Thiazolidinediones in the Treatment of Insulin Resistance and Type II Diabetes

  1. Jerrold M Olefsky
  1. Department of Signal Transduction, Parke-Davis Pharmaceutical Research Division Warner Lambert, Ann Arbor, Michigan Division of Endocrinology and Metabolis, Department of Medicine, University of California San Diego Veterans Administration Medical Center La Jolla, California
  1. Address correspondence and reprint requests to Alan R. Saltiel, Parke-Davis Pharmaceutical Research, 2800 Plymouth Rd., Ann Arbor, MI 48105.

Abstract

Insulin resistance, characterized by reduced responsiveness to normal circulating concentrations of insulin, is a common feature of almost all patients with type II diabetes. The presumed central roles of both peripheral and hepatic insulin resistance suggest that the enhancement of insulin action might be an effective pharmacological approach to diabetes. Thiazolidinediones are a new class of orally active drugs that are designed to enhance the actions of insulin. These agents reduce insulin resistance by increasing insulin-dependent glucose disposal and reducing hepatic glucose output. Clinical studies in patients with type II diabetes, as well as other syndromes characterized by insulin resistance, have demonstrated that thiazolidinediones may represent a safe and effective new treatment. Although the precise mechanism of action of these drugs remains unknown, transcriptional changes are observed in tissue culture cells that produce enhanced insulin action. This regulation of gene expression appears to be mediated by the interactions of thiazolidinediones with a family of nuclear receptors known as the peroxisome proliferator-activated receptors (PPARs). The further elucidation of the molecular actions of these drugs may reveal much about the underlying mechanisms of insulin resistance.

  • Received June 21, 1996.
  • Revision received August 29, 1996.
  • Accepted August 29, 1996.
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