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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


  • Bard-Chapeau EA
  • Hevener AL
  • Long S
  • Zhang EE
  • Olefsky JM
  • Feng GS


Nature medicine

Publication Data

May 5, 2005

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK33651
  • Agency: NIDDK NIH HHS, Id: DK60484
  • Agency: NIGMS NIH HHS, Id: GM53660

Mesh Terms

  • 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