Molecular analysis of insulin resistance in isolated ventricular cardiomyocytes of obese zucker rats. Kolter, Thomas, Ingo Uphues, and J[umlaut]urgen Eckel. Laboratory of Molecular Cardiology, Diabetes Research Institute, D[umlaut]usseldorf, Germany, Tel.: +49 211 3382 561
APStracts 4:0056E, 1997.
Isolated ventricular cardiomyocytes obtained from lean and genetically (fa/fa) obese Zucker rats were used to correlate alterations of insulin-induced glucose transport activation and GLUT4 translocation to possible defects of the insulin signalling cascade. Maximal stimulation with insulin was found to produce an unaltered translocation of GLUT4 to the plasma membrane (4.2 and 3.7 fold increase for lean and obese rats, respectively). However, a largely reduced sensitivity of 3-O-methylglucose transport could be detected in obese rats at physiological doses of insulin (completely unresponsive at 8 x 10-11 M compared to 3fold stimulation of glucose transport in lean controls). Tyrosine phosphorylation of the insulin receptor beta-subunit and the insulin receptor substrate-1 (IRS-1) were stimulated identically in cardiomyocytes from both lean and obese rats. Labelling of cells with 33P-orthophosphate revealed a marked increase in the serine/threonine phosphorylation of IRS-1 in the obese group (370% of lean controls) with a concomitant reduction in IRS-1 abundance (30-40%). The reduced sensitivity of glucose transport at 8 x 10-11 M insulin was then found to correlate to a completely blunted response of IRS-1-associated phosphatidylinositol 3-kinase (PI 3-kinase) activity in cardiomyocytes from obese rats. Those data show that cardiac insulin resistance of obesity involves defective insulin signalling at low concentrations of the hormone whereas GLUT4 translocation is fully operative in the isolated cell. It is suggested that hyperphosphorylation of IRS-1 may significantly contribute to the pathogenesis of insulin resistance in the heart. 

Received 16 September 1997; accepted in final form 18 February
1997.
APS Manuscript Number E464-6.
Article publication pending Am. J. Physiol. (Endocrinol. Metab.).
ISSN 1080-4757 Copyright 1997 The American Physiological Society.
Published in APStracts on 12 March 1997