Insulin Resistance Selectively Alters Cell-Surface Glucose Transporters but not their Total Protein Expression in Equine Skeletal Muscle

Background Insulin resistance (IR) has been widely recognized in humans, and more recently in horses, but its underlying mechanisms are still not well understood. The translocation of glucose transporter 4 (GLUT4) to the cell surface is the limiting step for glucose uptake in insulin-sensitive tissues. Although the downstream signaling pathways regulating GLUT translocation are not well defined, AS160 recently has emerged as a potential key component. In addition, the role of GLUT12, one of the most recently identified insulin-sensitive GLUTs, during IR is unknown. Hypothesis/Objectives We hypothesized that cell-surface GLUT will be decreased in muscle by an AS160-dependent pathway in horses with IR. Animals Insulin-sensitive (IS) or IR mares (n = 5/group). Methods Muscle biopsies were performed in mares classified as IS or IR based on results of an insulin-modified frequently sampled IV glucose tolerance test. By an exofacial bis-mannose photolabeled method, we specifically quantified active cell-surface GLUT4 and GLUT12 transporters. Total GLUT4 and GLUT12 and AS160 protein expression were measured by Western blots. Results IR decreased basal cell-surface GLUT4 expression (P = .027), but not GLUT12, by an AS160-independent pathway, without affecting total GLUT4 and GLUT12 content. Cell-surface GLUT4 was not further enhanced by insulin stimulation in either group. Conclusions and Clinical Importance IR induced defects in the skeletal muscle glucose transport pathway by decreasing active cell-surface GLUT4.