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Journal of Lipid Research, Vol. 49, 2657-2663, December 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Patient-Oriented and Epidemiological Research

A pilot study of the effects of pioglitazone and rosiglitazone on de novo lipogenesis in type 2 diabetes

Carine Beysen^*, Elizabeth J. Murphy^*,, Hirisadarahally Nagaraja, Martin Decaris^**, Timothy Riiff^*, Alex Fong^*, Marc K. Hellerstein^1,,** and Patrick J. Boyle

^* KineMed, Inc. Emeryville, CA
Department of Medicine, SF General Hospital, University of California at San Francisco, San Francisco, CA
Department of Internal Medicine, University of New Mexico School of Medicine MSC10 5550, Albuquerque, NM
^** Department of Nutritional Sciences and Toxicology, University of California at Berkeley, Berkeley, CA

Published, JLR Papers in Press, July 18, 2008.

This work was supported by a research grant from Takeda Pharmaceuticals North America Inc.

¹ To whom correspondence should be addressed. e-mail: march{at}nature.Berkeley.edu

Treatment of type 2 diabetes mellitus (T2DM) patients with pioglitazone results in a more favorable lipid profile, and perhaps more favorable cardiac outcomes, than treatment with rosiglitazone. Pioglitazone treatment increases VLDL-triacylglycerol clearance, but the role of de novo lipogenesis (DNL) has not been explored, and no direct comparison has been made between the thiazolidinediones (TZDs). Twelve subjects with T2DM and hypertriacylglyceridemia were randomized to either rosiglitazone or pioglitazone treatment. Stable isotope infusion studies were performed at baseline and after 20 weeks of treatment. Both treatments reduced glucose and HbA_1c concentrations equally. Pioglitazone treatment resulted in a 40% reduction in hepatic DNL (P < 0.01) and in a 25% reduction in hepatic glucose production (P < 0.05), while rosiglitazone did not significantly change either parameter, although comparisons of changes between treatments were not significantly different. These pilot results indicate that pioglitazone reduces hepatic DNL while rosiglitazone does not. Larger follow-up studies are required to confirm differential effects of these agents definitively. The reduction in DNL may underlie altered assembly or atherogenicity of lipoprotein particles and may reflect PPAR or other non-PPAR actions on the liver by pioglitazone. These differences might help explain previously reported differences in lipid profiles and cardiovascular disease outcomes for rosiglitazone and pioglitazone.

Supplementary key words stable isotopes • liver metabolism • lipid metabolism • carbohydrate metabolism

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; DNL, de novo lipogenesis; HGP, hepatic glucose production; MIDA, mass isotopomer distribution analysis; NEFA, nonesterified fatty acids; T2DM, type 2 diabetes mellitus; TAG, triacylglycerols; TZDs, thiazolidinediones; VLDL, very low density lipoprotein

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