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

Diabetologia. 2011 Jan;54(1):157-67. doi: 10.1007/s00125-010-1924-4. Epub 2010 Oct 13.


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.

Publication types

  • Controlled Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blood Glucose / metabolism
  • Blotting, Western
  • C-Peptide / blood
  • Diabetes Mellitus, Type 2 / blood
  • Electrophoresis, Polyacrylamide Gel
  • Exercise / physiology*
  • GTPase-Activating Proteins / metabolism*
  • Glucose Clamp Technique
  • Glycated Hemoglobin A / metabolism
  • Glycogen Synthase / metabolism
  • Humans
  • Insulin / metabolism*
  • Male
  • Middle Aged
  • Muscle, Skeletal / metabolism*
  • Phosphorylation


  • Blood Glucose
  • C-Peptide
  • GTPase-Activating Proteins
  • Glycated Hemoglobin A
  • Insulin
  • TBC1D4 protein, human
  • Glycogen Synthase