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

doi:10.1073/pnas.1409638111

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

Biochemistry

Research output: Contribution to journal › Article › peer-review

74 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 language	English (US)
Pages (from-to)	13217-13222
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	111
Issue number	36
DOIs	https://doi.org/10.1073/pnas.1409638111
State	Published - 2014

Keywords

Insulin resistance
Type two diabetes

ASJC Scopus subject areas

General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1073/pnas.1409638111

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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

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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.",

keywords = "Insulin resistance, Type two diabetes",

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

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AU - Lee, Young

AU - Berglund, Eric D.

AU - Yu, Xinxin

AU - Wang, May Yun

AU - Evans, Matthew R.

AU - Scherer, Philipp E.

AU - Holland, William L.

AU - Charron, Maureen J.

AU - Roth, Michael G.

AU - Unger, Roger H.

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AB - 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.

KW - Insulin resistance

KW - Type two diabetes

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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