l-arginine but not d-arginine stimulates insulin-mediated glucose uptake

Our study aims at investigating a possible role for l-arginine and d-arginine in insulin-mediated glucose uptake. Twelve lean healthy subjects volunteered for the study and were submitted to three euglycemic-hyperinsulinemic glucose clamps to investigate the effect of l-arginine (0.5 g/min in the last 60 minutes of the clamp), d-arginine (0.5 g/min in the last 60 minutes of the clamp), and saline 0.9% NaCl on insulin-mediated glucose uptake. All tests were made in random order. In study 1, l-arginine versus saline infusion was associated with a significant increase in blood flow (131% ± 7% v 87% ± 5%, P < .001) and whole-body glucose disposal ([WBGD] 61.4 ± 4.4 v 41.3 ± 3.5 μmol/kg fat-free mass [FFM] · min, P < .001). Analysis of substrate oxidation demonstrated that both oxidative and nonoxidative glucose metabolism was improved by l-arginine delivery. After adjustment for the change in blood flow, WBGD was still greater after l-arginine than after saline infusion. Along with l-arginine infusion and independently of the change in blood flow, the percent change in WBGD correlated with the percent change in plasma cGMP ( r = .56, P < .05). d-Arginine infusion did not affect insulin-mediated glucose uptake. In particular, WBGD (42.1 ± 3.4 v 41.3 ± 3.5 μmol/kg FFM · min, P = NS) was similar in both experimental conditions. Basal levels (2.8 ± 0.2 v 2.7 ± 0.3 nmol/L, P = NS) and the insulin-mediated increase (43% ± 5% v 39% ± 4%, P = NS) in plasma cGMP were also superimposable along with insulin plus d-arginine and insulin alone, respectively. Finally, blood flow (224 ± 29 v 230 ± 35 mL/min, P = NS) was not different at baseline and was similarly stimulated (84% ± 4% v 87% ± 5%, P = NS) by insulin infusion. In conclusion, l-arginine but not d-arginine stimulates insulin-mediated glucose uptake. Nitric oxide (NO), the metabolic mediator for l-arginine, potentiates insulin-mediated glucose uptake through the increase in blood flow. Nevertheless, an independent effect of intracellular cGMP on WBGD cannot be ruled out.