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Glucose toxicity and the development of diabetes in mice with muscle-specific inactivation of GLUT4
Jason K. Kim, … , Barbara B. Kahn, Gerald I. Shulman
Jason K. Kim, … , Barbara B. Kahn, Gerald I. Shulman
Published July 1, 2001
Citation Information: J Clin Invest. 2001;108(1):153-160. https://doi.org/10.1172/JCI10294.
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Article

Glucose toxicity and the development of diabetes in mice with muscle-specific inactivation of GLUT4

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Abstract

Using cre/loxP gene targeting, transgenic mice with muscle-specific inactivation of the GLUT4 gene (muscle GLUT4 KO) were generated and shown to develop a diabetes phenotype. To determine the mechanism, we examined insulin-stimulated glucose uptake and metabolism during hyperinsulinemic-euglycemic clamp in control and muscle GLUT4 KO mice before and after development of diabetes. Insulin-stimulated whole body glucose uptake was decreased by 55% in muscle GLUT4 KO mice, an effect that could be attributed to a 92% decrease in insulin-stimulated muscle glucose uptake. Surprisingly, insulin’s ability to stimulate adipose tissue glucose uptake and suppress hepatic glucose production was significantly impaired in muscle GLUT4 KO mice. To address whether these latter changes were caused by glucose toxicity, we treated muscle GLUT4 KO mice with phloridzin to prevent hyperglycemia and found that insulin-stimulated whole body and skeletal muscle glucose uptake were decreased substantially, whereas insulin-stimulated glucose uptake in adipose tissue and suppression of hepatic glucose production were normal after phloridzin treatment. In conclusion, these findings demonstrate that a primary defect in muscle glucose transport can lead to secondary defects in insulin action in adipose tissue and liver due to glucose toxicity. These secondary defects contribute to insulin resistance and to the development of diabetes.

Authors

Jason K. Kim, Ariel Zisman, Jonathan J. Fillmore, Odile D. Peroni, Ko Kotani, Pascale Perret, Haihong Zong, Jianying Dong, C. Ronald Kahn, Barbara B. Kahn, Gerald I. Shulman

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Figure 1

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Whole body and skeletal muscle metabolic parameters during hyperinsuline...
Whole body and skeletal muscle metabolic parameters during hyperinsulinemic-euglycemic clamps in awake mice at 20–21 weeks of age. (a) Basal plasma glucose concentration in the control (wild-type, lox/lox, and cre; open circles), muscle GLUT4 KO (MG4KO; filled circles), and PHZ-treated muscle GLUT4 KO (MG4KO + PHZ; open squares) mice. (b) Basal plasma insulin concentration in the control (open circles), muscle GLUT4 KO (filled circles), and PHZ-treated muscle GLUT4 KO (open squares) mice. (c) Insulin-stimulated whole body glucose uptake in vivo in control (open bar), heterozygous KO (Het KO; dark gray bar), muscle GLUT4 KO (black bar), and PHZ-treated muscle GLUT4 KO (MG4KO + PHZ; light gray bar) mice. (d) Insulin-stimulated glucose uptake in skeletal muscle (gastrocnemius) in vivo in control (open bar), heterozygous KO (dark gray bar), muscle GLUT4 KO (black bar), and PHZ-treated muscle GLUT4 KO (light gray bar) mice. Values are means plus or minus SE for 5–10 experiments. *P < 0.05 vs. control mice; #P < 0.05 for the PHZ-treated muscle GLUT4 KO mice vs. nontreated muscle GLUT4 KO mice.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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