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enhances myocardial glucose oxidation and improves contractile function in isolated working hearts of ZDF rats
1Division of Cardiology; University of Texas Medical School at Houston; 2Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas; and 3GlaxoSmithKline, Research Triangle Park, North Carolina
Submitted 8 February 2005 ; accepted in final form 24 March 2005
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. Male Zucker diabetic fatty (ZDF) and Zucker lean (ZL) rats, at 53–56 days of age, were treated with either GI-262570 (a nonthiazolidinedione PPAR 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 PPAR
-regulated genes and of myosin heavy chain-
were upregulated, whereas GLUT4 was downregulated compared with ZL. Agonist treatment of ZDF rats reduced PPAR-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 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.
peroxisome proliferator-activated receptor-; Zucker diabetic fatty rat; diabetes mellitus; obesity; insulin; myocardial contraction; metabolism
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