Insulin action impaired by deficiency of the G-protein subunit G ialpha2.
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 ialpha2 to show that G ialpha2 is critical for insulin action. G ialpha2 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 ialpha2 deficiency increases protein-tyrosine phosphatase activity and attenuates insulin-stimulated tyrosine phosphorylation of IRS (insulin-receptor substrate 1) in vivo. G ialpha2 deficiency creates a model for insulin resistance characteristic of noninsulin-dependent diabetes mellitus (NIDDM), implicating G ialpha2 as a positive regulator of insulin action.
Moxham
C M
CM
Department of Molecular Pharmacology, Diabetes and Metabolic Diseases Research Program, University Medical Center, SUNY/Stony Brook, New York 11794-8651, USA.
Malbon
C C
CC
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004195:Disease Models, Animal; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051275:Glucose Transporter Type 4; D006006:Glycogen Synthase / Q000378:metabolism; D006946:Hyperinsulinism / Q000378:metabolism; D007328:Insulin / Q000502:physiology*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D008066:Lipolysis; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins; D010750:Phosphoproteins / Q000378:metabolism; D016372:RNA, Antisense / Q000235:genetics
D001786:Blood Glucose; D051275:Glucose Transporter Type 4; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D010750:Phosphoproteins; D016372:RNA, Antisense; C495693:Slc2a4 protein, mouse; D006006:Glycogen Synthase; D019204:GTP-Binding Proteins