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Comparative Study
. 2005 Aug;289(2):E328-36.
doi: 10.1152/ajpendo.00055.2005. Epub 2005 Mar 29.

Activation of PPARgamma enhances myocardial glucose oxidation and improves contractile function in isolated working hearts of ZDF rats

Leonard S Golfman  1 , Christopher R Wilson, Saumya Sharma, Mathias Burgmaier, Martin E Young, Patrick H Guthrie, Melissa Van Arsdall, Julia V Adrogue, Kathleen K Brown, Heinrich Taegtmeyer
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Free article
Comparative Study

Activation of PPARgamma enhances myocardial glucose oxidation and improves contractile function in isolated working hearts of ZDF rats

Leonard S Golfman et al. Am J Physiol Endocrinol Metab. 2005 Aug.
Free article

Abstract

It is suggested that insulin resistance and metabolic maladaptation of the heart are causes of contractile dysfunction. We tested the hypothesis whether systemic PPARgamma activation, by changing the metabolic profile in a model of insulin resistance and type 2 diabetes (the ZDF rat) in vivo, improves contractile function of the heart in vitro. Male Zucker diabetic fatty (ZDF) and Zucker lean (ZL) rats, at 53-56 days of age, were treated with either GI-262570 (a nonthiazolidinedione PPARgamma agonist; A) or vehicle (V) for 1 wk. Agonist treatment resulted in correction of hyperglycemia and dyslipidemia, as well as in reduced hyperinsulinemia. The accumulation of triacylglycerols in the myocardium, characteristic of the ZDF rat, disappeared with treatment. Cardiac power and rates of glucose oxidation in the isolated working heart were significantly reduced in ZDF-V rats, but both parameters increased to nondiabetic levels with agonist treatment. In ZDF-V hearts, transcript levels of PPARalpha-regulated genes and of myosin heavy chain-beta were upregulated, whereas GLUT4 was downregulated compared with ZL. Agonist treatment of ZDF rats reduced PPARalpha-regulated genes and increased transcripts of GLUT4 and GLUT1. In conclusion, by changing the metabolic profile, reducing myocardial lipid accumulation, and promoting the downregulation of PPARalpha-regulated genes, PPARgamma activation leads to an increased capacity of the myocardium to oxidize glucose and to a tighter coupling of oxidative metabolism and contraction in the setting of insulin resistance and type 2 diabetes.

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