Author: ["Ariel Zisman","Odile D. Peroni","E. Dale Abel","M. Dodson Michael","Franck Mauvais-Jarvis","Bradford B. Lowell","Jørgen F.P. Wojtaszewski","Michael F. Hirshman","Antti Virkamaki","Laurie J. Goodyear","C. Ronald Kahn","Barbara B. Kahn"]
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Abstract
The prevalence of type 2 diabetes mellitus is growing worldwide. By the year 2020, 250 million people will be afflicted1. Most forms of type 2 diabetes are polygenic with complex inheritance patterns, and penetrance is strongly influenced by environmental factors2. The specific genes involved are not yet known, but impaired glucose uptake in skeletal muscle is an early, genetically determined defect that is present in non-diabetic relatives of diabetic subjects3. 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 tissue5. GLUT4 mediates glucose transport stimulated by insulin and contraction/exercise. The importance of GLUT4 and glucose uptake in muscle, however, was challenged by two recent observations. Whereas heterozygous GLUT4 knockout mice show moderate glucose intolerance6, homozygous whole-body GLUT4 knockout (GLUT4-null) mice have only mild perturbations in glucose homeostasis and have growth retardation, depletion of fat stores, cardiac hypertrophy and failure, and a shortened life span7. Moreover, muscle-specific inactivation of the insulin receptor results in minimal, if any, change in glucose tolerance8. To determine the importance of glucose uptake into muscle for glucose homeostasis, we disrupted GLUT4 selectively in mouse muscles. A profound reduction in basal glucose transport and near-absence of stimulation 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 glucose homeostasis.Cite this article
Zisman, A., Peroni, O., Abel, E. et al. Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance. Nat Med 6, 924–928 (2000). https://doi.org/10.1038/78693 