title: Quantification of the Contribution of GLP-1 to Mediating Insulinotropic Effects of DPP-4 Inhibition With Vildagliptin in Healthy Subjects and Patients With Type 2 Diabetes Using Exendin [9-39] as a GLP-1 Receptor Antagonist.
abstract: We quantified the contribution of GLP-1 as a mediator of the therapeutic effects of dipeptidyl peptidase 4 (DPP-4) inhibition (vildagliptin) by using the GLP-1 receptor antagonist exendin [9-39] in patients with type 2 diabetes and in healthy subjects. Thirty-two patients with type 2 diabetes and 29 age- and weight-matched healthy control subjects were treated in randomized order with 100 mg once daily vildagliptin or placebo for 10 days. Meal tests were performed (days 9 and 10) without and with a high-dose intravenous infusion of exendin [9-39]. The main end point was the ratio of the areas under the curve (AUCs) of integrated insulin secretion rates (total AUCISR) and glucose (total AUCglucose) over 4 h after the meal. Vildagliptin treatment more than doubled responses of intact GLP-1 and glucose-dependent insulinotropic polypeptide and lowered glucose responses without changing AUCISR/AUCglucose in healthy subjects. Vildagliptin significantly increased this ratio by 10.5% in patients with type 2 diabetes, and exendin [9-39] reduced it (both P < 0.0001). The percentage reduction in the AUCISR/AUCglucose ratio achieved with exendin [9-39] was significantly smaller after vildagliptin treatment than after placebo treatment (P = 0.026) and was equivalent to 47 ± 5% of the increments due to vildagliptin. Thus, other mediators appear to contribute significantly to the therapeutic effects of DPP-4 inhibition.
authors.affiliation: Diabeteszentrum Bad Lauterberg, Bad Lauterberg im Harz, Germany Division of Diabetology, Medical Department I, St. Josef-Hospital (Ruhr University Bochum), Bochum, Germany michael.nauck@rub.de.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nauck
authors.affiliation: PAREXEL, Berlin, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Kind
authors.affiliation: Diabeteszentrum Bad Lauterberg, Bad Lauterberg im Harz, Germany.
authors.forename: Lars D
authors.initials: LD
authors.lastname: Köthe
authors.affiliation: Department of Biomedical Sciences, Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jens J
authors.initials: JJ
authors.lastname: Holst
authors.affiliation: Department of Biomedical Sciences, Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Carolyn F
authors.initials: CF
authors.lastname: Deacon
authors.affiliation: PAREXEL, Berlin, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Broschag
authors.affiliation: Novartis Institute for BioMedical Research, Cambridge, MA.
authors.forename: Yan Ling
authors.initials: YL
authors.lastname: He
authors.affiliation: Novartis Institute for BioMedical Research, Cambridge, MA.
authors.forename: Lise
authors.initials: L
authors.lastname: Kjems
authors.affiliation: Novartis Pharmaceuticals, East Hanover, NJ.
authors.forename: James
authors.initials: J
authors.lastname: Foley
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D005260:Female; D005746:Gastric Emptying; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor / Q000037:antagonists & inhibitors / Q000378:metabolism; D064368:Healthy Volunteers; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009570:Nitriles / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000627:therapeutic use*; D011759:Pyrrolidines / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000077597:Vildagliptin
chemical_list: D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D007328:Insulin; D009570:Nitriles; D010446:Peptide Fragments; D011759:Pyrrolidines; C083773:exendin (9-39); D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D000077597:Vildagliptin; D000218:Adamantane