title: Double incretin receptor knockout (DIRKO) mice reveal an essential role for the enteroinsular axis in transducing the glucoregulatory actions of DPP-IV inhibitors.
abstract: Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are gut-derived incretins that potentiate glucose clearance following nutrient ingestion. Elimination of incretin receptor action in GIPR(-/-) or GLP-1R(-/-) mice produces only modest 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 improved glycemic response after exogenous administration 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-stimulated insulin secretion were decreased following oral but not intraperitoneal glucose challenge in DIRKO compared with GIPR(-/-) or GLP-1R(-/-) mice. Similarly, glucose-stimulated insulin secretion and the response to forskolin were well preserved in perifused DIRKO islets. Although the dipeptidyl peptidase-IV (DPP-IV) inhibitors valine pyrrolidide (Val-Pyr) and SYR106124 lowered glucose and increased plasma insulin in wild-type and single incretin receptor knockout mice, the glucose-lowering actions of DPP-IV inhibitors were eliminated in DIRKO mice. These findings demonstrate that glucose-stimulated insulin secretion is maintained despite complete absence of both incretin receptors, and they delineate a critical role for incretin receptors as essential downstream targets for the acute glucoregulatory actions of DPP-IV inhibitors.
authors.affiliation: Banting and Best Diabetes Centre, Department of Medicine, Toronto General Hospital, University of Toronto, 200 Elizabeth Street, Toronto, Ontario, Canada M5G 2C4.
authors.forename: Tanya
authors.initials: T
authors.lastname: Hansotia
authors.forename: Laurie L
authors.initials: LL
authors.lastname: Baggio
authors.forename: Dominique
authors.initials: D
authors.lastname: Delmeire
authors.forename: Simon A
authors.initials: SA
authors.lastname: Hinke
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Yamada
authors.forename: Katsushi
authors.initials: K
authors.lastname: Tsukiyama
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Seino
authors.forename: Jens J
authors.initials: JJ
authors.lastname: Holst
authors.forename: Frans
authors.initials: F
authors.lastname: Schuit
authors.forename: D J
authors.initials: DJ
authors.lastname: Drucker
mesh_terms: D000818:Animals; D018819:Dipeptidyl Peptidase 4 / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007422:Intestines / Q000502:physiology*; D007515:Islets of Langerhans / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009930:Organic Chemicals / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011964:Receptors, Gastrointestinal Hormone / Q000819:agonists / Q000172:deficiency / Q000502:physiology*; D018027:Receptors, Glucagon / Q000819:agonists / Q000172:deficiency / Q000502:physiology*; D014633:Valine / Q000494:pharmacology; D014688:Venoms / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D009930:Organic Chemicals; D010455:Peptides; D011758:Pyrroles; D011964:Receptors, Gastrointestinal Hormone; D018027:Receptors, Glucagon; C487120:Syrrx 106124; D014688:Venoms; C112092:valine-pyrrolidide; D000077270:Exenatide; C041086:gastric inhibitory polypeptide receptor; D018819:Dipeptidyl Peptidase 4; D014633:Valine; D005947:Glucose