GLUT4 and UBC9 Protein Expression Is Reduced in Muscle from Type 2 Diabetic Patients with Severe Insulin Resistance

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.

Insulin Signaling in Type 2 Diabetes

“…The intracellular level of IRS1, on the other hand, is in human adipocytes not affected by insulin resistance or T2D (10,12), although the contrary has been suggested (21). The concentration of the insulin-regulated glucose transporter (GLUT4) is also reduced (to 30 -70%) in adipocytes from diabetic patients compared with cells from non-diabetics (22)(23)(24). In our model we therefore introduced the lower concentrations of IR and GLUT4, and a parameter that can increase or decrease the mTORC1-mediated phosphorylation of IRS1 at Ser-307 (v2c in Fig.…”

Endoproteolytic Cleavage of TUG Protein Regulates GLUT4 Glucose Transporter Translocation

“…Ubc9 is well described as a SUMO E2, which binds GLUT4 and controls its targeting and, probably secondarily, its stability (1,29,34,65,67). It is formally possible that Ubc9 could mediate TUGUL conjugation.…”

From physical inactivity to immobilization: Dissecting the role of oxidative stress in skeletal muscle insulin resistance and atrophy

“…Although that seems relevant in adipose tissue [8,159,160], this is not the case in skeletal muscle. Indeed, GLUT4 protein expression is, in most of the cases, unaltered in skeletal muscle of type 2 diabetic patients despite evidence for oxidative stress [161,162]. In addition, exercise (single bout or training) is well known to stimulate both GLUT4 expression and RONS production in skeletal muscle [163].…”