Abstract
Insulin regulates glucose homeostasis by binding and activating the insulin receptor, and defects in insulin responses (insulin resistance) induce type 2 diabetes. SH2-B, an Src homology 2 (SH2) and pleckstrin homology domain-containing adaptor protein, binds via its SH2 domain to insulin receptor in response to insulin; however, its physiological role remains unclear. Here we show that SH2-B was expressed in the liver, skeletal muscle, and fat. Systemic deletion of SH2-B impaired insulin receptor activation and signaling in the liver, skeletal muscle, and fat, including tyrosine phosphorylation of insulin receptor substrate 1 (IRS1) and IRS2 and activation of the phosphatidylinositol 3-kinase/Akt and the Erk1/2 pathways. Consequently, SH2-B-/- knockout mice developed age-dependent hyperinsulinemia, hyperglycemia, and glucose intolerance. Moreover, SH2-B directly enhanced autophosphorylation of insulin receptor and tyrosine phosphorylation of IRS1 and IRS2 in an SH2 domain-dependent manner in cultured cells. Our data suggest that SH2-B is a physiological enhancer of insulin receptor activation and is required for maintaining normal insulin sensitivity and glucose homeostasis during aging.
Copyright 2004 American Society for Microbiology
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Adipose Tissue / metabolism
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Aging / physiology*
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Animals
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Blood Glucose / metabolism
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Carrier Proteins / genetics*
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Carrier Proteins / metabolism*
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Cell Line
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Dietary Fats
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Glucose Intolerance*
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Homeostasis
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Humans
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Insulin / metabolism
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Insulin Receptor Substrate Proteins
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Insulin Resistance / physiology*
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Intracellular Signaling Peptides and Proteins
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Islets of Langerhans / cytology
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Islets of Langerhans / metabolism
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Islets of Langerhans / pathology
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Liver / metabolism
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Male
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Mice
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Mice, Inbred Strains
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Mice, Knockout
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Mitogen-Activated Protein Kinases / metabolism
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Muscle, Skeletal / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoproteins / metabolism
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Receptor, Insulin / metabolism
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Signal Transduction / physiology
Substances
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Adaptor Proteins, Signal Transducing
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Blood Glucose
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Carrier Proteins
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Dietary Fats
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IRS1 protein, human
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IRS2 protein, human
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Insulin
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Insulin Receptor Substrate Proteins
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Intracellular Signaling Peptides and Proteins
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Irs1 protein, mouse
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Irs2 protein, mouse
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Phosphoproteins
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Proto-Oncogene Proteins
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SH2B1 protein, human
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Sh2bpsm1 protein, mouse
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Receptor, Insulin
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinases