Hyperglycemia in rodent models of type 2 diabetes requires insulin-resistant alpha cells

Young Lee, Eric D. Berglund, Xinxin Yu, May Yun Wang, Matthew R. Evans, Philipp E. Scherer, William L. Holland, Maureen J. Charron, Michael G. Roth, Roger H. Unger

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

To determine the role of glucagon action in diet-induced and genetic type 2 diabetes (T2D), we studied high-fat-diet-induced obese (DIO) and leptin receptor-defective (LepR-/-) rodents with and without glucagon receptors (GcgRs). DIO and LepR-/-,GcgR+/+mice both developed hyperinsulinemia, increased liver sterol response element binding protein 1c, and obesity. DIO GcgR+/+mice developed mild T2D, whereas LepR-/-,GcgR+/+mice developed severe T2D. High-fat-fed (HFF) glucagon receptor-null mice did not develop hyperinsulinemia, increased liver sterol response element binding protein 1c mRNA, or obesity. Insulin treatment of HFF GcgR-/-to simulate HFFinduced hyperinsulinemia caused obesity and mild T2D. LepR-/-, GcgR-/-did not develop hyperinsulinemia or hyperglycemia. Adenoviral delivery of GcgR to GcgR-/-,LepR-/-mice caused the severe hyperinsulinemia and hyperglycemia of LepR-/-mice to appear. Spontaneous disappearance of the GcgR transgene abolished the hyperinsulinemia and hyperglycemia. In conclusion, T2D hyperglycemia requires unsuppressible hyperglucagonemia from insulin-resistant α cells and is prevented by glucagon suppression or blockade.

Original languageEnglish (US)
Pages (from-to)13217-13222
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number36
DOIs
StatePublished - Jan 1 2014

Keywords

  • Insulin resistance
  • Type two diabetes

ASJC Scopus subject areas

  • General

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    Lee, Y., Berglund, E. D., Yu, X., Wang, M. Y., Evans, M. R., Scherer, P. E., Holland, W. L., Charron, M. J., Roth, M. G., & Unger, R. H. (2014). Hyperglycemia in rodent models of type 2 diabetes requires insulin-resistant alpha cells. Proceedings of the National Academy of Sciences of the United States of America, 111(36), 13217-13222. https://doi.org/10.1073/pnas.1409638111