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

TY - JOUR

T1 - Intact regulation of the AMPK signaling network in response to exercise and insulin in skeletal muscle of male patients with type 2 diabetes

T2 - Illumination of AMPK activation in recovery from exercise

AU - Kjøbsted, Rasmus

AU - Pedersen, Andreas J T

AU - Hingst, Janne R

AU - Sabaratnam, Rugivan

AU - Birk, Jesper Bratz

AU - Kristensen, Jonas Møller

AU - Højlund, Kurt

AU - Wojtaszewski, Jørgen

N1 - CURIS 2016 NEXS 110

PY - 2016/5

Y1 - 2016/5

N2 - Current evidence on exercise-mediated AMPK regulation in skeletal muscle of patients with type 2 diabetes (T2D) is inconclusive. This may relate to inadequate segregation of trimeric complexes in the investigation of AMPK activity. We examined the regulation of AMPK and downstream targets ACC-β, TBC1D1, and TBC1D4 in muscle biopsy specimens obtained from 13 overweight/obese patients with T2D and 14 weight-matched male control subjects before, immediately after, and 3 h after exercise. Exercise increased AMPK α2α2γ3 activity and phosphorylation of ACCβ Ser221, TBC1D1 Ser237/Thr596, and TBC1D4 Ser704. Conversely, exercise decreased AMPK α1β2γ1 activity and TBC1D4 Ser318/Thr642 phosphorylation. Interestingly, compared with preexercise, 3 h into exercise recovery, AMPK α2β2γ1 and α1β2γ1 activity were increased concomitant with increased TBC1D4 Ser318/Ser341/Ser704 phosphorylation. No differences in these responses were observed between patients with T2D and control subjects. Subjects were also studied by euglycemic-hyperinsulinemic clamps performed at rest and 3 h after exercise. We found no evidence for insulin to regulate AMPK activity. Thus, AMPK signaling is not compromised in muscle of patients with T2D during exercise and insulin stimulation. Our results reveal a hitherto unrecognized activation of specific AMPK complexes in exercise recovery. We hypothesize that the differential regulation of AMPK complexes plays an important role for muscle metabolism and adaptations to exercise.

AB - Current evidence on exercise-mediated AMPK regulation in skeletal muscle of patients with type 2 diabetes (T2D) is inconclusive. This may relate to inadequate segregation of trimeric complexes in the investigation of AMPK activity. We examined the regulation of AMPK and downstream targets ACC-β, TBC1D1, and TBC1D4 in muscle biopsy specimens obtained from 13 overweight/obese patients with T2D and 14 weight-matched male control subjects before, immediately after, and 3 h after exercise. Exercise increased AMPK α2α2γ3 activity and phosphorylation of ACCβ Ser221, TBC1D1 Ser237/Thr596, and TBC1D4 Ser704. Conversely, exercise decreased AMPK α1β2γ1 activity and TBC1D4 Ser318/Thr642 phosphorylation. Interestingly, compared with preexercise, 3 h into exercise recovery, AMPK α2β2γ1 and α1β2γ1 activity were increased concomitant with increased TBC1D4 Ser318/Ser341/Ser704 phosphorylation. No differences in these responses were observed between patients with T2D and control subjects. Subjects were also studied by euglycemic-hyperinsulinemic clamps performed at rest and 3 h after exercise. We found no evidence for insulin to regulate AMPK activity. Thus, AMPK signaling is not compromised in muscle of patients with T2D during exercise and insulin stimulation. Our results reveal a hitherto unrecognized activation of specific AMPK complexes in exercise recovery. We hypothesize that the differential regulation of AMPK complexes plays an important role for muscle metabolism and adaptations to exercise.

U2 - 10.2337/db15-1034

DO - 10.2337/db15-1034

M3 - Journal article

C2 - 26822091

SN - 0012-1797

VL - 65

SP - 1219

EP - 1230

JO - Diabetes

JF - Diabetes

IS - 5

ER -