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 a cells and is prevented by glucagon suppression or blockade.

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