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

Glenn K Mcconell,Erik A Richter,Jørgen F P Wojtaszewski,Michael Nyberg,Christian Frøsig,Lasse Gliemann,Kim A Sjøberg,Ylva Hellsten,Bente Kiens,Frederik Ceutz

doi:10.1113/jp278600

Glenn K Mcconell, Erik A Richter + Show 8 more

Open Access

https://doi.org/10.1113/jp278600

Copy DOI

Abstract

Increased insulin action is an important component of the health benefits of exercise, but its regulation is complex and not fully elucidated. Previous studies of insulin-stimulated GLUT4 translocation to the skeletal muscle membrane found insufficient increases to explain the increases in glucose uptake. By determination of leg glucose uptake and interstitial muscle glucose concentration, insulin-induced muscle membrane permeability to glucose was calculated 4h after one-legged knee-extensor exercise during a submaximal euglycaemic-hyperinsulinaemic clamp. It was found that during submaximal insulin stimulation, muscle membrane permeability to glucose in humans increases twice as much in previously exercised vs. rested muscle and outstrips the supply of glucose, which then becomes limiting for glucose uptake. This methodology can now be employed to determine muscle membrane permeability to glucose in people with diabetes, who have reduced insulin action, and in principle can also be used to determine membrane permeability to other substrates or metabolites. Increased insulin action is an important component of the health benefits of exercise, but the regulation of insulin action in vivo is complex and not fully elucidated. Previously determined increases in skeletal muscle insulin-stimulated GLUT4 translocation are inconsistent and mostly cannot explain the increases in insulin action in humans. Here we used leg glucose uptake (LGU) and interstitial muscle glucose concentration to calculate insulin-induced muscle membrane permeability to glucose, a variable not previously possible to quantify in humans. Muscle membrane permeability to glucose, measured 4h after one-legged knee-extensor exercise, increased ∼17-fold during a submaximal euglycaemic-hyperinsulinaemic clamp in rested muscle (R) and ∼36-fold in exercised muscle (EX). Femoral arterial infusion of NG -monomethyl l-arginine acetate or ATP decreased and increased, respectively, leg blood flow (LBF) in both legs but did not affect membrane glucose permeability. Decreasing LBF reduced interstitial glucose concentrations to ∼2mM in the exercised but only to ∼3.5mM in non-exercised muscle and abrogated the augmented effect of insulin on LGU in the EX leg. Increasing LBF by ATP infusion increased LGU in both legs with uptake higher in the EX leg. We conclude that it is possible to measure functional muscle membrane permeability to glucose in humans and it increases twice as much in exercised vs. rested muscle during submaximal insulin stimulation. We also show that muscle perfusion is an important regulator of muscle glucose uptake when membrane permeability to glucose is high and we show that the capillary wall can be a significant barrier for glucose transport.

Highlights

Insulin stimulates greater skeletal muscle glucose uptake via increased glucose delivery, muscle membrane glucose transport and molecular signaling which increases the metabolism of glucose
Considering that the whole leg is drained by the femoral vein and that only the quadriceps femoris muscle is active during kneeextensions (Andersen et al, 1985), it seems reasonable to assume that the increased leg glucose uptake (LGU) in the previously exercised leg is due solely to increased uptake in the quadriceps and that the rest of the muscles in the exercised leg display glucose uptake similar to uptake in the contralateral rested leg
We further show that skeletal muscle membrane permeability increases remarkably during insulin stimulation (17-fold) and this was more than two times as high in the exercised leg compared with the rested leg

Summary

Introduction

Insulin stimulates greater skeletal muscle glucose uptake via increased glucose delivery, muscle membrane glucose transport and molecular signaling which increases the metabolism of glucose. 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 ttubules (Wilson & Cushman, 1994; Lund et al, 1995; Kennedy et al, 1999; Ryder et al, 2000; Bryant et al, 2002; Koistinen et al, 2003). Surface labelling studies have produced ~8 fold increases in cell surface GLUT-4 and glucose transport with insulin in rat muscle (Wilson & Cushman, 1994; Lund et al, 1995), 5.7 fold in human muscle (Ryder et al, 2000) and 2.1 fold in human muscle strips (Koistinen et al, 2003). Studies using differential centrifugation to isolate plasma membranes indicate that insulin increases skeletal muscle plasma membrane GLUT4 by ~2-fold (100%) in both rats (Sternlicht et al, 1988; Goodyear et al, 1990; Hirshman et al, 1990; Klip & Paquet, 1990; Marette et al, 1992; Lund et al, 1993; Dombrowski et al, 1998) and humans (Goodyear et al, 1996; Thorell et al, 1999) which is a lot less that the 3-5 fold increase observed in glucose transport in the same systems (Sternlicht et al, 1988; Hirshman et al, 1990; Thorell et al, 1999)

Methods

Results

Conclusion