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Diabetes. 2016 Aug;65(8):2440-7. doi: 10.2337/db16-0107. Epub 2016 Apr 5.

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.

Author information

1
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.
2
PAREXEL, Berlin, Germany.
3
Diabeteszentrum Bad Lauterberg, Bad Lauterberg im Harz, Germany.
4
Department of Biomedical Sciences, Panum Institute, University of Copenhagen, Copenhagen, Denmark.
5
Novartis Institute for BioMedical Research, Cambridge, MA.
6
Novartis Pharmaceuticals, East Hanover, NJ.

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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT02639130.

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PMID:
27207543
DOI:
10.2337/db16-0107
[Indexed for MEDLINE]
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