Enhanced GLUT4-dependent glucose transport relieves nutrient stress in obese mice through changes in lipid and amino acid metabolism

Jami M. Gurley, Olga Ilkayeva, Robert M. Jackson, Beth A. Griesel, Phillip White, Satochi Matsuzaki, Rizwan Qaisar, Holly Van Remmen, Kenneth M. Humphries, Christopher B. Newgard, Ann Louise Olson

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Impaired GLUT4-dependent glucose uptake is a contributing factor in the development of whole-body insulin resistance in obese patients and obese animal models. Previously, we demonstrated that transgenic mice engineered to express the human GLUT4 gene under the control of the human GLUT4 promoter (i.e., transgenic [TG] mice) are resistant to obesity-induced insulin resistance. A likely mechanism underlying increased insulin sensitivity is increased glucose uptake in skeletalmuscle. The purpose of this study was to investigate the broader metabolic consequences of enhanced glucose uptake into muscle. We observed that the expression of several nuclear and mitochondrially encoded mitochondrial enzymes was decreased in TG mice but that mitochondrial number, size, and fatty acid respiration rates were unchanged. Interestingly, both pyruvate and glutamate respiration rates were decreased in TG mice. Metabolomics analyses of skeletal muscle samples revealed that increased GLUT4 transgene expression was associated with decreased levels of some tricarboxylic acid intermediates and amino acids, whereas the levels of several glucogenic amino acids were elevated. Furthermore, fasting acyl carnitines in obese TG mice were decreased, indicating that increased GLUT4-dependent glucose flux decreases nutrient stress by altering lipid and amino acid metabolism in skeletal muscle.

Original languageEnglish (US)
Pages (from-to)3585-3597
Number of pages13
JournalDiabetes
Volume65
Issue number12
DOIs
StatePublished - Dec 1 2016

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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