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

Abstract

Aims/hypothesis Insulin and exercise stimulate skeletal muscle glycogen synthase (GS) activity by dephosphorylation and changes in kinetic properties. The aim of this study was to investigate the effects of insulin, exercise and post-exercise insulin stimulation on GS phosphorylation, activity and substrate affinity in obesity and type 2 diabetes. Methods Obese men with type 2 diabetes (n=13) and weightmatched controls (n = 14) underwent euglycaemichyperinsulinaemic clamps in the rested state and 3 h after 60 min of cycling (70% maximal pulmonary oxygen uptake [V :O 2max ]) . Biopsies from vastus lateralis muscle were obtained before and after clamps, and before and immediately after exercise. Results Insulin-stimulated glucose uptake was lower in diabetic patients vs obese controls with or without prior exercise. Post exercise, glucose partitioning shifted away from oxidation and towards storage in both groups. Insulin and, more potently, exercise increased GS activity (fractional velocity [FV]) and substrate affinity in both groups. Both stimuli caused dephosphorylation of GS at sites 3a+3b, with exercise additionally decreasing phosphorylation at sites 2+2a. In both groups, changes in GS activity, substrate affinity and dephosphorylation at sites 3a+3b by exercise were sustained 3 h post exercise and further enhanced by insulin. Post exercise, reduced GS activity and substrate affinity as well as increased phosphorylation at sites 2+2a were found in diabetic patients vs obese controls. Conclusions/interpretation Exercise-induced activation of muscle GS in obesity and type 2 diabetes involves dephosphorylation of GS at sites 3a+3b and 2+2a and enhanced substrate affinity, which is likely to facilitate glucose partitioning towards storage. Lower GS activity and increased phosphorylation at sites 2+2a in type 2 diabetes in the recovery period imply an impaired response to exercise.

Intact Regulation of the AMPK Signaling Network in Response to Exercise and Insulin in Skeletal Muscle of Male Patients With Type 2 Diabetes: Illumination of AMPK Activation in Recovery From Exercise

“…By the end of exercise, the rate of perceived exhaustion (20 grade Borg scale; 15 6 1 [Con] and 15 6 1 [T2D]) and the pulmonary respiratory exchange ratio (0.89 6 0.01 [Con] and 0.89 6 0.01 [T2D]) were similar in the two groups. As previously reported from this study (31), muscle glycogen levels and utilization (;50%) during exercise were similar between the two groups. In response to exercise, serum insulin concentrations decreased from 63 6 12 to 34 6 7 pmol/L (T2D) and from 46 6 7 to 21 6 3 pmol/L (Con), with no significant differences between the groups (Table 1).…”

“…The experimental design has been described thoroughly in a previous publication on this study in which detailed information can be found (31).…”

“…The two groups were matched according to age (T2D: 55 6 2, control [Con]: 55 6 2 years), BMI (T2D: 29.7 6 1.0, Con: 29.0 6 0.9 kg $ m 22 ), and self-reported physical activity level (T2D: 5,558 6 943, Con: 5,248 6 952 MET min/week [International Physical Activity Questionnaire score]) (31). Patients with T2D were treated by diet alone (n = 4), by diet combined with metformin (n = 5), or by metformin and sulfonylurea (n = 4).…”

“…1). On the baseline day, overnight-fasted subjects underwent a 4 h euglycemic-hyperinsulinemic clamp ( (31). Muscle biopsy specimens were obtained from two insertions (4-5 cm apart) in the vastus lateralis of one leg before and 4 h after insulin stimulation.…”

“…Muscle lysates, SDS-PAGE, and Western blot analyses were prepared and performed as previously described (5,31 , all phospho-specific antibodies were purchased from Cell Signaling Technology (Danvers, MA). Total Akt2, ACC, TBC1D1, and TBC1D4 protein were determined using specific antibodies, as previously specified (25).…”