Endocrinology, Vol 125, 2341-2349, Copyright © 1989 by Endocrine Society

ARTICLES

Mechanism of insulin resistance induced by sustained levels of cytosolic free calcium in rat adipocytes

B Draznin, D Lewis, N Houlder, N Sherman, M Adamo, WT Garvey, D LeRoith and K Sussman
Research Service, Veterans Administration Medical Center, Denver, Colorado 80220.

We have recently provided evidence that elevated levels of cytosolic free Ca2+ ([Ca2+]i) decreased insulin-stimulated glucose uptake in isolated rat adipocytes. To investigate the mechanism of Ca2+ action, we examined the effects of elevated levels of [Ca2+]i on insulin binding, autophosphorylation, and tyrosine kinase activity (TKA) of insulin receptors as well as basal and insulin-stimulated cellular distribution of glucose transporters. The latter was assessed by cytochalasin-B binding to plasma membrane and cytosolic fractions. Elevated concentrations of [Ca2+]i were maintained by incubating adipocytes with a depolarizing concentration of K+ (40 mM). Basal nonstimulated glucose uptake was not altered by increased levels of [Ca2+]i. Adipocytes with higher [Ca2+]i (220 +/- 15 nM) showed 30% reduction in insulin-stimulated 2-deoxyglucose uptake compared with control cells ([Ca2+]i, 140 +/- 18 nM). Moreover, adipocytes with higher levels of [Ca2+]i demonstrated an approximately 10% reduction in autophosphorylation and TKA of insulin receptors without a change in insulin binding. Both basal and insulin-stimulated distributions of glucose transporters were unaffected by sustained levels of [Ca2+]i. The effects of elevated [Ca2+]i were not mimicked by protein kinase-C activation. These observations suggest that 1) elevated or sustained levels of [Ca2+]i impair insulin-stimulated glucose uptake; and 2) Ca2+- induced impairment appears to reside at the postbinding steps of insulin action and probably interferes with the TKA of insulin receptors and the intrinsic activity of glucose transporters.

This article has been cited by other articles:

				W.-Q. Zhao, F. G. De Felice, S. Fernandez, H. Chen, M. P. Lambert, M. J. Quon, G. A. Krafft, and W. L. Klein Amyloid beta oligomers induce impairment of neuronal insulin receptors FASEB J, January 1, 2008; 22(1): 246 - 260. [Abstract] [Full Text] [PDF]

				A. G. Pittas, J. Lau, F. B. Hu, and B. Dawson-Hughes The Role of Vitamin D and Calcium in Type 2 Diabetes. A Systematic Review and Meta-Analysis J. Clin. Endocrinol. Metab., June 1, 2007; 92(6): 2017 - 2029. [Abstract] [Full Text] [PDF]

				S. Ayturk, A. Gursoy, N. Bascil Tutuncu, D. T. Ertugrul, and N. Guvener Demirag Changes in Insulin Sensitivity and Glucose and Bone Metabolism over Time in Patients with Asymptomatic Primary Hyperparathyroidism J. Clin. Endocrinol. Metab., November 1, 2006; 91(11): 4260 - 4263. [Abstract] [Full Text] [PDF]

				P. G. Cammisotto and L. J. Bukowiecki Role of calcium in the secretion of leptin from white adipocytes Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2004; 287(6): R1380 - R1386. [Abstract] [Full Text] [PDF]

				M. Jacqmain, E. Doucet, J.-P. Despres, C. Bouchard, and A. Tremblay Calcium intake, body composition, and lipoprotein-lipid concentrations in adults Am. J. Clinical Nutrition, June 1, 2003; 77(6): 1448 - 1452. [Abstract] [Full Text] [PDF]

				J. M. Alexiewicz, D. Kumar, M. Smogorzewski, M. Klin, and S. G. Massry Polymorphonuclear Leukocytes in Non-Insulin-dependent Diabetes Mellitus: Abnormalities in Metabolism and Function Ann Intern Med, December 15, 1995; 123(12): 919 - 924. [Abstract] [Full Text]