Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance
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Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance. / Zisman, Ariel; Peroni, Odile D; Abel, E Dale; Michael, M Dodson; Mauvais-Jarvis, Franck; Lowell, Bradford B; Wojtaszewski, Jørgen; Hirshman, Michael F; Virkamaki, Antti; Goodyear, Laurie J; Kahn, C Ronald; Kahn, Barbara B.
In: Nature Medicine, Vol. 6, No. 8, 2000, p. 924-928.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance
AU - Zisman, Ariel
AU - Peroni, Odile D
AU - Abel, E Dale
AU - Michael, M Dodson
AU - Mauvais-Jarvis, Franck
AU - Lowell, Bradford B
AU - Wojtaszewski, Jørgen
AU - Hirshman, Michael F
AU - Virkamaki, Antti
AU - Goodyear, Laurie J
AU - Kahn, C Ronald
AU - Kahn, Barbara B
N1 - (Ekstern)
PY - 2000
Y1 - 2000
N2 - 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 homeostasls 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.
AB - 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 homeostasls 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.
UR - http://www.scopus.com/inward/record.url?scp=0033834248&partnerID=8YFLogxK
U2 - 10.1038/78693
DO - 10.1038/78693
M3 - Journal article
C2 - 10932232
AN - SCOPUS:0033834248
VL - 6
SP - 924
EP - 928
JO - Nature Medicine
JF - Nature Medicine
SN - 1078-8956
IS - 8
ER -
ID: 242716136