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

Nat Med. 2005 May;11(5):567-71. doi: 10.1038/nm1227. Epub 2005 Apr 10.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • 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 / metabolism*
  • Mice
  • Mice, Transgenic
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Signal Transduction / physiology*
  • Tyrosine / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Blood Glucose
  • DNA Primers
  • Gab1 protein, mouse
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • Irs1 protein, mouse
  • Irs2 protein, mouse
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • Tyrosine
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases