INSULIN ACTION IMPAIRED BY DEFICIENCY OF THE G-PROTEIN SUBUNIT G(I-ALPHA-2)

Integration of information between tyrosine kinase(1) and G-protein-me diated pathways(2) is necessary, but remains poorly understood. Here w e use cells from transgenic mice harbouring inducible expression of RN A antisense to the gene encoding G(i alpha 2) (refs 3, 4) to show that G(i alpha 2) is critical for insulin action. G(i alpha 2) deficiency in adipose tissue and liver produces hyperinsulinaemia, impaired gluco se tolerance and resistance to insulin in vivo. Insulin resistance aff ects glucose-transporter activity and recruitment, counterregulation o f lipolysis, and activation of glycogen synthase, all of which are car dinal responses to insulin(5). G(i alpha 2) deficiency increases prote in-tyrosine phosphatase activity and attenuates insulin-stimulated tyr osine phosphorylation of IRS (insulin-receptor substrate 1) in vivo. G (i alpha 2) deficiency creates a model for the insulin resistance char acteristic of noninsulin-dependent diabetes mellitus (NIDDM)(6), impli cating G(i alpha 2) as a positive regulator of insulin action.