Insulin action impaired by deficiency of the G-protein subunit G(iα2)

Integration of information between tyrosine kinase and G-protein-mediated pathways is necessary, but remains poorly understood. Here we use cells from transgenic mice harbouring inducible expression of RNA antisense to the gene encoding G(iα2) to show that G(iα2) is critical for insulin action. G(iα2) deficiency in adipose tissue and liver produces hyperinsulinaemia, 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 insulin. G(iα2) deficiency increases protein-tyrosine phosphatase activity and attenuates insulin stimulated tyrosine phosphorylation of IRS (insulin-receptor substrate 1) in vivo. G(iα2) deficiency creates a model for the insulin resistance characteristic of noninsulin-dependent diabetes mellitus (NIDDM), implicating G(iα2) as a positive regulator of insulin action.