Abstract
AimsSubgroups of patients with type 2 diabetes mellitus demand large insulin doses to maintain euglycemia. These patients are characterized by severe skeletal muscle insulin resistance and the underlying pathology remains unclear. The purpose of this study was to examine protein expression of the principal glucose transporter, GLUT4, and associated proteins in skeletal muscle from type 2 diabetic patients characterized by severe insulin resistance.MethodsSeven type 2 diabetic patients with severe insulin resistance (mean insulin dose 195 IU/day) were compared with seven age matched type 2 diabetic patients who did not require insulin treatment, and with an age matched healthy control group. Protein expression of GLUT4 and associated proteins was assessed in muscle and fat biopsies using standard western blotting techniques.ResultsGLUT4 protein expression was significantly reduced by ∼30 pct in skeletal muscle tissue from severely insulin resistant type 2 diabetic subjects, compared with both healthy controls and type 2 diabetic subjects that did not require insulin treatment. In fat tissue, GLUT4 protein expression was reduced in both diabetic groups. In skeletal muscle, the reduced GLUT4 expression in severe insulin resistance was associated with decreased ubiquitin-conjugating enzyme 9 (UBC9) expression while expression of GLUT1, TBC1D1 and AS160 was not significantly different among type 2 diabetic patients and matched controls.ConclusionsType 2 diabetic patients with severe insulin resistance have reduced expression of GLUT4 in skeletal muscle compared to patients treated with oral antidiabetic drugs alone. GLUT4 protein levels may therefore play a role in the pathology behind type 2 diabetes mellitus among subgroups of patients, and this may explain the heterogeneous response to insulin treatment. This new finding contributes to the understanding of the underlying mechanisms for the development of extreme insulin resistance.
Highlights
Type 2 diabetic patients with extreme insulin resistance represent a major therapeutic challenge in terms of achieving glycaemic goals
When AS160 and TBC1D1 are phosphorylated on key residues, GLUT4 is released and translocates to the cell surface where it docks and fuses with the membrane [3]
We examined expression of GLUT4 and associated proteins in skeletal muscle from type 2 diabetic patients characterized by severe insulin resistance
Summary
Type 2 diabetic patients with extreme insulin resistance represent a major therapeutic challenge in terms of achieving glycaemic goals. Many patients require several hundred units of insulin daily, but despite large amounts of daily insulin, glycemic control remains poor, and it may be difficult to decide whether to increase insulin dosages further or regard patients as being noncompliant It is unknown whether such patients have defects in the mechanisms that control insulin stimulated glucose uptake. After translocation to the cell surface, GLUT4 can either be recycled back to intracellular vesicles or be targeted for lysosomal degradation [4]. This process is regulated by ubiquitinconjugating enzyme 9 (UBC9) which controls attachment of Small
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
