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Full-Text Articles in Medical Genetics
Increased Abundance Of The Receptor-Type Protein-Tyrosine Phosphatase Lar Accounts For The Elevated Insulin Receptor Dephosphorylating Activity In Adipose Tissue Of Obese Human Subjects, Falyaz Ahmad, Robert V. Considine, Barry J. Goldstein
Increased Abundance Of The Receptor-Type Protein-Tyrosine Phosphatase Lar Accounts For The Elevated Insulin Receptor Dephosphorylating Activity In Adipose Tissue Of Obese Human Subjects, Falyaz Ahmad, Robert V. Considine, Barry J. Goldstein
Department of Medicine Faculty Papers
Protein-tyrosine phosphatases (PTPases) have an essential role in the regulation of the steady-state phosphorylation of the insulin receptor and other proteins in the insulin signalling pathway. To examine whether increased PTPase activity is associated with adipose tissue insulin resistance in human obesity we measured PTPase enzyme activity towards the insulin receptor in homogenates of subcutaneous adipose tissue from a series of six lean and six nondiabetic, obese (body mass index > 30) subjects. The obese subjects had a mean 1.74-fold increase in PTPase activity (P < 0.0001) with a striking positive correlation by linear regression analysis between PTPase activity and body mass index among all of the samples (R = 0.918; P < 0.0001). The abundance of three candidate insulin receptor PTPases in adipose tissue was also estimated by immunoblot analysis. The most prominent increase was a 2.03-fold rise in the transmembrane PTPase LAR (P < 0.001). Of the three PTPase examined, only immunodepletion of LAR protein from the homogenates with neutralizing antibodies resulted in normalization of the PTPase activity towards the insulin receptor, demonstrating that the increase in LAR was responsible for the enhanced PTPase activity in the adipose tissue from obese subjects. These studies suggest that increased PTPase activity towards the insulin receptor is a pathogenetic factor in the insulin resistance of adipose tissue in human obesity and provide evidence for a potential role of the LAR PTPase in the regulation of insulin signalling in disease states.
Identification Of Persistent Defects In Insulin Receptor Structure And Function In Capillary Endothelial Cells From Diabetic Rats, Ching Fai Kwok, Barry J. Goldstein, Dirk Muller-Wieland, Tian-Shing Lee, C. Ronald Kahn, George L. King
Identification Of Persistent Defects In Insulin Receptor Structure And Function In Capillary Endothelial Cells From Diabetic Rats, Ching Fai Kwok, Barry J. Goldstein, Dirk Muller-Wieland, Tian-Shing Lee, C. Ronald Kahn, George L. King
Department of Medicine Faculty Papers
Insulin actions and receptors were studied in capillary endothelial cells cultured from diabetic BB rats and their nondiabetic colony mates. The endothelial cells from diabetic rats of 2 mo duration had persistent biological and biochemical defects in culture. Compared with normal rats, endothelial cells from diabetic rats grew 44% more slowly. Binding studies of insulin and insulin-like growth factor I (IGF-I) showed that cells from diabetic rats had 50% decrease of insulin receptor binding (nondiabetic: 4.6 +/- 0.7; diabetic: 2.6 +/- 0.4% per milligram protein, P < 0.01), which was caused by a 50% decrease in the number of binding sites per milligram protein, whereas IGF-I binding was not changed. Insulin stimulation of 2-deoxy-glucose uptake and alpha-aminoisobutyric acid uptake were also severely impaired with a 80-90% decrease in maximal stimulation, in parallel with a 62% decrease in insulin-stimulated autophosphorylation (P < 0.05). 125I-insulin cross-linking revealed an 140-kD alpha subunit of the insulin receptor similar to …