Exercise increases human skeletal muscle insulin sensitivity via coordinated increases in microvascular perfusion and molecular signaling

TY - JOUR

T1 - Exercise increases human skeletal muscle insulin sensitivity via coordinated increases in microvascular perfusion and molecular signaling

AU - Sjøberg, Kim Anker

AU - Frøsig, Christian

AU - Kjøbsted, Rasmus

AU - Sylow, Lykke

AU - Kleinert, Maximilian

AU - Betik, Andrew C

AU - Shaw, Christopher S

AU - Kiens, Bente

AU - Wojtaszewski, Jørgen

AU - Rattigan, Stephen

AU - Richter, Erik

AU - McConell, Glenn K

N1 - CURIS 2017 NEXS 138

PY - 2017/6/1

Y1 - 2017/6/1

N2 - 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 contrastenhanced ultrasound) by 65% in the exercised leg and 25% in the rested leg (P < 0.05) and that leg glucose uptake increased 50% more (P < 0.05) in the exercised leg than in the rested leg. Importantly, infusion of the nitric oxide synthase inhibitor L-NG-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 Ser318 and Ser704 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.

AB - 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 contrastenhanced ultrasound) by 65% in the exercised leg and 25% in the rested leg (P < 0.05) and that leg glucose uptake increased 50% more (P < 0.05) in the exercised leg than in the rested leg. Importantly, infusion of the nitric oxide synthase inhibitor L-NG-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 Ser318 and Ser704 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.

KW - Journal Article

U2 - 10.2337/db16-1327

DO - 10.2337/db16-1327

M3 - Journal article

C2 - 28292969

SN - 0012-1797

VL - 66

SP - 1501

EP - 1510

JO - Diabetes

JF - Diabetes

IS - 6

ER -