Impaired skeletal muscle glucose utilization under insulin action is a major defect in the etiology of type 2 diabetes. This is underscored by a new mouse model of type 2 diabetes generated by genetic disruption of one allele of glucose transporter 4 (GLUT4(+/-)), the insulin-responsive glucose transporter in muscle and adipose tissue. Male GLUT4(+/-) mice exhibited decreased GLUT4 expression and glucose uptake in muscle that accompanied impaired whole-body glucose utilization, hyperinsulinemia, hyperglycemia, and heart histopathology. To determine whether development of the diabetic phenotype in GLUT4(+/-) mice can be forestalled by preventing the onset of impaired muscle GLUT4 expression and glucose utilization, standard genetic crossing was performed to introduce a fast-twitch muscle-specific GLUT4 transgene-the myosin light chain (MLC) promoter-driven transgene MLC-GLUT4- into GLUT4(+/-) mice (MLC-GLUT4(+/-) mice). GLUT4 expression and 2- deoxyglucose uptake levels were normalized in fast-twitch muscles of MLC- GLUT4(+/-) mice. In contrast to GLUT4(+/-) mice, MLC-GLUT4(+/-) mice exhibited normal whole-body glucose utilization. In addition, development of hyperinsulinemia and hyperglycemia observed in GLUT4(+/-) mice was prevented in MLC-GLUT4(+/-) mice. The occurrence of diabetic heart histopathology in MLC-GLUT4(+/-) mice was reduced to control levels. Based on these results, we propose that the onset of a diabetic phenotype in GLUT4(+/-) mice can be avoided by preventing decreases in muscle GLUT4 expression and glucose uptake.
ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism