Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance

The prevalence of type 2 diabetes mellitus is growing worldwide. By the yea r 2020, 250 million people will be afflicted(1). Most forms of type 2 diabe tes are polygenic with complex inheritance patterns, and penetrance is stro ngly influenced by environmental factors(2). The specific genes involved ar e not yet known, but impaired glucose uptake in skeletal muscle is an early , genetically determined defect that is present in nondiabetic relatives of diabetic subjects(3). The rate-limiting step in muscle glucose use is the transmembrane transport of glucose mediated by glucose transporter (GLUT) 4 (ref. 4), which is expressed mainly in skeletal muscle, heart and adipose tissues. GLUT4 mediates glucose transport stimulated by insulin and contrac tion/exercise. The importance of GLUT4 and glucose uptake in muscle, howeve r, was challenged by two recent observations. Whereas heterozygous GLUT4 kn ockout mice show moderate glucose intolerance(6), homozygous whole-body GLU T4 knockout (GLUT4-null) mice have only mild perturbations in glucose homeo stasis and have growth retardation, depletion of fat stores, cardiac hypert rophy and failure, and a shortened life span(7). Moreover, muscle-specific inactivation of the insulin receptor results in minimal, if any, change in glucose tolerances. To determine the importance of glucose uptake into musc le for glucose homeostasis, we disrupted GLUT4 selectively in mouse muscles . A profound reduction in basal glucose transport and near-absence of stimu lation by insulin or contraction resulted. These mice showed severe insulin resistance and glucose intolerance from an early age. Thus, GLUT4-mediated glucose transport in muscle is essential to the maintenance of normal gluc ose homeostasis.