Journal article
Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance
Nature medicine, Vol.6(8), pp.924-928
08/2000
DOI: 10.1038/78693
PMID: 10932232
Abstract
The prevalence of type 2 diabetes mellitus is growing worldwide. By the year 2020, 250 million people will be afflicted. Most forms of type 2 diabetes are polygenic with complex inheritance patterns, and penetrance is strongly influenced by environmental factors. 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 subjects. 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 tissue. 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 intolerance, 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 span. Moreover, muscle-specific inactivation of the insulin receptor results in minimal, if any, change in glucose tolerance. 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.
Details
- Title: Subtitle
- Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance
- Creators
- Bradford B Lowell - Endocrine Division, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical SchoolE. Dale Abel - Endocrine Division, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical SchoolAntti Virkamaki - Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical SchoolAriel Zisman - Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical SchoolC. Ronald Kahn - Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical SchoolFranck Mauvais-Jarvis - Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical SchoolLaurie J Goodyear - Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical SchoolOdile D Peroni - Endocrine Division, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical SchoolM. Dodson Michael - Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical SchoolMichael F Hirshman - Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical SchoolBarbara B Kahn - Endocrine Division, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical SchoolJørgen F.P Wojtaszewski - Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical School
- Resource Type
- Journal article
- Publication Details
- Nature medicine, Vol.6(8), pp.924-928
- DOI
- 10.1038/78693
- PMID
- 10932232
- ISSN
- 1078-8956
- eISSN
- 1546-170X
- Language
- English
- Date published
- 08/2000
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984024406602771
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