Double Incretin Receptor Knockout (DIRKO) Mice Reveal an Essential Role for the Enteroinsular Axis in Transducing the Glucoregulatory Actions of DPP-IV Inhibitors

and glucagon-like peptide 1 (GLP-1) are gut-derived incretins that potentiate glucose clearance following nutrient ingestion. Elimination of incretin receptor ac-tion in GIPR/ or GLP-1R/ mice produces only mod-est impairment in glucose homeostasis, perhaps due to compensatory upregulation of the remaining incretin. We have now studied glucose homeostasis in double incretin receptor knockout (DIRKO) mice. DIRKO mice exhibit normal body weight and fail to exhibit an im-proved glycemic response after exogenous administra-tion of GIP or the GLP-1R agonist exendin-4. Plasma glucagon and the hypoglycemic response to exogenous insulin were normal in DIRKO mice. Glycemic excursion was abnormally increased and levels of glucose-stimu-lated insulin secretion were decreased following ora