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Insulin Reduces Plasma Arginase Activity in Type 2 Diabetic Patients

¹ Department of Endocrinology, Diabetes and Metabolism, Cleveland Clinic, Cleveland, Ohio
² Department of Cell Biology, Lerner Institute, Cleveland Clinic, Cleveland, Ohio
³ Diabetes Division, University of Texas Health Science Center, San Antonio, Texas

Address correspondence and reprint requests to Sangeeta R. Kashyap, MD, 9500 Euclid Ave., Cleveland, OH 44195. E-mail: kashyas{at}ccf.org

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 [¹⁴C] guanidoinoarginine to [¹⁴C] 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 · min^–1 · 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 µmol · ml^–1 · h^–1; P < 0.05) and markedly declined in diabetic subjects with 4-h insulin infusion (to 0.13 ± 0.04 µmol · ml^–1 · 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.

Abbreviations: ADMA, asymmetric dimethylarginine • NOS, nitric oxide synthase

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