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Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation.

Nutritional excess and/or obesity represent well-known predisposition factors for the development of non-insulin-dependent diabetes mellitus (NIDDM). However, molecular links between obesity and NIDDM are only beginning to emerge. Here, we demonstrate that nutrients suppress phosphatidylinositol 3 (PI3)-kinase/Akt signaling via Raptor-dependent mTOR (mammalian target of rapamycin)-mediated phosphorylation of insulin receptor substrate 1 (IRS-1). Raptor directly binds to and serves as a scaffold for mTOR-mediated phosphorylation of IRS-1 on Ser636/639. These serines lie close to the Y(632)MPM motif that is implicated in the binding of p85alpha/p110alpha PI3-kinase to IRS-1 upon insulin stimulation. Phosphomimicking mutations of these serines block insulin-stimulated activation of IRS-1-associated PI3-kinase. Knockdown of Raptor as well as activators of the LKB1/AMPK pathway, such as the widely used antidiabetic compound metformin, suppress IRS-1 Ser636/639 phosphorylation and reverse mTOR-mediated inhibition on PI3-kinase/Akt signaling. Thus, diabetes-related hyperglycemia hyperactivates the mTOR pathway and may lead to insulin resistance due to suppression of IRS-1-dependent PI3-kinase/Akt signaling.

Pubmed ID: 16354680


  • Tzatsos A
  • Kandror KV


Molecular and cellular biology

Publication Data

January 15, 2006

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK52057
  • Agency: NIDDK NIH HHS, Id: DK56736

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Cells, Cultured
  • Diabetes Mellitus, Type 2
  • Glucose
  • Humans
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Leucine
  • Mice
  • Monomeric GTP-Binding Proteins
  • Mutation
  • Neuropeptides
  • Phosphatidylinositol 3-Kinases
  • Phosphoproteins
  • Phosphorylation
  • Protein Kinases
  • Proteins
  • Proto-Oncogene Proteins c-akt
  • Rats
  • Serine
  • Signal Transduction
  • Sirolimus
  • TOR Serine-Threonine Kinases