Insulin action impaired by deficiency of the G-protein subunit Giα2

INTEGRATION of information between tyrosine kinase1 and G-protein-mediated pathways2 is necessary, but remains poorly understood. Here we use cells from transgenic mice harbouring inducible expression of RNA antisense to the gene encoding Giα2 (refs 3, 4) to show that Giα2 is critical for insulin action. Giα2 deficiency in adipose tissue and liver produces hyperinsulin-aemia, impaired glucose tolerance and resistance to insulin in vivo. Insulin resistance affects glucose-transporter activity and recruitment, counterregulation of lipolysis, and activation of glycogen synthase, all of which are cardinal responses to insulin5. Giα2 deficiency increases protein-tyrosine phosphatase activity and attenuates insulin-stimulated tyrosine phosphorylation of IRS (insulin-receptor substrate 1) in vivo. Giα2 deficiency creates a model for the insulin resistance characteristic of non-insulin-dependent diabetes mellitus (NIDDM)6, implicating Giα2 as a positive regulator of insulin action.