Nitric oxide is required for the insulin sensitizing effects of contraction in mouse skeletal muscle.

Xinmei Zhang,Danielle Hiam,Stephen Rattigan,Glenn K Mcconell,Alan Hayes,Anthony Zulli,Yet‐Hoi Hong

doi:10.1113/jp275133

Abstract

People with insulin resistance or type 2 diabetes can substantially increase their skeletal muscle glucose uptake during exercise and insulin sensitivity after exercise. Skeletal muscle nitric oxide (NO) is important for glucose uptake during exercise, although how prior exercise increases insulin sensitivity is unclear. In the present study, we examined whether NO is necessary for normal increases in skeletal muscle insulin sensitivity after contraction ex vivo in mouse muscle. The present study uncovers, for the first time, a novel role for NO in the insulin sensitizing effects of ex vivo contraction, which is independent of blood flow. The factors regulating the increase in skeletal muscle insulin sensitivity after exercise are unclear. We examined whether nitric oxide (NO) is required for the increase in insulin sensitivity after ex vivo contractions. Isolated C57BL/6J mouse EDL muscles were contracted for 10min or remained at rest (basal) with or without the NO synthase (NOS) inhibition (NG -monomethyl-l-arginine; l-NMMA; 100μm). Then, 3.5h post contraction/basal, muscles were exposed to saline or insulin (120μUml-1 ) with or without l-NMMA during the last 30min. l-NMMA had no effect on basal skeletal muscle glucose uptake. The increase in muscle glucose uptake with insulin (57%) was significantly (P<0.05) greater after prior contraction (140% increase). NOS inhibition during the contractions had no effect on this insulin-sensitizing effect of contraction, whereas NOS inhibition during insulin prevented the increase in skeletal muscle insulin sensitivity post-contraction. Soluble guanylate cyclase inhibition, protein kinase G (PKG) inhibition or cyclic nucleotide phosphodiesterase inhibition each had no effect on the insulin-sensitizing effect of prior contraction. In conclusion, NO is required for increases in insulin sensitivity several hours after contraction of mouse skeletal muscle via a cGMP/PKG independent pathway.

Highlights

Increased physical activity is important for both the prevention and management of type 2 diabetes (T2D) (Wojtaszewski & Richter, 2006)
As previously reported (Gao et al, 1994), a serum factor is required for an increase in insulin sensitivity after ex vivo rat skeletal muscle contraction, and we found that serum alone has no effect on mouse skeletal muscle glucose uptake at rest (Levinger et al, 2016).Whether serum is required during ex vivo contraction of mouse skeletal muscle for increases in insulin-stimulated glucose uptake has not previously been examined
In contrast to our hypothesis, NO synthase (NOS) inhibition during contraction had no effect on insulin-stimulated glucose uptake 3.5 hrs later

Summary

Introduction

Increased physical activity is important for both the prevention and management of type 2 diabetes (T2D) (Wojtaszewski & Richter, 2006). After the initial insulin-independent increases in glucose uptake post-contraction have worn off in 2-3 hrs (Gao et al, 1994; Funai et al, 2010), skeletal muscle remains more sensitive to insulin for 24-48 hrs in both rodents (Cartee et al, 1989) and humans (Mikines et al, 1988). Acute exercise increases skeletal muscle insulin sensitivity in both people with T2D and matched controls (Devlin et al, 1987). Insulin activates insulin signalling pathways in skeletal muscle which results in GLUT-4 translocation to the plasma membrane and increased glucose transport. Even though there are increases in insulin-stimulated glucose uptake after acute contraction or exercise, there is little evidence of greater proximal insulin signalling (Wojtaszewski et al, 2000; Wojtaszewski & Richter, 2006). There are indications that more distal insulin signalling may be increased by acute exercise

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