Abstract
OBJECTIVE: We sought to determine whether dysregulation of arginine metabolism is related to insulin resistance and underlies impaired nitric oxide (NO) generation in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: We measured plasma arginase activity, arginine metabolites, and skeletal muscle NO synthase (NOS) activity in 12 type 2 diabetic and 10 age-/BMI-matched nondiabetic subjects before and following a 4-h euglycemic-hyperinsulinemic clamp with muscle biopsies. Arginine metabolites were determined by tandem mass spectroscopy. Arginase activity was determined by conversion of [(14)C] guanidoinoarginine to [(14)C] urea. RESULTS: Glucose disposal (R(d)) was reduced by 50% in diabetic versus control subjects. NOS activity was fourfold reduced in the diabetic group (107 +/- 45 vs. 459 +/- 100 pmol x min(-1) x mg protein(-1); P < 0.05) and failed to increase with insulin. Plasma arginase activity was increased by 50% in the diabetic versus control group (0.48 +/- 0.11 vs. 0.32 +/- 0.12 micromol x ml(-1) x h(-1); P < 0.05) and markedly declined in diabetic subjects with 4-h insulin infusion (to 0.13 +/- 0.04 micromol x ml(-1) x h(-1) vs. basal; P < 0.05). In both groups collectively, plasma arginase activity correlated positively with fasting plasma glucose (R = 0.46, P < 0.05) and A1C levels (R = 0.51, P < 0.02) but not with R(d). CONCLUSIONS: Plasma arginase activity is increased in type 2 diabetic subjects with impaired NOS activity, correlates with the degree of hyperglycemia, and is reduced by physiologic hyperinsulinemia. Elevated arginase activity may contribute to impaired NO generation in type 2 diabetes, and insulin may ameliorate this defect via reducing arginase activity.