title: Evidence for neural contribution to islet effects of DPP-4 inhibition in mice.
abstract: It has been suggested that neural mechanisms may contribute to effects of the incretin hormones, and, therefore, also to the effects of dipeptidyl peptidase (DPP-4) inhibition. We therefore examined whether muscarinic mechanisms are involved in the stimulation of insulin secretion by DPP-4 inhibition. Fasted, anesthetized mice were given intraperitoneal saline or the muscarinic antagonist atropine (5mg/kg) before duodenal glucose (75mg/mouse), with or without the DPP-4 inhibitor NVPDPP728 (0.095mg/mouse), or before intravenous glucose (0.35g/kg) with or without co-administration with GLP-1 or glucose-dependent insulinotropic polypeptide (GIP) (both 3nmol/kg). Furthermore, isolated islets were incubated (1h) in 2.8 and 11.1mM glucose, with or without GIP or GLP-1 (both 100nM), in the presence or absence of atropine (100µM). Duodenal glucose increased circulating insulin and this effect was potentiated by DPP-4 inhibition. The increase in insulin achieved by DPP-4 inhibition was reduced by atropine by approximately 35%. Duodenal glucose also elicited an increase in circulating intact GLP-1 and GIP and this was augmented by DPP-4 inhibition, but these effects were not affected by atropine. Atropine did also not affect the augmentation by GLP-1 and GIP on glucose-stimulated insulin secretion from isolated islets. Based on these findings, we suggest that muscarinic mechanisms contribute to the stimulation of insulin secretion by DPP-4 inhibition through neural effects induced by GLP-1 and GIP whereas neural effects do not affect the levels of GLP-1 or GIP or the islet effects of the two incretin hormones.
authors.affiliation: Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Ahlkvist
authors.affiliation: Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Bilal
authors.initials: B
authors.lastname: Omar
authors.affiliation: Metabolic Unit, Institute of Neurosciences, National Research Council, Padova, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pacini
authors.affiliation: Department of Clinical Sciences, Lund University, Lund, Sweden. Electronic address: bo.ahren@med.lu.se.
authors.forename: Bo
authors.initials: B
authors.lastname: Ahrén
mesh_terms: D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D005260:Female; D005947:Glucose / Q000008:administration & dosage / Q000494:pharmacology; D054795:Incretins / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009424:Nervous System Physiological Phenomena / Q000187:drug effects; D011976:Receptors, Muscarinic / Q000378:metabolism
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D054795:Incretins; D007328:Insulin; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D002217:Carbachol; D018819:Dipeptidyl Peptidase 4; D005947:Glucose
keywords: DPP-4 inhibition; GIP; GLP-1; Insulin; Vagus nerve