1. Department of Molecular Pharmacology, Diabetes and Metabolic Diseases Research Program, University Medical Center, SUNY/Stony Brook, Stony Brook, New York 11794-8651, USA

Abstract

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 G_i2 (refs 3, 4) to show that G_i2 is critical for insulin action. G_i2 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. G_i2 deficiency increases protein-tyrosine phosphatase activity and attenuates insulin-stimulated tyrosine phosphorylation of IRS (insulin-receptor substrate 1) in vivo. G_i2 deficiency creates a model for the insulin resistance characteristic of non-insulin-dependent diabetes mellitus (NIDDM)⁶, implicating G_i2 as a positive regulator of insulin action.