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 insulin-stimulated 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.

Keywords: AMP-activated protein kinase; Akt substrate of 160 kDa; glucose transporter 4; insulin sensitivity; physical activity.

Fig. 1.

Acute exercise leads to subsequently elevated insulin-stimulated glucose uptake by skeletal muscle in multiple species, including rats and humans. A: glucose uptake by insulin-stimulated perfused rat hindlimb muscle is greater ∼1 h after treadmill running (45-min duration) compared with muscle from nonexercising control rats. Redrawn from Richter et al. (92). B: glucose uptake by insulin-stimulated human thigh muscle is greater ∼6 to 10 h after 1-legged knee extension exercise (60-min duration) compared with nonexercising contralateral muscle. Redrawn from Richter et al. (94).

Fig. 2.

Insulin-signaling pathway for insulin-stimulated GLUT4 translocation and glucose transport in skeletal muscle. IRS-1, insulin receptor substrate-1; PI3K; phosphatidylinositol 3-kinase; PIP2, phosphatidylinositol 2-phosphate; PIP3, phosphatidylinositol-3,4,5-trisphosphate; PAK1, p21-activated kinase 1; PDK1, phosphoinositide kinase-1; mTORC2, mechanistic target of rapamycin 2; AS160, Akt substrate of 160 kDa (also known as TBC1D4); aPKC, atypical PKC; Ral-GAPβ, Ral-GTPase-activating protein-β; Ral-GAPα1, Ral-GTPase-activating protein-α1; GSV, GLUT4 storage vesicle.

Fig. 3.

Effects of 1 exercise session by individuals with normal insulin sensitivity on subsequent (several hours postexercise) insulin signaling, GLUT4 translocation, and glucose transport in skeletal muscle stimulated with a physiological insulin dose. 1) Proximal insulin signaling steps (including insulin receptor binding, IRS-1 PI3K activity, and Akt activity) are not enhanced postexercise. 2) Phosphorylation of AS160 is increased on Ser⁵⁸⁸ and Thr⁶⁴² postexercise. 3) Insulin-stimulated GLUT4 glucose transporter translocation and glucose transport are increased postexercise.

Fig. 4.

Acute exercise leads to subsequently elevated insulin-stimulated glucose uptake in muscles from both humans and rats with normal or subnormal insulin sensitivity. Data presented are for rats with normal insulin sensitivity or insulin resistance induced by a high-fat diet. Postexercise values in the insulin-resistant group increase to values similar to normal rats without exercise (indicated by the dashed line) but do not reach values equal to postexercise normal rats performing comparable exercise. A: glucose uptake measured in rat epitrochlearis muscles incubated without or with a physiological insulin dose (100 μU/ml) at ∼3 h postexercise. *P < 0.05 for glucose uptake without insulin of normal insulin sensitivity (normal) + 3 h postexercise vs. normal + no exercise; †P < 0.05 for glucose uptake with insulin of normal + 3 h postexercise vs. all other groups with insulin; ‡P < 0.05 for glucose uptake with insulin of normal + no exercise vs. insulin-resistant + 3 h postexercise. B: Δ-insulin glucose uptake values (Δ-insulin = value with insulin − value without insulin for paired muscles). *P < 0.05 for insulin-resistant + no exercise vs. all other groups; †P < 0.05 for normal + 3 h postexercise vs. all other groups; ‡P < 0.05 for insulin-resistant + no exercise vs. insulin-resistant + 3 h postexercise. Redrawn with permission from Castorena et al. (14).