Exercise Increases Human Skeletal Muscle Insulin Sensitivity via Coordinated Increases in Microvascular Perfusion and Molecular Signaling

Abstract

Insulin resistance is a major health risk, and although exercise clearly improves skeletal muscle insulin sensitivity, the mechanisms are unclear. Here we show that initiation of a euglycemic-hyperinsulinemic clamp 4 h after single-legged exercise in humans increased microvascular perfusion (determined by contrast-enhanced ultrasound) by 65% in the exercised leg and 25% in the rested leg ( < 0.05) and that leg glucose uptake increased 50% more ( < 0.05) in the exercised leg than in the rested leg. Importantly, infusion of the nitric oxide synthase inhibitor l--monomethyl-l-arginine acetate (l-NMMA) into both femoral arteries reversed the insulin-stimulated increase in microvascular perfusion in both legs and abrogated the greater glucose uptake in the exercised compared with the rested leg. Skeletal muscle phosphorylation of TBC1D4 Ser and Ser and glycogen synthase activity were greater in the exercised leg before insulin and increased similarly in both legs during the clamp, and l-NMMA had no effect on these insulin-stimulated signaling pathways. Therefore, acute exercise increases insulin sensitivity of muscle by a coordinated increase in insulin-stimulated microvascular perfusion and molecular signaling at the level of TBC1D4 and glycogen synthase in muscle. This secures improved glucose delivery on the one hand and increased ability to take up and dispose of the delivered glucose on the other hand.

Insulin‐induced membrane permeability to glucose in human muscles at rest and following exercise

“…Furthermore, if NOS inhibition decreased skeletal muscle glucose uptake by reducing the amount of insulin delivered to the skeletal muscle cells, then NOS inhibition would be expected to reduce glucose uptake also in the rested leg, which was not the case in either our previous (Sjoberg et al . ) or our current study.…”

“…l ‐NMMA co‐infusion during the EHC did not affect the muscle membrane permeability to glucose (rested leg: 16.4 ± 2.2; exercised leg 43.3 ± 11.5 ml min −1 kg −1 ), which is in line with our previous observation that NOS inhibition during a EHC has no effect on the greater activation of skeletal muscle insulin signalling by exercise (Sjoberg et al . ). ATP co‐infusion during the last part of the EHC also had no significant effect of muscle membrane permeability to glucose compared with the clamp alone.…”

“…Indeed, muscle membrane permeability to glucose was unchanged with NOS inhibition and ATP infusion in the two legs, which fits with our previous study showing that these treatments affect glucose uptake by altering blood flow rather than insulin signalling (Sjoberg et al . ). Conversely, when increasing LBF in the fasted state in insulin‐resistant type 2 diabetic patients where LGU is low due to a low glucose extraction across the leg, the effect of increasing LBF on LGU was not apparent (Henstridge et al .…”

“…, ; Sjoberg et al . , , ) is likely important to prevent draining the interstitial space of glucose when muscle membrane permeability increases, but whether supply becomes limiting for maintaining the interstitial muscle glucose concentration is not known. The increase in muscle membrane permeability with insulin and exercise is generally thought to be the result of translocation of GLUT4 glucose transporters to the cell membrane and t‐tubules (Wilson & Cushman, ; Lund et al .…”

Lifestyle Medicine: An Answer to Type 2 Diabetes Pandemics?

“…Estos últimos trabajos citados no han incluido intervención en los niveles de actividad física de sus participantes para facilitar el posterior análisis de los resultados. Es necesario mencionar que en lo que se refiere a la actividad física existe un cuerpo sólido de evidencia que demuestra que la actividad muscular disminuye la resistencia central, periférica y vascular a la insulina logrando mejorías significativas en la función pancreática y en el grado de control de la enfermedad 14,15 .…”