Disruption of the SH2-B gene causes age-dependent insulin resistance and glucose intolerance.
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.
Duan
Chaojun
C
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109-0622, USA.
Yang
Hongyan
H
White
Morris F
MF
Rui
Liangyou
L
D048868:Adaptor Proteins, Signal Transducing; D000273:Adipose Tissue / Q000378:metabolism; D000375:Aging / Q000502:physiology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D004041:Dietary Fats; D018149:Glucose Intolerance; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D001786:Blood Glucose; D002352:Carrier Proteins; D004041:Dietary Fats; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin; C526292:IRS1 protein, human; C526297:IRS2 protein, human; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; C518910:SH2B1 protein, human; C115327:Sh2bpsm1 protein, mouse; C494918:AKT1 protein, human