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This version published online on December 16, 2004
Endocrinology, doi:10.1210/en.2004-1174
A more recent version of this article appeared on April 1, 2005
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Submitted on September 2, 2004
Accepted on December 10, 2004

Inhibition of DPP-4 Augments Insulin Secretion in Response to Exogenously Administered GLP-1, GIP, PACAP and GRP in Mice

BO AHRÉN* and THOMAS E. HUGHES

Department of Medicine, Lund University, B11 BMC, SE-221 84 LUND, Sweden, and Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, Massachusetts, U.S.A.

* To whom correspondence should be addressed. E-mail: bo.ahren{at}med.lu.se.

Inhibition of dipeptidyl peptidase-4 (DPP-4) is currently being explored as a new approach to the treatment of type 2 diabetes. This concept has emerged from the powerful and rapid action of the enzyme to inactivate glucagon-like peptide-1 (GLP-1). However, also other bioactive peptides with potential influence of islet function are substrates of DPP-4. Whether this inactivation may add to the beneficial effects of DPP-4 inhibition is not known. In this study, we explored whether DPP-4 inhibition by valine-pyrrolidide (val-pyr; 100 µmol/kg administered through gastric gavage at t30 min) affects the insulin and glucose responses to intravenous glucose (1 g/kg) together with GLP-1 (10 nmol/kg), GIP (glucose-dependent insulinotropic peptide; 10 nmol/kg), PACAP38 (pituitary adenylate cyclase activating polpeptide; 1.3 nmol/kg) or GRP (gastrin releasing peptide; 20 nmol/kg) given at t=0 in anesthetized C57BL/6J mice. It was found that the acute (1-5 min) insulin response to GLP-1 was augmented by val-pyr by 80% (4.2 ± 0.4 vs. 7.6 ± 0.8 nmol/liter), that to GIP by 40% (2.7 ± 0.3 vs. 3.8 ± 0.4 nmol/liter), that to PACAP38 by 75% (4.6 ± 0.5 vs. 8.1 ± 0.6 nmol/liter) and that to GRP by 25% (1.8 ± 0.2 vs. 2.3 ± 0.3 nmol/liter; all P < 0.05 or less). This was associated with enhanced glucose elimination rate after GLP-1 (KG 2.1 ± 0.2 vs. 3.1 ± 0.3%/min) and PACAP38 (2.1 ± 0.3 vs. 3.2 ± 0.3%/min; both P < 0.01), but not after GIP or GRP. The augmented insulin response to GRP by val-pyr was prevented by the GLP-1 receptor antagonist, exendin3 (9-39), raising the possibility that GRP effects may occur secondary to stimulation of GLP.1 secretion. We conclude that DPP-4 inhibition augments the insulin response not only to GLP-1 but also to GIP, PACAP38 and GRP.
Key words: DPP-4 • valine-pyrrolidide • GLP-1 • PACAP • GRP • GIP • insulin secretion • glucose tolerance • mice




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