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Peroxisome Proliferator-Activated Receptor (PPAR)- Agonism Prevents the Onset of Type 2 Diabetes in Zucker Diabetic Fatty Rats: A Comparison with PPAR Agonism

Departments of Metabolic Disorders (R.B., J.Y., C.L., Z.L., J.B.P., B.B.Z., D.E.M., T.W.D.), Immunology (J.W.W., E.I.Z.), and Medicinal Chemistry (A.A.), Merck Research Laboratories, Rahway, New Jersey 07065

Address all correspondence and requests for reprints to: Raynald Bergeron, Ph.D., Professeur agrégé, Département de kinésiologie, Université de Montréal, C.P. 6128, Montréal, Québec, Canada H3C 3J7. E-mail: raynald.bergeron{at}umontreal.com.

Peroxisome proliferator-activated receptor (PPAR)- agonists are insulin sensitizers, whereas PPAR agonists are lipid-lowering agents in humans. Chronic treatment with PPAR agonists has been shown to prevent the onset of diabetes in young Zucker diabetic fatty (ZDF) rats; however, the effects of PPAR agonists have not been well characterized in this model. Here we investigated chronic efficacy of PPAR and nonthiazolidinedione (nTZD) PPAR agonists on the onset of diabetes in 6-wk-old male ZDF rats. Whereas treatment with the nTZD PPAR agonist completely prevented development of hyperglycemia, PPAR activation was associated with lowering of food intake and body weight and reductions in fed and fasting hyperglycemia, with prevention of the hyperinsulinemic peak preceding the development of hyperglycemia in ZDF rats. Both compounds improved glucose tolerance during an oral glucose tolerance test with concomitant increases in insulin response. Such improvements of insulin secretion were associated with increased islet to total pancreatic area ratio and pancreatic insulin contents. Hyperinsulinemic-euglycemic clamp studies demonstrated that nTZD PPAR reduced basal endogenous glucose production and increased insulin-stimulated glucose disposal, consistent with an improved insulin action as a cause of the improved glucose homeostasis. In contrast, activation of PPAR did not significantly improve glucose metabolism during the hyperinsulinemic-euglycemic clamp. In conclusion, chronic treatment of ZDF rats with a PPAR agonist completely prevented the onset of diabetes by improving both insulin action and secretion, whereas PPAR agonism was partially effective, primarily by improving the pancreatic islet insulin response. Unlike the PPAR agonist, the PPAR agonist demonstrated efficacy without inducing body weight gain and cardiomegaly. This study suggests a possible role for PPAR agonists in the prevention of type 2 diabetes mellitus.

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