Increased insulin receptor signaling and glycogen synthase activity contribute to the synergistic effect of exercise on insulin action

Abstract

The purpose of this study was to determine the factors contributing to the ability of exercise to enhance insulin-stimulated glucose disposal. Sixteen insulin-resistant nondiabetic and seven Type 2 diabetic subjects underwent two hyperinsulinemic (40 mU x m-2 x min-1) clamps, once without and once with concomitant exercise at 70% peak O2 consumption. Exercise was begun at the start of insulin infusion and was performed for 30 min. Biopsies of the vastus lateralis were performed before and after 30 min of insulin infusion (immediately after cessation of exercise). Exercise synergistically increased insulin-stimulated glucose disposal in nondiabetic [from 4.6 +/- 0.4 to 9.5 +/- 0.8 mg x kg fat-free mass (FFM)-1x min-1] and diabetic subjects (from 4.3 +/- 1.0 to 7.9 +/- 0.7 mg. kg FFM-1x min-1) subjects. The rate of glucose disposal also was significantly greater in each group after cessation of exercise. Exercise enhanced insulin-stimulated increases in glycogen synthase fractional velocity in control (from 0.07 +/- 0.02 to 0.22 +/- 0.05, P < 0.05) and diabetic (from 0.08 +/- 0.03 to 0.15 +/- 0.03, P < 0.01) subjects. Exercise also enhanced insulin-stimulated glucose storage (glycogen synthesis) in nondiabetic (2.9 +/- 0.9 vs. 4.9 +/- 1.1 mg x kg FFM-1x min-1) and diabetic (1.7 +/- 0.5 vs. 4.2 +/- 0.8 mg x kg FFM-1. min-1) subjects. Increased glucose storage accounted for the increase in whole body glucose disposal when exercise was performed during insulin stimulation in both groups; effects of exercise were correlated with enhancement of glucose disposal and glucose storage (r = 0.93, P < 0.001). Exercise synergistically enhanced insulin-stimulated insulin receptor substrate 1-associated phosphatidylinositol 3-kinase activity (P < 0.05) and Akt Ser473 phosphorylation (P < 0.05) in nondiabetic subjects but had little effect in diabetic subjects. The data indicate that exercise, performed in conjunction with insulin infusion, synergistically increases insulin-stimulated glucose disposal compared with insulin alone. In nondiabetic and diabetic subjects, increased glycogen synthase activation is likely to be involved, in part, in this effect. In nondiabetic, but not diabetic, subjects, exercise-induced enhancement of insulin stimulation of the phosphatidylinositol 3-kinase pathway is also likely to be involved in the exercise-induced synergistic enhancement of glucose disposal.

Exercise under hyperinsulinaemic conditions increases whole-body glucose disposal without affecting muscle glycogen utilisation in type 1 diabetes

“…Moreover, superimposition of exercise on the hyperinsulinaemic conditions did not influence the phosphorylation of Akt, GSK3α and β and ERK1/2. This is contrary to previously reported findings in healthy volunteers and rats [12,13,26,27]. It is possible that the hyperglycaemic conditions could have had an inhibitory effect on Akt activation, as observed in patients with type 2 diabetes [12].…”

“…This is contrary to previously reported findings in healthy volunteers and rats [12,13,26,27]. It is possible that the hyperglycaemic conditions could have had an inhibitory effect on Akt activation, as observed in patients with type 2 diabetes [12]. The above data indicate that at least some of the additional increase in glucose uptake during exercise, especially in the HI trial, might not have entered contracting muscle.…”

“…The phosphorylated forms of protein kinase B (PKB/Akt), glycogen synthase kinase 3 (GSK3) α and β isoforms and extracellular signal-regulated protein kinase (ERK 1,2, also known as EPHB2) are intracellular signalling targets potentially involved in the regulation of both insulin-and exercise-mediated glucose uptake [12,13]. However, the impact of hyperinsulinaemia and exercise in patients with type 1 diabetes on these insulin-signalling targets is not known.…”

Dysregulation of muscle glycogen synthase in recovery from exercise in type 2 diabetes

“…An enhanced post-exercise insulin sensitivity has been demonstrated both for glucose-tolerant individuals and for various insulin-resistant populations, including patients with type 2 diabetes, with the change mainly accounted for by an increase in NOGD [11][12][13]. As glycogen synthesis is the primary pathway of NOGD [1], these changes favour glycogen replenishment after exercise [13,17,[35][36][37].…”

“…Interestingly, glycogen-lowering exercise also increases GS activity per se [15]. This regulation does not seem to be impaired in insulin-resistant muscle [16,17], indicating differential regulation of GS by insulin and exercise.…”