Dual PPAR / activation provides enhanced improvement of insulin sensitivity and glycemic control in ZDF rats

Brand, Christian L., Jeppe Sturis, Carsten F. Gotfredsen, Jan Fleckner, Christian Fledelius, Bo F. Hansen, Birgitte Andersen, Ji-Ming Ye, Per Sauerberg, and Karsten Wassermann. Dual PPAR / activation provides enhanced improvement of insulin sensitivity and glycemic control in ZDF rats. Am J Physiol Endocrinol Metab 284: E841–E854, 2003. First published December 10, 2002; 10.1152/ajpendo.00348.2002.—Improvement of insulin sensitivity and lipid and glucose metabolism by coactivation of both nuclear peroxisome proliferator-activated receptor (PPAR) and PPAR potentially provides beneficial effects over existing PPAR and preferential drugs, respectively, in treatment of type 2 diabetes. We examined the effects of the dual PPAR / agonist ragaglitazar on hyperglycemia and whole body insulin sensitivity in early and late diabetes stages in Zucker diabetic fatty (ZDF) rats and compared them with treatment with the PPAR preferential agonist rosiglitazone. Despite normalization of hyperglycemia and Hb A1c and reduction of plasma triglycerides by both compounds in both prevention and early intervention studies, ragaglitazar treatment resulted in overall reduced circulating insulin and improved insulin sensitivity to a greater extent than after treatment with rosiglitazone. In late-intervention therapy, ragaglitazar reduced Hb A1c by 2.3% compared with 1.1% by rosiglitazone. Improvement of insulin sensitivity caused by the dual PPAR / agonist ragaglitazar seemed to have beneficial impact over that of the PPAR preferential activator rosiglitazone on glycemic control in frankly diabetic ZDF rats.