Regulation of IRS-2 tyrosine phosphorylation in fasting and diabetes

Intracellular insulin signaling involves a series of alternative and comple mentary pathways created by the multiple substrates of the insulin receptor (IRS) and the various isoforms of the SH2 domain signaling molecules that can interact with substrate. In this study we investigated IRS-1 and IRS-2 tyrosine phosphorylation, their association with P13-kinase and the phospho rylation of Akt, a serine-threonine kinase situated downstream to PI 3-kina se, in liver and muscle of two animal models of insulin resistance: 72 h of fasting and STZ-diabetic rats. There was an upregulation in insulin-induce d IRS-1 and IRS-2 tyrosine phosphorylation and association with P13-kinase in liver and muscle of both animal models of insulin resistance. However, A kt phosphorylation showed different regulation, increasing in fasting and d ecreasing in STZ-diabetic rats, Since an important difference between these two animal models of insulin resistance is the plasma glucose levels, we c an suggest that in STZ diabetic rats, the reduction in Akt phosphorylation is probably related to hyperglycemia and may certainly contribute to the mo lecular mechanism of insulin resistance observed in these animals. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.