Glycemic improvement in diabetic db/db mice by overexpression of the human insulin-regulatable glucose transporter (GLUT4)

E. Michael Gibbs, Jeffrey L. Stock, Scott C. McCoid, Hans A. Stukenbrok, Jeffrey E. Pessin, Ralph W. Stevenson, A. J. Milici, John D. McNeish

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183 Scopus citations

Abstract

The effects of increased GLUT4 (insulin-regulatable muscle/fat glucose transporter) expression on glucose homeostasis in a genetic model of non- insulin-dependent diabetes mellitus were determined by expressing a human GLUT4 transgene (hGLUT4) in diabetic C57BL/KsJ-db/db mice. A genomic hGLUT4 construct was microinjected directly into pronuclear murine embryos of db/+ matings to maintain the inbred background. Four lines of hGLUT4 transgenic mice were bred to homozygosity at the db locus and all showed a marked reduction of both fasted and fed plasma glucose levels (to ~ 50 and 360 mg/dl, respectively) compared with age-matched nontransgenic db/db mice (~ 215 and 550 mg/dl, respectively), as well as an enhanced disposal of an oral glucose challenge. In situ immunocytochemical localization of GLUT4 protein in muscle from hGLUT4 db/db mice showed elevated plasma membrane-associated GLUT4 protein in the basal state, which markedly increased after an insulin/glucose injection. In contrast, nontransgenic db/db mice had low levels of plasma membrane-associated GLUT4 protein in the basal state with a relatively small increase after an insulin/glucose challenge. Since the intracellular GLUT4 levels in db/db mice were similar to nontransgenic db/+ mice, the glucose transport defect in db/db mice is at the level of glucose transporter translocation. Together, these data demonstrate that GLUT4 upregulation overcomes the glucose transporter translocation defect and alleviates insulin resistance in genetically diabetic mice, thus resulting in markedly improved glycemic control.

Original languageEnglish (US)
Pages (from-to)1512-1518
Number of pages7
JournalJournal of Clinical Investigation
Volume95
Issue number4
DOIs
StatePublished - Apr 1995

Keywords

  • basal metabolism
  • gene expression
  • genetic models
  • non-insulin-dependent diabetes mellitus
  • upregulation

ASJC Scopus subject areas

  • Medicine(all)

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    Gibbs, E. M., Stock, J. L., McCoid, S. C., Stukenbrok, H. A., Pessin, J. E., Stevenson, R. W., Milici, A. J., & McNeish, J. D. (1995). Glycemic improvement in diabetic db/db mice by overexpression of the human insulin-regulatable glucose transporter (GLUT4). Journal of Clinical Investigation, 95(4), 1512-1518. https://doi.org/10.1172/JCI117823