期刊
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
卷 289, 期 2, 页码 E328-E336出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00055.2005
关键词
peroxisome proliferator; activated receptor-gamma; Zucker diabetic fatty rat; diabetes mellitus; obesity; insulin; myocardial contraction; metabolism
资金
- NHLBI NIH HHS [R01-HL-43133, R01-HL-73162, T32-HL-07591] Funding Source: Medline
It is suggested that insulin resistance and metabolic maladaptation of the heart are causes of contractile dysfunction. We tested the hypothesis whether systemic PPAR gamma 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 gamma 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 alpha-regulated genes and of myosin heavy chain-beta were upregulated, whereas GLUT4 was downregulated compared with ZL. Agonist treatment of ZDF rats reduced PPAR alpha-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 alpha-regulated genes, PPAR gamma 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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