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

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

doi:10.1194/jlr.m800165-jlr200

Abstract

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 PPARalpha or other non-PPARgamma 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.

Highlights

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
There were no significant differences between the rosiglitazone and pioglitazone treatment groups at baseline with respect to age, weight, body mass index, or metabolic parameters
Three subjects were on metformin alone and three subjects were on metformin in combination with sulfonylurea

Summary

Introduction

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 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, comparisons of changes between treatments were not significantly different. The reduction in DNL may underlie altered assembly or atherogenicity of lipoprotein particles and may reflect PPARa or other non-PPARg 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.—Beysen, C., E. The peroxisome proliferator-activated receptor (PPAR)-g agonists, pioglitazone and rosiglitazone, are widely used for treatment of T2DM These thiazolidinediones (TZDs) lower glucose concentrations by improving insulin sensitivity [5,6,7].

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Conclusion