Prevention of insulin resistance and diabetes in mice heterozygous for GLUT4 ablation by transgenic complementation of GLUT4 in skeletal muscle

Impaired skeletal muscle glucose utilization under insulin action is a majo r defect in the etiology of type 2 diabetes. This is underscored by a new m ouse model of type 2 diabetes generated by genetic disruption of one allele of glucose transporter 4 (GLUT4(+/-)), the insulin-responsive glucose tran sporter in muscle and adipose tissue. Male GLUT4(+/-) mice exhibited decrea sed 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-th e 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 co ntrast to GLUT4+/- mice, MLC-GLUT4" mice exhibited normal whole-body glucos e utilization. In addition, development of hyperinsulinemia and hyperglycem ia observed in GLUT4(+/-) mice was prevented in MLC-GLUT4(+/-) mice. The oc currence of diabetic heart histopathology in RlnC-GLUT4(+/-) mice was reduc ed to control levels. Based on these results, we propose that the onset of a diabetic phenotype in GLUT4(+/-) mice can be avoided by preventing decrea ses in muscle GLUT4 expression and glucose uptake.