Compensatory alterations for insulin signal transduction and glucose transport in insulin-resistant diabetes. Bonini, James A., Jerry R. Colca, Charlene Dailey, Morris White, and Cecilia Hofmann. Department of Molecular and Cellular Biochemistry, Loyola University Stritch School of Medicine, Maywood, IL 60153; Metabolic Diseases Research, The Upjohn Company, Kalamazoo, MI 49001; Research Division, Joslin Diabetes Center, Boston, MA; Research Service, Hines VA Hospital, Hines, IL 60141 and Shock/Trauma Institute, Loyola University Medical Center, Maywood, IL 60153
APStracts 2:0118E, 1995.
Insulin binding activates the receptor tyrosine kinase toward the insulin receptor substrate-1 (IRS-1). Phosphorylated IRS-1 then interacts with the p85[alpha] subunit of phosphatidylinositol 3 -kinase (PI3K), Nck, growth factor receptor-bound protein 2 (GRB2), and Syp, thus branching insulin's signal for both mitogenic and metabolic responses. To determine if the expression of these proteins is altered in insulin resistance, the levels of these proteins were compared in adipose and liver tissues of nondiabetic mice and obese insulin-resistant diabetic KKAy mice. Insulin receptor and PI3K p85[alpha] protein levels were significantly lower in KKAy mice compared to control nondiabetic mice, while IRS-1 protein levels were not altered. In contrast, the protein levels of GRB2, Nck, Syp, and GLUT1 were dramatically elevated in KKAy fat, with less striking changes in liver. Treatment of diabetic animals with pioglitazone, an insulin-sensitizing antihyperglycemic agent, partially corrected the expression of some of these proteins. Taken together, these findings suggest that the insulin-resistant diabetic condition is characterized by changes in expression of insulin signal transduction components that may be associated with altered glucose metabolism. 

Received 18 January 1995; accepted in final form 16 May 1995.
APS Manuscript Number E15-5.
Article publication pending Am. J. Physiol. (Endocrinol. Metab.).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 30 May 1995.