Dipeptidyl peptidase IV inhibitor potentiates duodenal bicarbonate secretion and prevents intestinal mucosal injury in rats

Abstract

Luminal nutrients stimulate enteroendocrine cells, which release gut hormones, including glucagon-like peptide-2 (GLP-2). Luminal co-perfusion of L-glutamate (L-Glu) and 5′-inosine monophosphate (IMP) synergistically increases duodenal bicarbonate secretion (DBS) via GLP-2 release, rapidly degraded by dipeptidyl peptidase (DPP) IV. We thus hypothesized that DPPIV inhibition enhances luminal nutrient-induced DBS and prevents intestinal injury. We measured DBS in a perfused rat duodenal loop. L-Glu and IMP were co-perfused +/− perfusion or iv injection of a selective DPPIV inhibitor NVP-728. The effect of a long-acting DPPIV inhibitor K579 (ig or ip) was also examined on indomethacin (IND)-induced intestinal injury. DPPIV activity was highly present on the brush border and submucosal layer. L-Glu/IMP perfusion increased DBS, inhibited by the GLP-2 receptor antagonist. NVP-728 iv enhanced the L-Glu/IMP-induced DBS, whereas perfused NVP-728 had no effect, suggesting that submucosal DPPIV degrades GLP-2. Pretreatment of K579 dose-dependently reduced the index of IND-induced intestinal ulcers. DPPIV inhibition potentiated L-Glu/IMP-induced DBS via GLP-2 pathway and prevented intestinal injury, suggesting that the modulation of endogenous GLP-2 by luminal nutrients and DPPIV inhibition may be therapeutic for intestinal mucosal injury and healing. Ajinomoto Inc, R01 DK54221