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Am J Physiol Endocrinol Metab 284: E841-E854, 2003. First published December 10, 2002; doi:10.1152/ajpendo.00348.2002
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Vol. 284, Issue 4, E841-E854, April 2003

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

Christian L. Brand1, Jeppe Sturis1, Carsten F. Gotfredsen1, Jan Fleckner1, Christian Fledelius1, Bo F. Hansen1, Birgitte Andersen1, Ji-Ming Ye2, Per Sauerberg1, and Karsten Wassermann1

1 Research and Development, Novo Nordisk, DK-2880 Bagsvaerd, Denmark; and 2 Garvan Institute of Medical Research, Darlinghurst, Sydney 2010, Australia

Improvement of insulin sensitivity and lipid and glucose metabolism by coactivation of both nuclear peroxisome proliferator-activated receptor (PPAR)gamma and PPARalpha potentially provides beneficial effects over existing PPARgamma and alpha  preferential drugs, respectively, in treatment of type 2 diabetes. We examined the effects of the dual PPARalpha /gamma 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 PPARgamma 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 PPARalpha /gamma agonist ragaglitazar seemed to have beneficial impact over that of the PPARgamma -preferential activator rosiglitazone on glycemic control in frankly diabetic ZDF rats.

euglycemic clamp; peroxisome proliferator-activated receptor; ragaglitazar; rosiglitazone; type 2 diabetes; Zucker diabetic fatty


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