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Letter

Nature Medicine 11, 567 - 571 (2005)
Published online: 10 April 2005 | doi:10.1038/nm1227

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

Emilie A Bard-Chapeau1, Andrea L Hevener2, Shinong Long1, Eric E Zhang1,3, Jerrold M Olefsky2 & Gen-Sheng Feng1,3

Insulin receptor substrate-1 (IRS-1) and IRS-2 are known to transduce and amplify signals emanating from the insulin receptor1, 2, 3. Here we show that Grb2-associated binder 1 (Gab1), despite its structural similarity to IRS proteins4, 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.