition to the complex was the observation by Welborn and colleagues in the mid-1960s that hypertension was commonly associated with hyperinsulinemia (5). Finally, the realization that individuals with insulin resistance both were hypercoagulable and had impaired fibrinolysis (6) added a pathologic basis for an increase in acute CAD events to the well accepted association of the insulin resistance syndrome with risk factors for atherosclerosis. As the components of the syndrome have increased, scientific interest and excitement, as well as the opportunities to investigate the links between insulin resistance and cardiovascular disease, have multiplied. In this Perspective I will attempt to provide an overview of what we do and do not know about the contribution of insulin resistance to the various components of the insulin resistance syndrome and to cardiovascular disease.
Xanya Sofra Weiss
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