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)|
|Number of pages||6|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - 2014|
- Insulin resistance
- Type two diabetes
ASJC Scopus subject areas