Systemic Nitric Oxide Synthase Inhibition Increases Insulin Sensitivity in Man

1. Recent evidence shows that skeletal muscle blood flow is an important determinant of insulin sensitivity and that insulin-mediated vasodilatation is nitric oxide dependent. These results have given rise to the hypothesis that endothelial nitric oxide inhibition may decrease insulin sensitivity in humans.

2. We examined this hypothesis directly by evaluating the effects of systemic nitric oxide synthase inhibition with N^G-monomethyl l-arginine (3 mg h⁻¹ kg⁻¹) on whole-body glucose uptake (euglycaemic hyperinsulinaemic clamp) and calf blood flow (bilateral calf venous occlusion plethysmography) in 16 healthy male subjects in a randomized, double-blind, placebo-controlled, crossover study.

3. N^G-Monomethyl l-arginine infusion was associated with a pressor effect (119/61 ± 2/2 compared with 114/58 ± 2/2 mmHg for placebo; P < 0.001), and a negative chronotropic response (57 ± 2 compared with 62 ± 2 beats/min for placebo; P < 0.001). The glucose infusion rate was significantly increased after infusion of N^G-monomethyl l-arginine (8.9 ± 0.9 compared with 7.9 ± 0.8 mg min⁻¹ kg⁻¹ for placebo; P = 0.002). Whole-body glucose uptake increased during the clamp, with values of 9.4 ± 0.7 and 10.9 ± 0.8 mg min⁻¹ kg⁻¹ for placebo and N^G-monomethyl l-arginine respectively (P = 0.036; 95% confidence interval 0.2,2.8). N^G-Monomethyl l-arginine was associated with increased calf blood flow by comparison with placebo (P < 0.05, area under curve).

4. These data show for the first time that systemic inhibition of nitric oxide synthesis increases rather than decreases whole-body glucose uptake. We suggest that the higher skeletal muscle blood flow seen after N^G-monomethyl l-arginine may explain the observed increase in whole-body glucose uptake.