Deletion of Gab1 in the liver leads to enhanced glucose tolerance and improved hepatic insulin action

• Published in: Nature medicine Vol. 11; no. 5; pp. 567 - 571
• Main Authors: Feng, Gen-Sheng, Bard-Chapeau, Emilie A, Hevener, Andrea L, Long, Shinong, Zhang, Eric E, Olefsky, Jerrold M
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01-05-2005
• Subjects: Animals; Blood Chemical Analysis; Blood Glucose; DNA Primers; Enzyme-Linked Immunosorbent Assay; Extracellular Signal-Regulated MAP Kinases - metabolism; Genetic Engineering; Glucose Tolerance Test; Insulin - metabolism; Insulin Receptor Substrate Proteins; Intracellular Signaling Peptides and Proteins; Liver; Liver - metabolism; Mice; Mice, Transgenic; Phosphoproteins - genetics; Phosphoproteins - metabolism; Phosphorylation; Protein-Serine-Threonine Kinases - metabolism; Proteins; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Signal Transduction - physiology; Tyrosine - metabolism
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm1227

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.