Abstract 972: Insulin Lowers Plasma and Endothelial Asymmetric Dimethyl L-Arginine Levels
BACKGROUND: Insulin increases nitric oxide (NO) production, and augments blood flow in normal insulin sensitive subjects. This insulin effect is impaired in Type 2 diabetes (DM).
HYPOTHESIS: We hypothesized that this insulin effect might be, at least in part, due to lowering of asymmetric dimethyl L-arginine (ADMA), a naturally occurring inhibitor of nitric oxide synthase. We tested the hypothesis that insulin lowers ADMA concentrations at the level of the endothelium, as well as plasma, in normal insulin sensitive subjects, and that this insulin effect is blunted in DM.
METHODS: We studied a group of normal non-diabetic volunteers, (n= 6, age 34±3 years, BMI 28±4, LDL-cholesterol122±10mg/dl) as well as a group of BMI-matched DM subjects (n= 4, age 44±3 years, BMI 27±4, LDL-cholesterol 112±14mg/dl). Microvascular endothelial cells were isolated from subcutaneous adipose tissue biopsy samples. ADMA levels were measured (HPLC) in these endothelial cells as well as in plasma at baseline, and at steady state of a 240-minute euglycemic hyperinsulinemic clamp (120 mU/m2/min). Endothelial and plasma ADMA levels at steady-state hyperinsulinemia were compared with those at baseline, and the difference expressed as a percentage change from baseline.
RESULTS: Glucose and insulin levels at steady state were comparable in both groups. In the non-diabetic subjects, endothelial ADMA as well as plasma ADMA levels decreased by 52±10% (p<0.05) and 28±4% (p=0.01) respectively, in response to the euglycemic hyperinsulinemia. In contrast, in the DM subjects, there was no change in either the endothelial ADMA levels (480±690%; p=0.2) or the plasma ADMA levels (4±20%i; p=0.4) in response to euglycemic hyperinsulinemia.
CONCLUSIONS: The results of our studies indicate that insulin lowers plasma as well as endothelial cell ADMA levels in normal subjects and that this insulin effect is impaired in DM. The lowering of endothelial ADMA levels is likely to contribute to increased NO generation, and thus the insulin mediated vasodilation observed in response to hyperinsulinemia. Failure to lower endothelial ADMA levels in DM may contribute to impaired vascular function and to higher rates of cardiovascular disease in the DM subjects.