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Department of Medicine (B.A.), Lund University, SE-221 84 Lund, Sweden; and Novartis Institutes for Biomedical Research (T.E.H.), Cambridge, Massachusetts 02139
Address all correspondence and requests for reprints to: Dr. Bo Ahrén, Department of Medicine, Lund University, B11 BMC, SE-221 84 Lund, Sweden. 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, other bioactive peptides with potential influence of islet function are also 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 t = –30 min) affects the insulin and glucose responses to iv glucose (1 g/kg) together with GLP-1 (10 nmol/kg), glucose-dependent insulinotropic polypeptide (GIP; 10 nmol/kg), pituitary adenylate cyclase-activating polypeptide 38 (PACAP38; 1.3 nmol/kg), or gastrin-releasing peptide (GRP; 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 [glucose elimination constant (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.
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