ALTERATIONS IN SKELETAL-MUSCLE PROTEIN-TYROSINE-PHOSPHATASE ACTIVITY AND EXPRESSION IN INSULIN-RESISTANT HUMAN OBESITY AND DIABETES

Obese human subjects have increased protein-tyrosine phosphatase (PTPa se) activity in adipose tissue that can dephosphorylate and inactivate the insulin receptor kinase, To extend these findings to skeletal mus cle, we measured PTPase activity in the skeletal muscle particulate fr action and cytosol from a series of lean controls, insulin-resistant o bese (body mass index > 30) nondiabetic subjects, and obese individual s with non-insulin-dependent diabetes. PTPase activities in subcellula r fractions from the nondiabetic obese subjects were increased to 140- 170% of the level in lean controls (P < 0.05), In contrast, PTPase act ivity in both fractions from the obese subjects with non-insulin-depen dent diabetes was significantly decreased to 39% of the level in contr ols (P < 0.05), By immunoblot analysis, leukocyte antigen related (LAR ) and protein-tyrosine phosphatase 1B had the greatest increase (three fold) in the particulate fraction from obese, nondiabetic subjects, an d immunodepletion of this fraction using an affinity-purified antibody directed at the cytoplasmic domain of leukocyte antigen related norma lized the PTPase activity when compared to the activity from control s ubjects, These findings provide further support for negative regulatio n of insulin action by specific PTPases in the pathogenesis of insulin resistance in human obesity, while other regulatory mechanisms may be operative in the diabetic state.