Compensatory alterations for insulin signal transduction and glucose transport in insulin-resistant diabetes.
Insulin binding activates the receptor tyrosine kinase toward the insulin receptor substrate-1 (IRS-1). Phosphorylated IRS-1 then interacts with the p85 alpha subunit of phosphatidylinositol 3-kinase (PI3K), Nck, growth factor receptor-bound protein 2 (GRB2), and Syp, thus branching insulin's signal for both mitogenic and metabolic responses. To determine whether the expression of these proteins is altered in insulin resistance, the levels of these proteins were compared in adipose and liver tissues of nondiabetic mice and obese insulin-resistant diabetic KKAy mice. IR and PI3K p85 alpha protein levels were significantly lower in KKAy mice than in control nondiabetic mice, whereas IRS-1 protein levels were not altered. In contrast, the protein levels of GRB2, Nck, Syp, and GLUT-1 were dramatically elevated in KKAy fat, with less striking changes in liver. Treatment of diabetic animals with pioglitazone, an insulin-sensitizing antihyperglycemic agent, partially corrected the expression of some of these proteins. Taken together, these findings suggest that the insulin-resistant diabetic condition is characterized by changes in expression of insulin signal transduction components that may be associated with altered glucose metabolism.
D000222:Adaptation, Physiological; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001692:Biological Transport; D003920:Diabetes Mellitus / Q000235:genetics / Q000503:physiopathology*; D051380:GRB2 Adaptor Protein; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1; D006824:Hybridization, Genetic; D007328:Insulin / Q000502:physiology*; D007333:Insulin Resistance; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; D051272:Glucose Transporter Type 1; C495949:Grb2 protein, mouse; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D009004:Monosaccharide Transport Proteins; D011506:Proteins; D012333:RNA, Messenger; C495678:Slc2a1 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011972:Receptor, Insulin; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse; D005947:Glucose