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

• Published in: Endocrinology (Philadelphia) Vol. 147; no. 9; pp. 4252 - 4262
• Main Authors: Bergeron, Raynald, Yao, Jun, Woods, John W, Zycband, Emanuel I, Liu, Cherrie, Li, Zhihua, Adams, Alan, Berger, Joel P, Zhang, Bei B, Moller, David E, Doebber, Thomas W
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01.09.2006
• Subjects: Animals; Biological and medical sciences; Blood Glucose - metabolism; Body Weight - drug effects; Diabetes Mellitus, Type 2 - prevention & control; Diabetes. Impaired glucose tolerance; Eating - drug effects; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fasting; Food; Fundamental and applied biological sciences. Psychology; Glucose Clamp Technique; Glucose Tolerance Test; Homeostasis; Hyperglycemia - prevention & control; Insulin - blood; Insulin - pharmacology; Islets of Langerhans - pathology; Male; Medical sciences; Muscle, Skeletal - chemistry; PPAR alpha - agonists; PPAR alpha - pharmacology; PPAR gamma - agonists; Rats; Rats, Zucker; Triglycerides - analysis; Vertebrates: endocrinology; Endocrinopathy; Type 2 diabetes; Vertebrata; Mammalia; Rat; Animal; Rodentia; Metabolic diseases; Peroxisome proliferator activated receptor
• DOI: 10.1210/en.2005-1535
• ISSN: 0013-7227

Peroxisome proliferator-activated receptor (PPAR)-γ agonists are insulin sensitizers, whereas PPARα agonists are lipid-lowering agents in humans. Chronic treatment with PPARγ agonists has been shown to prevent the onset of diabetes in young Zucker diabetic fatty (ZDF) rats; however, the effects of PPARα agonists have not been well characterized in this model. Here we investigated chronic efficacy of PPARα and nonthiazolidinedione (nTZD) PPARγ agonists on the onset of diabetes in 6-wk-old male ZDF rats. Whereas treatment with the nTZD PPARγ agonist completely prevented development of hyperglycemia, PPARα 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 PPARγ 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 PPARα did not significantly improve glucose metabolism during the hyperinsulinemic-euglycemic clamp. In conclusion, chronic treatment of ZDF rats with a PPARγ agonist completely prevented the onset of diabetes by improving both insulin action and secretion, whereas PPARα agonism was partially effective, primarily by improving the pancreatic islet insulin response. Unlike the PPARγ agonist, the PPARα agonist demonstrated efficacy without inducing body weight gain and cardiomegaly. This study suggests a possible role for PPARα agonists in the prevention of type 2 diabetes mellitus.