INSULIN-RECEPTOR SUBSTRATE (IRS)1 IS REDUCED AND IRS-2 IS THE MAIN DOCKING PROTEIN FOR PHOSPHATIDYLINOSITOL 3-KINASE IN ADIPOCYTES FROM SUBJECTS WITH NON-INSULIN-DEPENDENT DIABETES-MELLITUS

The large docking protein IRS-1 is a major substrate for the insulin r eceptor and other tyrosine kinases. It plays a key role in eliciting m any of insulin's actions, including binding and activation of phosphat idylinositol (PI) 3-kinase and the subsequent increase in glucose tran sport. Gene disruption of IRS-1 in mice is associated with an impaired insulin-stimulated glucose disposal in vivo and glucose transport in vitro, but the survival of the animals and residual insulin sensitivit y is dependent on the presence of the alternative docking protein IRS- 2. We examined the expression and function of IRS-1 and IRS-2 in adipo cytes from healthy and diabetic individuals. Cells from subjects with non-insulin-dependent diabetes mellitus (NIDDM), but not with insulin dependent diabetes mellitus, had an impaired insulin effect and a mark ed reduction (70 +/- 6%) in the expression of IRS-1 protein, whereas I RS-2 was unchanged. In normal cells, IRS-1 was the main docking protei n for the binding and activation of insulin-stimulated PI 3-kinase; IR S-2 was also functional but required a higher insulin concentration fo r a similar binding and activation of PI 3-kinase. In contrast in NIDD M cells with a low IRS-1 content, IRS-2 became the main docking protei n. These findings may provide important reasons for the insulin resist ance in NIDDM.