Context: Impairment of insulin-mediated capillary recruitment in skeletal muscle contributes to a hampered glucose uptake in obesity.

Objective: The objective of this study was to evaluate whether metacholine (MCh), a nitric oxide (NO) vasodilator, potentiates muscle capillary recruitment and forearm glucose uptake (FGU) during physiologic hyperinsulinemia.

Design: The double forearm technique (i.e. infused vs control forearm) was combined with intramuscular microdialysis during an OGTT in 15 non-diabetic, obese subjects divided into a group of insulin-resistant (IR; n=7) and insulin-sensitive (IS; n=8) individuals.

Results: Following the OGTT, forearm blood flow (FBF) in the control (Ctrl) forearm was unchanged, while it increased about threefold (p<0.0001 vs baseline) in response to MCh. Capillary permeability-surface area product for glucose (PS_glu) (capillary recruitment), FGU and interstitial (i) insulin concentrations rose significantly over time (p<0.001) in both forearms. Compared with IS, the IR subjects exhibited lower PS_glu (p<0.001) and FGU (p<0.01) in the Ctrl arm, while this difference was insignificant in the MCh arm despite the blunted FBF increase. Moreover, in IR individuals MCh significantly (p<0.05) ameliorated the delayed onset of insulin action i.e. the FGU response to hyperinsulinemia. Finally, we found PS_glu to be a strong and independent predictor of FGU response (R²adj. 0.72; p<0.0001).

Conclusions: Metacholine-induced vasodilation may improve the microvascular and metabolic responses to physiologic hyperinsulinemia in obese, IR individuals. Further studies are required to unravel whether stimulation of NO production in skeletal muscle may represent an attractive therapeutic approach to bypassing cellular resistance to glucose disposal.