Exercise and GLUT4

Abstract

The glucose transporter GLUT4 is critical for skeletal muscle glucose uptake in response to insulin and muscle contraction/exercise. Exercise increases GLUT4 translocation to the sarcolemma and t-tubule and, over the longer term, total GLUT4 protein content. Here, we review key aspects of GLUT4 biology in relation to exercise, with a focus on exercise-induced GLUT4 translocation, postexercise metabolism and muscle insulin sensitivity, and exercise effects on GLUT4 expression.

Exercise as a Therapeutic Intervention in Gestational Diabetes Mellitus

“…Specifically, during exercise, the redistribution of GLUT4 glucose transporters from the cell interior to the cell surface facilitates glucose uptake by two separate, but additive pathways (Figure 1) [22,[24][25][26][29][30][31][32]. The first pathway is the insulin-dependent pathway that begins with insulin binding to its receptor (IRS) and the phosphorylation of intracellular tyrosine residues in IRS.…”

“…PI3P activates the protein kinase B isoform (Akt) and the protein kinase C (aPKC) and triggers the translocation of GLUT4 to the cell membrane [33]. The second pathway that facilitates glucose uptake during exercise is a non-insulin dependent pathway which is mediated by several cellular events related to muscle contraction per se [22,25,28,29]. Potential signals mediating this exercise-induced GLUT4 translocation include: (a) the release of Ca 2+ by the sarcoplasmic reticulum to be used for muscle contraction, which causes an increase in intracellular Ca 2+ concentration and activates the Ca 2+ /calmodulin-dependent protein kinase (CaMK), (b) the reduction in the ATP/ADP ratio and the activation of AMP-protein kinase (AMPK), and (c) the transient increase in oxidative stress [28,34,35].…”

Regulation of nutrient uptake by AMP-activated protein kinase

“…Once exercise/contraction ceases, muscle glucose uptake returns slowly to basal levels [136,139] and during the recovery period insulin sensitivity is increased [136,137]. It is clear that contraction-stimulated glucose transport is mediated by GLUT4 translocation from intracellular compartments, phenocopying the effects of insulin, yet the initial signalling pathways utilised by insulin and contraction are different [92, 105,134,[140][141][142].…”

“…Several potential mediators of contraction-stimulated glucose uptake have been proposed, including Ca 2+ , AMPK (see section 2.4), NO, reactive oxygen species (ROS) and Rac1 [136,137]. In particular, NO synthesis has been demonstrated to be required for increased skeletal muscle glucose uptake during contraction since inhibition of NO synthesis attenuates contraction-mediated glucose uptake in skeletal muscle [144,145].…”

“…As Rac1 is also implicated in insulin-stimulated glucose uptake [130,131], this suggests that Rac1 activation might be one distal convergence point between insulin-and contraction-activated signalling pathways, although Rac1 has been reported to be unnecessary for contraction-mediated increases in insulin sensitivity following exercise [147]. In addition, capillary recruitment in muscle during contraction increases the supply of glucose for transport, thereby increasing glucose uptake in vivo [136,137]. Given that contraction mimics the effects of insulin yet occurs independently of insulin signalling, the signalling underlying contraction-stimulated glucose uptake is an area of significant interest for therapies to normalise blood glucose in people with type 2 diabetes or insulin resistance.…”