title: Physiological and pharmacological mechanisms through which the DPP-4 inhibitor sitagliptin regulates glycemia in mice.
abstract: Inhibition of dipeptidyl peptidase-4 (DPP-4) activity improves glucose homeostasis through a mode of action related to the stabilization of the active forms of DPP-4-sensitive hormones such as the incretins that enhance glucose-induced insulin secretion. However, the DPP-4 enzyme is highly expressed on the surface of intestinal epithelial cells; hence, the role of intestinal vs. systemic DPP-4 remains unclear. To analyze mechanisms through which the DPP-4 inhibitor sitagliptin regulates glycemia in mice, we administered low oral doses of the DPP-4 inhibitor sitagliptin that selectively reduced DPP-4 activity in the intestine. Glp1r(-/-) and Gipr(-/-) mice were studied and glucagon-like peptide (GLP)-1 receptor (GLP-1R) signaling was blocked by an i.v. infusion of the corresponding receptor antagonist exendin (9-39). The role of the dipeptides His-Ala and Tyr-Ala as DPP-4-generated GLP-1 and glucose-dependent insulinotropic peptide (GIP) degradation products was studied in vivo and in vitro on isolated islets. We demonstrate that very low doses of oral sitagliptin improve glucose tolerance and plasma insulin levels with selective reduction of intestinal but not systemic DPP-4 activity. The glucoregulatory action of sitagliptin was associated with increased vagus nerve activity and was diminished in wild-type mice treated with the GLP-1R antagonist exendin (9-39) and in Glp1r(-/-) and Gipr(-/-) mice. Furthermore, the dipeptides liberated from GLP-1 (His-Ala) and GIP (Tyr-Ala) deteriorated glucose tolerance, reduced insulin, and increased portal glucagon levels. The predominant mechanism through which DPP-4 inhibitors regulate glycemia involves local inhibition of intestinal DPP-4 activity, activation of incretin receptors, reduced liberation of bioactive dipeptides, and activation of the gut-to-pancreas neural axis.
authors.affiliation: Institut de Recherche sur les Maladies Métaboliques et Cardiovasculaires de l'Hôpital Rangueil, Inserm U1048, BP 84225, 31432 Toulouse Cedex 4, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Waget
authors.forename: Cendrine
authors.initials: C
authors.lastname: Cabou
authors.forename: Myriam
authors.initials: M
authors.lastname: Masseboeuf
authors.forename: Pierre
authors.initials: P
authors.lastname: Cattan
authors.forename: Mattieu
authors.initials: M
authors.lastname: Armanet
authors.forename: Mélis
authors.initials: M
authors.lastname: Karaca
authors.forename: Julien
authors.initials: J
authors.lastname: Castel
authors.forename: Celine
authors.initials: C
authors.lastname: Garret
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Payros
authors.forename: Adriano
authors.initials: A
authors.lastname: Maida
authors.forename: Thierry
authors.initials: T
authors.lastname: Sulpice
authors.forename: Jens J
authors.initials: JJ
authors.lastname: Holst
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
authors.forename: Christophe
authors.initials: C
authors.lastname: Magnan
authors.forename: Rémy
authors.initials: R
authors.lastname: Burcelin
mesh_terms: D000328:Adult; D000818:Animals; D001786:Blood Glucose / Q000032:analysis*; D004151:Dipeptides / Q000494:pharmacology; D018819:Dipeptidyl Peptidase 4 / Q000502:physiology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D005934:Glucagon / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D011719:Pyrazines / Q000494:pharmacology*; D011964:Receptors, Gastrointestinal Hormone / Q000502:physiology; D018027:Receptors, Glucagon / Q000502:physiology; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000494:pharmacology*; D014630:Vagus Nerve / Q000502:physiology
chemical_list: D001786:Blood Glucose; D004151:Dipeptides; D054873:Dipeptidyl-Peptidase IV Inhibitors; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D011719:Pyrazines; D011964:Receptors, Gastrointestinal Hormone; D018027:Receptors, Glucagon; D014230:Triazoles; C034124:histidinoalanine; D005934:Glucagon; C041086:gastric inhibitory polypeptide receptor; D018819:Dipeptidyl Peptidase 4; D000068900:Sitagliptin Phosphate