Mechanisms for greater insulin-stimulated glucose uptake in normal and insulin-resistant skeletal muscle after acute exercise

Abstract

Enhanced skeletal muscle and whole body insulin sensitivity can persist for up to 24 -48 h after one exercise session. This review focuses on potential mechanisms for greater postexercise and insulinstimulated glucose uptake (ISGU) by muscle in individuals with normal or reduced insulin sensitivity. A model is proposed for the processes underlying this improvement; i.e., triggers initiate events that activate subsequent memory elements, which store information that is relayed to mediators, which translate memory into action by controlling an end effector that directly executes increased insulin-stimulated glucose transport. Several candidates are potential triggers or memory elements, but none have been conclusively verified. Regarding potential mediators in both normal and insulin-resistant individuals, elevated postexercise ISGU with a physiological insulin dose coincides with greater Akt substrate of 160 kDa (AS160) phosphorylation without improved proximal insulin signaling at steps from insulin receptor binding to Akt activity. Causality remains to be established between greater AS160 phosphorylation and improved ISGU. The end effector for normal individuals is increased GLUT4 translocation, but this remains untested for insulin-resistant individuals postexercise. Following exercise, insulin-resistant individuals can attain ISGU values similar to nonexercising healthy controls, but after a comparable exercise protocol performed by both groups, ISGU for the insulin-resistant group has been consistently reported to be below postexercise values for the healthy group. Further research is required to fully understand the mechanisms underlying the improved postexercise ISGU in individuals with normal or subnormal insulin sensitivity and to explain the disparity between these groups after similar exercise. insulin sensitivity; physical activity; glucose transporter 4; AMP-activated protein kinase; Akt substrate of 160 kDa Importance of Insulin-Stimulated Glucose Uptake by Skeletal MuscleUNDERSTANDING THE MECHANISMS regulating insulin-stimulated glucose uptake by skeletal muscle is important because 1) muscle accounts for most insulin-mediated glucose disposal (21) and 2) muscle insulin resistance is a key defect in the progression to type 2 diabetes mellitus (20,43,97). Even in nondiabetic individuals, insulin resistance increases the risk for atherogenesis, cardiovascular disease, hypertension, cognitive dysfunction, and some cancers (27,45,69).Insulin and exercise can independently increase glucose uptake secondary to redistribution of GLUT4 glucose transporters from the cell interior to cell surface membranes (CSM) (19,25,93). Elevated insulin-independent glucose uptake during exercise is mostly reversed by ϳ2-3 h postexercise, whereas enhanced muscle and whole body insulin sensitivity, detectable at ϳ1-4 h postexercise, can persist for up to 24 -48 h (1, 12, 13, 79, 88, 92, 124).Exercise capacity is related to muscle glycogen availability, and glycogen stores are diminished by vigorous exercise (59). Increase...

Exercise training prevents skeletal muscle plasma membrane cholesterol accumulation, cortical actin filament loss, and insulin resistance in C57BL/6J mice fed a western-style high-fat diet

“…Here we similarly found that these HF‐fed skeletal muscle membrane/cytoskeletal abnormalities and insulin resistance were improved in exercised mice, and that these exercised mice showed improved glucose tolerance. While it is possible that the beneficial effects we measured could be attributed to a lingering insulin‐mimetic action of exercise, studies suggest that acute exercise‐stimulated glucose transport is mostly reversed by ~2‐3 h postexercise (Cartee 2015b). Regardless, our studies reveal that an aspect of skeletal muscle insulin resistance improved by exercise, whether acute, chronic, or a combination of both, is membrane/cytoskeletal defects that impair GLUT4 regulation by insulin.…”

“…In addition to this favorable effect of exercise on mitigating PM cholesterol accumulation/toxicity, other processes underlying increased insulin sensitivity postexercise could exist. For example, several studies raise the possibility that lower glycogen and/or sustained insulin‐independent AS160 phosphorylation postexercise might sensitize skeletal muscle to insulin (reviewed in (Cartee 2015b)). While we did not measure glycogen or AS160 phosphorylation, the importance of decreased glycogen and/or increased AS160 activity toward enhanced insulin‐sensitivity is unclear (Cartee 2015b).…”

“…For example, several studies raise the possibility that lower glycogen and/or sustained insulin‐independent AS160 phosphorylation postexercise might sensitize skeletal muscle to insulin (reviewed in (Cartee 2015b)). While we did not measure glycogen or AS160 phosphorylation, the importance of decreased glycogen and/or increased AS160 activity toward enhanced insulin‐sensitivity is unclear (Cartee 2015b). Ex vivo and in situ analyses demonstrate that glycogen reduction and enhanced insulin sensitivity are not correlated (Cartee 2015b).…”

“…Throughout the 1‐wk familiarization and 2‐wk exercise intervention, mice were maintained on either their LF‐ or HF‐diets. Following the last sham‐exercise or exercise session, mice were fasted for 5‐6 h before analyses, a time when elevated insulin‐independent glucose uptake during exercise is mostly reversed; that is, ~2‐3 h postexercise (Cartee 2015b). …”

“…More pertinent to studies conducted in this report is that exercise increases skeletal muscle insulin sensitivity by poorly understood local changes in insulin action and GLUT4 functionality (Holloszy 2005; Maarbjerg et al. 2011; Cartee 2015b). For example, animal and human studies report that exercise increases insulin sensitivity without a simultaneous increase in proximal insulin signaling (Goodyear et al.…”