AJP - Endocrinology and Metabolism, Vol 273, Issue 1 E59-E67, Copyright © 1997 by American Physiological Society

ARTICLES

Molecular analysis of insulin resistance in isolated ventricular cardiomyocytes of obese Zucker rats

T. Kolter, I. Uphues and J. Eckel
Laboratory of Molecular Cardiology, Diabetes Research Institute, Dusseldorf, Germany.

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 GLUT-4 translocation to possible defects of the insulin signaling cascade. Maximal stimulation with insulin was found to produce an unaltered translocation of GLUT-4 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 with 3-fold stimulation of glucose transport in lean controls). Tyrosine phosphorylation of the insulin receptor beta-subunit and the insulin receptor substrate 1 (IRS-1) was stimulated identically in cardiomyocytes from both lean and obese rats. Labeling of cells with [33P]orthophosphate revealed a marked increase in the serine and/or 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 activity in cardiomyocytes from obese rats. Those data show that cardiac insulin resistance of obesity involves defective insulin signaling at low concentrations of the hormone, whereas GLUT-4 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.

This article has been cited by other articles:

				Y.-R. Cho, H.-J. Kim, S.-Y. Park, H. J. Ko, E.-G. Hong, T. Higashimori, Z. Zhang, D. Y. Jung, M. S. Ola, K. F. LaNoue, et al. Hyperglycemia, maturity-onset obesity, and insulin resistance in NONcNZO10/LtJ males, a new mouse model of type 2 diabetes Am J Physiol Endocrinol Metab, July 1, 2007; 293(1): E327 - E336. [Abstract] [Full Text] [PDF]

				M. Meier, H. H Klein, J. Kramer, M. Drenckhan, and M. Schutt Calpain inhibition impairs glycogen syntheses in HepG2 hepatoma cells without altering insulin signaling J. Endocrinol., April 1, 2007; 193(1): 45 - 51. [Abstract] [Full Text] [PDF]

				A. D. Hafstad, G. H. Solevag, D. L. Severson, T. S. Larsen, and E. Aasum Perfused hearts from Type 2 diabetic (db/db) mice show metabolic responsiveness to insulin Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H1763 - H1769. [Abstract] [Full Text] [PDF]

				R. Carroll, A. N. Carley, J. R. B. Dyck, and D. L. Severson Metabolic effects of insulin on cardiomyocytes from control and diabetic db/db mouse hearts Am J Physiol Endocrinol Metab, May 1, 2005; 288(5): E900 - E906. [Abstract] [Full Text] [PDF]

				P. Hu, D. Zhang, L. Swenson, G. Chakrabarti, E. D. Abel, and S. E. Litwin Minimally invasive aortic banding in mice: effects of altered cardiomyocyte insulin signaling during pressure overload Am J Physiol Heart Circ Physiol, August 7, 2003; 285(3): H1261 - H1269. [Abstract] [Full Text] [PDF]

				M. W. Greene, H. Sakaue, L. Wang, D. R. Alessi, and R. A. Roth Modulation of Insulin-stimulated Degradation of Human Insulin Receptor Substrate-1 by Serine 312 Phosphorylation J. Biol. Chem., February 28, 2003; 278(10): 8199 - 8211. [Abstract] [Full Text] [PDF]

				J. Duan, H.-Y. Zhang, S. D. Adkins, B. H. Ren, F. L. Norby, X. Zhang, J. N. Benoit, P. N. Epstein, and J. Ren Impaired cardiac function and IGF-I response in myocytes from calmodulin-diabetic mice: role of Akt and RhoA Am J Physiol Endocrinol Metab, February 1, 2003; 284(2): E366 - E376. [Abstract] [Full Text] [PDF]

				R. J. Sidell, M. A. Cole, N. J. Draper, M. Desrois, R. E. Buckingham, and K. Clarke Thiazolidinedione Treatment Normalizes Insulin Resistance and Ischemic Injury in the Zucker Fatty Rat Heart Diabetes, April 1, 2002; 51(4): 1110 - 1117. [Abstract] [Full Text] [PDF]

				A. Kessler, I. Uphues, D. M. Ouwens, M. Till, and J. Eckel Diversification of cardiac insulin signaling involves the p85{alpha}/{beta} subunits of phosphatidylinositol 3-kinase Am J Physiol Endocrinol Metab, January 1, 2001; 280(1): E65 - E74. [Abstract] [Full Text] [PDF]

				L.-y. Qiao, J. L. Goldberg, J. C. Russell, and X. J. Sun Identification of Enhanced Serine Kinase Activity in Insulin Resistance J. Biol. Chem., April 9, 1999; 274(15): 10625 - 10632. [Abstract] [Full Text] [PDF]