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Systemic nitric oxide synthase inhibition increases insulin sensitivity in man
R Butler1, A D Morris, A D Struthers
1University Department of Clinical Pharmacology, Ninewells Hospital and Medical School, Dundee, U.K.
Abstract:
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 NG-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. NG-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 NG-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 NG-monomethyl L-arginine respectively (P = 0.036; 95% confidence interval 0.2,2.8). NG-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 NG-monomethyl L-arginine may explain the observed increase in whole-body glucose uptake.
Insights
Systemic nitric oxide synthase inhibition with NG-monomethyl L-arginine unexpectedly increased whole-body glucose uptake and skeletal muscle blood flow in healthy males. This challenges the hypothesis that nitric oxide inhibition decreases insulin sensitivity.
Area of Science:
- Physiology
- Metabolism
- Cardiovascular Science
Background:
- Skeletal muscle blood flow is a key determinant of insulin sensitivity.
- Insulin-mediated vasodilation relies on nitric oxide.
- Previous evidence suggests nitric oxide inhibition may impair insulin sensitivity.
Purpose of the Study:
- To investigate the direct effects of systemic nitric oxide synthase inhibition on insulin sensitivity and skeletal muscle blood flow in humans.
- To test the hypothesis that inhibiting nitric oxide reduces insulin sensitivity.
Main Methods:
- A randomized, double-blind, placebo-controlled, crossover study involving 16 healthy males.
- Systemic nitric oxide synthase inhibition using NG-monomethyl L-arginine (NMA).
- Assessment of whole-body glucose uptake via euglycaemic hyperinsulinaemic clamp and calf blood flow using venous occlusion plethysmography.
Main Results:
- NMA infusion caused a pressor effect and a negative chronotropic response.
- Whole-body glucose uptake significantly increased following NMA infusion (P = 0.036).
- Calf blood flow was also significantly elevated with NMA compared to placebo (P < 0.05).
Conclusions:
- Systemic inhibition of nitric oxide synthesis paradoxically increases whole-body glucose uptake.
- Increased skeletal muscle blood flow following NMA may mediate the enhanced glucose uptake.
- These findings challenge the established link between nitric oxide inhibition and decreased insulin sensitivity.