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

Proc Natl Acad Sci U S A. 2014 Sep 9;111(36):13217-22. doi: 10.1073/pnas.1409638111. Epub 2014 Aug 25.

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 HFF-induced 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Body Temperature / drug effects
  • Body Weight / drug effects
  • Cell Line
  • Ceramides / pharmacology
  • Cricetinae
  • Diabetes Mellitus, Type 2 / complications*
  • Diabetes Mellitus, Type 2 / pathology*
  • Diet
  • Disease Models, Animal
  • Feeding Behavior / drug effects
  • Glucagon / metabolism
  • Glucagon-Secreting Cells / drug effects
  • Glucagon-Secreting Cells / metabolism
  • Glucagon-Secreting Cells / pathology*
  • Hyperglycemia / blood
  • Hyperglycemia / complications*
  • Hyperglycemia / pathology*
  • Hyperinsulinism / blood
  • Hyperinsulinism / complications
  • Hyperinsulinism / pathology
  • Insulin / blood
  • Insulin / genetics
  • Insulin / pharmacology*
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / pathology
  • Lipogenesis / drug effects
  • Male
  • Mice, Inbred C57BL
  • RNA, Messenger / blood
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Receptors, Glucagon / metabolism

Substances

  • Blood Glucose
  • Ceramides
  • Insulin
  • RNA, Messenger
  • Receptors, Glucagon
  • Glucagon