Insulin reduces plasma arginase activity in type 2 diabetic patients.
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.


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.
Kashyap
Sangeeta R
SR
Department of Endocrinology, Diabetes and Metabolism, Cleveland Clinic, Cleveland, Ohio, USA. kashyas@ccf.org
Lara
Abigail
A
Zhang
Renliang
R
Park
Young Mi
YM
DeFronzo
Ralph A
RA
D000328:Adult; D001119:Arginase / Q000378:metabolism*; D001120:Arginine / Q000097:blood / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D002250:Carbon Radioisotopes; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology*; D005260:Female; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000627:therapeutic use*; D007527:Isoenzymes / Q000097:blood; D008297:Male; D008875:Middle Aged; D012016:Reference Values
D001786:Blood Glucose; D002250:Carbon Radioisotopes; D007328:Insulin; D007527:Isoenzymes; D001120:Arginine; D001119:Arginase