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01-01-2011 | Article

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

Authors: B. F. Vind, C. Pehmøller, J. T. Treebak, J. B. Birk, M. Hey-Mogensen, H. Beck-Nielsen, J. R. Zierath, J. F. P. Wojtaszewski, K. Højlund

Published in: Diabetologia | Issue 1/2011

Abstract

Aims/hypothesis

Insulin-mediated glucose disposal rates (R _d) 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, non-diabetic control individuals before and after 10 weeks of endurance exercise-training.

Results

Before training, reductions in insulin-stimulated R _d, together with impaired insulin-stimulated glycogen synthase fractional velocity, Akt Thr³⁰⁸ phosphorylation and phosphorylation of TBC1D4 at Ser³¹⁸, Ser⁵⁸⁸ 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 R _d (~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.

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Title: 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
Authors: B. F. Vind
C. Pehmøller
J. T. Treebak
J. B. Birk
M. Hey-Mogensen
H. Beck-Nielsen
J. R. Zierath
J. F. P. Wojtaszewski
K. Højlund
Publication date: 01-01-2011
Publisher: Springer-Verlag
Published in: Diabetologia / Issue 1/2011
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-010-1924-4

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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

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

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