Diabetes in mice with selective impairment of insulin action in Glut4-expressing tissues

Hua V. Lin, Hongxia Ren, Varman T. Samuel, Hui Young Lee, Taylor Y. Lu, Gerald I. Shulman, Domenico Accili

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

OBJECTIVE - Impaired insulin-dependent glucose disposal in muscle and fat is a harbinger of type 2 diabetes, but murine models of selective insulin resistance at these two sites are conspicuous by their failure to cause hyperglycemia. A defining feature of muscle and fat vis-à-vis insulin signaling is that they both express the insulin-sensitive glucose transporter Glut4. We hypothesized that diabetes is the result of impaired insulin signaling in all Glut4-expressing tissues. RESEARCH DESIGN AND METHODS - To test the hypothesis, we generated mice lacking insulin receptors at these sites ("GIRKO" mice), including muscle, fat, and a subset of Glut4-positive neurons scattered throughout the central nervous system. RESULTS - GIRKO mice develop diabetes with high frequency because of reduced glucose uptake in peripheral organs, excessive hepatic glucose production, and β-cell failure. CONCLUSIONS - The conceptual advance of the present findings lies in the identification of a tissue constellation that melds cell-autonomous mechanisms of insulin resistance (in muscle/fat) with cell-nonautonomous mechanisms (in liver and β-cell) to cause overt diabetes. The data are consistent with the identification of Glut4 neurons as a distinct neuroanatomic entity with a likely metabolic role.

Original languageEnglish (US)
Pages (from-to)700-709
Number of pages10
JournalDiabetes
Volume60
Issue number3
DOIs
StatePublished - Mar 1 2011

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ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Lin, H. V., Ren, H., Samuel, V. T., Lee, H. Y., Lu, T. Y., Shulman, G. I., & Accili, D. (2011). Diabetes in mice with selective impairment of insulin action in Glut4-expressing tissues. Diabetes, 60(3), 700-709. https://doi.org/10.2337/db10-1056