Impaired insulin-induced site-specific phosphorylation of TBC1 domain family, member 4 (TBC1D4) in skeletal muscle of type 2 diabetes patients is restored by endurance exercise-training

TY - JOUR

T1 - Impaired insulin-induced site-specific phosphorylation of TBC1 domain family, member 4 (TBC1D4) in skeletal muscle of type 2 diabetes patients is restored by endurance exercise-training

AU - Vind, B. F.

AU - Pehmøller, Christian

AU - Treebak, Jonas Thue

AU - Birk, Jesper Bratz

AU - Hey-Mogensen, M.

AU - Beck-Nielsen, H.

AU - Zierath, J. R.

AU - Wojtaszewski, Jørgen

AU - Højlund, K.

N1 - CURIS 2011 5200 141

PY - 2011/1

Y1 - 2011/1

N2 - Aims/hypothesis: Insulin-mediated glucose disposal rates (Rd) are reduced in type 2 diabetic patients, a process in which intrinsic signalling defects are thought to be involved. Phosphorylation of TBC1 domain family, member 4 (TBC1D4) is at present the most distal insulin receptor signalling event linked to glucose transport. In this study, we examined insulin action on site-specific phosphorylation of TBC1D4 and the effect of exercise training on insulin action and signalling to TBC1D4 in skeletal muscle from type 2 diabetic patients. Methods: During a 3 h euglycaemic-hyperinsulinaemic (80 mU min -1 m-2) clamp, we obtained M. vastus lateralis biopsies from 13 obese type 2 diabetic and 13 obese, nondiabetic control individuals before and after 10 weeks of endurance exercise-training. Results: Before training, reductions in insulin-stimulated Rd, together with impaired insulin-stimulated glycogen synthase fractional velocity, Akt Thr308 phosphorylation and phosphorylation of TBC1D4 at Ser318, Ser 588 and Ser751 were observed in skeletal muscle from diabetic patients. Interestingly, exercise-training normalised insulin-induced TBC1D4 phosphorylation in diabetic patients. This happened independently of increased TBC1D4 protein content, but exercise-training did not normalise Akt phosphorylation in diabetic patients. In both groups, training-induced improvements in insulin-stimulated Rd (∼20%) were associated with increased muscle protein content of Akt, TBC1D4, α2-AMP-activated kinase (AMPK), glycogen synthase, hexokinase II and GLUT4 (20-75%). Conclusions/interpretation: Impaired insulin-induced site-specific TBC1D4 phosphorylation may contribute to skeletal muscle insulin resistance in type 2 diabetes. The mechanisms by which exercise-training improves insulin sensitivity in type 2 diabetes may involve augmented signalling of TBC1D4 and increased skeletal muscle content of key insulin signalling and effector proteins, e.g., Akt, TBC1D4, AMPK, glycogen synthase, GLUT4 and hexokinase II.

AB - Aims/hypothesis: Insulin-mediated glucose disposal rates (Rd) are reduced in type 2 diabetic patients, a process in which intrinsic signalling defects are thought to be involved. Phosphorylation of TBC1 domain family, member 4 (TBC1D4) is at present the most distal insulin receptor signalling event linked to glucose transport. In this study, we examined insulin action on site-specific phosphorylation of TBC1D4 and the effect of exercise training on insulin action and signalling to TBC1D4 in skeletal muscle from type 2 diabetic patients. Methods: During a 3 h euglycaemic-hyperinsulinaemic (80 mU min -1 m-2) clamp, we obtained M. vastus lateralis biopsies from 13 obese type 2 diabetic and 13 obese, nondiabetic control individuals before and after 10 weeks of endurance exercise-training. Results: Before training, reductions in insulin-stimulated Rd, together with impaired insulin-stimulated glycogen synthase fractional velocity, Akt Thr308 phosphorylation and phosphorylation of TBC1D4 at Ser318, Ser 588 and Ser751 were observed in skeletal muscle from diabetic patients. Interestingly, exercise-training normalised insulin-induced TBC1D4 phosphorylation in diabetic patients. This happened independently of increased TBC1D4 protein content, but exercise-training did not normalise Akt phosphorylation in diabetic patients. In both groups, training-induced improvements in insulin-stimulated Rd (∼20%) were associated with increased muscle protein content of Akt, TBC1D4, α2-AMP-activated kinase (AMPK), glycogen synthase, hexokinase II and GLUT4 (20-75%). Conclusions/interpretation: Impaired insulin-induced site-specific TBC1D4 phosphorylation may contribute to skeletal muscle insulin resistance in type 2 diabetes. The mechanisms by which exercise-training improves insulin sensitivity in type 2 diabetes may involve augmented signalling of TBC1D4 and increased skeletal muscle content of key insulin signalling and effector proteins, e.g., Akt, TBC1D4, AMPK, glycogen synthase, GLUT4 and hexokinase II.

U2 - 10.1007/s00125-010-1924-4

DO - 10.1007/s00125-010-1924-4

M3 - Journal article

C2 - 20938636

SN - 0012-186X

VL - 54

SP - 157

EP - 167

JO - Diabetologia

JF - Diabetologia

IS - 1

ER -