Journal 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

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

2011

Overview

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.

• Publisher: Berlin/Heidelberg : Springer-Verlag,Springer-Verlag,Springer,Springer Nature B.V
• Subject: Akt / Biological and medical sciences / Blood Glucose - metabolism / Blotting, Western / C-Peptide - blood / Diabetes Mellitus, Type 2 - blood / Diabetes. Impaired glucose tolerance / Electrophoresis, Polyacrylamide Gel / Endocrine pancreas. Apud cells (diseases) / Endocrinopathies / Etiopathogenesis. Screening. Investigations. Target tissue resistance / Exercise - physiology / Exercise-training / Fundamental and applied biological sciences. Psychology / Glucose Clamp Technique / Glycated Hemoglobin A - metabolism / Glycogen synthase / Glycogen Synthase - metabolism / GTPase-Activating Proteins - metabolism / Human Physiology / Humans / Insulin - metabolism / Insulin signalling / Internal Medicine / Male / Medical sciences / Medicine / Medicine & Public Health / Metabolic Diseases / Middle Aged / Muscle, Skeletal - metabolism / noninsulin-dependent diabetes mellitus / Phosphorylation / Striated muscle. Tendons / TBC1D4 / Vertebrates: osteoarticular system, musculoskeletal system