COMPENSATORY ALTERATIONS FOR INSULIN SIGNAL-TRANSDUCTION AND GLUCOSE-TRANSPORT IN INSULIN-RESISTANT DIABETES

Insulin binding activates the receptor tyrosine kinase toward the insu lin receptor substrate-1 (IRS-1). Phosphorylated IRS-1 then interacts with the p85 alpha subunit of phosphatidylinositol S-kinase (PI3K), Nc k, growth factor receptor-bound protein 2 (GRB2), and Syp, thus branch ing insulin's signal for both mitogenic and metabolic responses. To de termine whether 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 diabeti c KKA(y) mice. IR and PI3K p85 alpha protein levels were significantly lower in KKA(y) mice than in control nondiabetic mice, whereas IRS-1 protein levels were not altered. In contrast, the protein levels of GR B2, Nck, Syp, and GLUT-1 were dramatically elevated in KKA(y) fat, wit h less striking changes in liver. Treatment of diabetic animals with p ioglitazone, an insulin-sensitizing antihyperglycemic agent, partially corrected the expression of some of these proteins. Taken together, t hese 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.