Deletion of Gab1 in the liver leads to enhanced glucose tolerance and improved hepatic insulin action.
Insulin receptor substrate-1 (IRS-1) and IRS-2 are known to transduce and amplify signals emanating from the insulin receptor. Here we show that Grb2-associated binder 1 (Gab1), despite its structural similarity to IRS proteins, is a negative modulator of hepatic insulin action. Liver-specific Gab1 knockout (LGKO) mice showed enhanced hepatic insulin sensitivity with reduced glycemia and improved glucose tolerance. In LGKO liver, basal and insulin-stimulated tyrosine phosphorylation of IRS-1 and IRS-2 was elevated, accompanied by enhanced Akt/PKB activation. Conversely, Erk activation by insulin was suppressed in LGKO liver, leading to defective IRS-1 Ser612 phosphorylation. Thus, Gab1 acts to attenuate, through promotion of the Erk pathway, insulin-elicited signals flowing through IRS and Akt proteins, which represents a novel balancing mechanism for control of insulin signal strength in the liver.
Pubmed ID: 15821749 RIS Download
Animals | Blood Chemical Analysis | Blood Glucose | DNA Primers | Enzyme-Linked Immunosorbent Assay | Extracellular Signal-Regulated MAP Kinases | Genetic Engineering | Glucose Tolerance Test | Insulin | Insulin Receptor Substrate Proteins | Intracellular Signaling Peptides and Proteins | Liver | Mice | Mice, Transgenic | Phosphoproteins | Phosphorylation | Protein-Serine-Threonine Kinases | Proto-Oncogene Proteins | Proto-Oncogene Proteins c-akt | Signal Transduction | Tyrosine