Insulin resistance: From predisposing factor to therapeutic target in type 2 diabetes

Background: Insulin resistance contributes to the pathogenesis of type 2 diabetes and is closely linked with cardiovascular risk factors and premature cardiovascular disease. Objective: The purpose of this paper was to review the importance of insulin resistance as a core defect in type 2 diabetes, a potential contributor to accelerated atherosclerosis, and a potential target for insulin-sensitizing agents. Methods: Articles considered for inclusion in this review were identified through a search of MEDLINE/PubMed for reports published from 1966 to April 2003. Search terms used were insulin resistance, diabetes, insulin sensitivity, obesity, cardiovascular disease, metformin, thiazolidinediones, pioglitazone, rosiglitazone, and troglitazone. Results: An overview of the epidemiology, natural history, and pathophysiology of type 2 diabetes is provided, with a focus on insulin resistance and a related discussion of the impact of current therapies used to treat insulin-resistant patients. In particular, information on insulin-sensitizing agents-metformin and the currently available thiazolidinediones (TZDs), pioglitazone and rosiglitazone-is presented. Although metformin has been shown to indirectly reduce insulin resistance, TZDs are the only available agents that have been shown to directly lower insulin resistance. Conclusions: Recent evidence indicates that metformin, pioglitazone, and rosiglitazone may improve the dyslipidemic profile, reduce vascular inflammation, and improve endothelial dysfunction, all of which may be particularly important to physicians seeking treatment options to prevent or reduce cardiovascular complications in patients with type 2 diabetes.