Inhibition of dipeptidyl peptidase-4 augments insulin secretion in response to exogenously administered glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, pituitary adenylate cyclase-activating polypeptide, and gastrin-releasing peptide in mice

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 mu mol/ 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 ( K-G) 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, exendin(3) ( 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.