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enhances myocardial glucose oxidation and improves contractile function in isolated working hearts of ZDF rats
1 Division of Cardiology, University of Texas Medical School at Houston, Houston, Texas, USA
2 Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas, USA
3 GlaxoSmithKline, Research Triangle Park, North Carolina, USA
* To whom correspondence should be addressed. E-mail: Heinrich.Taegtmeyer{at}uth.tmc.edu.
Background: It is suggested that insulin resistance and metabolic maladaptation of the heart are causes of contractile dysfunction. We tested the hypothesis whether systemic PPAR
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. Methods and Results: Male Zucker diabetic fatty (ZDF) and Zucker Lean (ZL) rats, at 53-56 days of age, were treated with either GI262570 (a non-TZD PPAR agonist; A) or vehicle (V) for one week. 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 non-diabetic levels with agonist treatment. In ZDF-V hearts, transcript levels of PPAR
-regulated genes and of MHC
were upregulated, while GLUT-4 was downregulated compared to ZL. Agonist treatment of ZDF rats reduced PPAR-regulated genes, and increased transcripts of GLUT-4 and GLUT-1. Conclusion: By changing the metabolic profile, reducing myocardial lipid accumulation and promoting the downregulation of PPAR-regulated genes, PPAR 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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