Marked impairment of protein tyrosine phosphatase 1B activity in adipose tissue of obese subjects with and without type 2 diabetes mellitus

Protein tyrosine phosphatases (PTPs) are required for the dephosphorylation of the insulin receptor (IR) and its initial cellular substrates, and it h as recently been reported that PTP-1B may play a role in the pathogenesis o f insulin resistance in obesity and type 2 diabetes mellitus (DM), We there fore determined the amount and activity of PTP-1B in abdominal adipose tiss ue obtained from lean nondiabetic subjects (lean control (LC)), obese nondi abetic subjects (obese control (OC)), and subjects with both type 2 DM (DM2 ) and obesity (obese diabetic (OD)), PTP-1B protein levels were 3-fold high er in OC than in LC (1444 +/- 195 U vs 500 +/- 146 U (mean +/- SEM), P < .0 15), while OD exhibited a 5.5-fold increase (2728 +/- 286 U, P < .01), PTP activity was assayed by measuring the dephosphorylating activity toward a p hosphorus 32-labeled synthetic dodecapeptide, In contrast to the increased PTP-1B protein levels, PTP-1B activity per unit of PTP-1B protein was marke dly reduced, by 71% and 88% in OC and On, respectively. Non-PTP-1B tyrosine phosphatase activity was comparable in all three groups. Similar results w ere obtained when PTP-1B activity was measured against intact human IR, A s ignificant correlation was found between body mass index (BMI) and PTP-1B l evel (r = 0.672, P < .02), whereas BMI and PTP-1B activity per unit of PTP- 1B showed a strong inverse correlation (r = -0.801, P < .002). These data s uggest that the insulin resistance of obesity and DM2 is characterized by t he increased expression of a catalytically impaired PTP-1B in adipose tissu e and that impaired PTP-1B activity may be pathogenic for insulin resistanc e in these conditions.