Insulin resistance in fat cells from obese Zucker rats - Evidence for an impaired activation and translocation of protein kinase B and glucose transporter 4

The effect of insulin on glucose transport, glucose transporter 4 (Glut4) t ranslocation, and intracellular signaling were measured in fat cells from l ean and obese Zucker rats of different ages. Insulin-stimulated glucose tra nsport was markedly reduced in adipocytes from old and obese animals. The p rotein content of Glut4 and insulin receptor substrates (IRS) 1 and 2 were also reduced while other proteins, including the p85 subunit of PI3-kinase, Shc and the MAP kinases (ERK1 and 2) were essentially unchanged. There was a marked impairment in the insulin stimulated tyrosine phosphorylation of IRS-1 and 2 as well as activation of PI3-kinase and PKB in cells from old a nd obese animals. Furthermore, insulin-stimulated translocation of both Glu t4 and PKB to the plasma membrane was virtually abolished. The phosphotyros ine phosphatase inhibitor, vanadate, increased the insulin-stimulated upstr eam signaling including PI3-kinase and PKB activities as well as rate of gl ucose transport. Thus, the insulin resistance in cells from old and obese Z ucker rats can be accounted for by an impaired translocation process, due t o signaling defects leading to a reduced activation of PI3-kinase and PKB, as well as an attenuated Glut4 protein content.