Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Cells, Cultured
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Diabetes Mellitus, Type 2 / metabolism*
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Glucose / metabolism*
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Glucose / pharmacology
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Humans
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Insulin / metabolism
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Insulin Receptor Substrate Proteins
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Leucine / metabolism
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Leucine / pharmacology
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Mice
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Monomeric GTP-Binding Proteins / metabolism
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Mutation
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Neuropeptides / metabolism
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphoproteins / analysis
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Phosphoproteins / genetics
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Phosphoproteins / metabolism*
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Phosphorylation / drug effects
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Protein Kinases / metabolism*
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Proteins / genetics
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Proteins / metabolism*
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Proto-Oncogene Proteins c-akt / metabolism*
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Ras Homolog Enriched in Brain Protein
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Rats
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Regulatory-Associated Protein of mTOR
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Serine / metabolism
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Signal Transduction / drug effects
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Sirolimus / pharmacology
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TOR Serine-Threonine Kinases
Substances
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Adaptor Proteins, Signal Transducing
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IRS1 protein, human
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Insulin
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Insulin Receptor Substrate Proteins
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Irs1 protein, mouse
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Irs1 protein, rat
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Neuropeptides
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Phosphoproteins
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Proteins
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RHEB protein, human
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RPTOR protein, human
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Ras Homolog Enriched in Brain Protein
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Regulatory-Associated Protein of mTOR
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Serine
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Protein Kinases
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MTOR protein, human
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mTOR protein, mouse
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mTOR protein, rat
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Monomeric GTP-Binding Proteins
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Leucine
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Glucose
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Sirolimus