Glucagon-like peptide-1 analogue LY315902: effect on intestinal motility and release of insulin and somatostatin.

Abstract

LY315902 is an analogue of GLP-1 that yields a reduced clearance and longer half-life. The aim of the study is to assess the effect of LY315902 on fasting gastrointestinal motility, somatostatin and insulin release. Sprague-Dawley rats were fitted with three bipolar electrodes, 15, 25 and 35 cm distal to the pylorus. The effect of LY315902 and GLP-1 on migrating myoelectric complex (MMC) cycle length, duration and propagating velocity of activity fronts was studied for 60 min in conscious animals. The effect of LY315902 and GLP-1 on fasting small bowel motility was dose-dependent and treatment with exendin (9-39)amide, a GLP-1 receptor antagonist, together with LY315902 and GLP-1 completely antagonised the inhibitory effect of LY315902 and GLP-1 on fasting small bowel motility. Pretreatment with the nitric oxide (NO) synthase inhibitor N(omega)-nitro-L-arginine (L-NNA) partly blocked the action of both LY315902 and GLP-1. Plasma insulin concentrations were not different from controls during infusion of LY315902 or GLP-1, while somatostatin concentrations were significantly higher during LY315902 and GLP-1 compared to saline. LY315902 has a longer duration of inhibitory action on the MMC than GLP-1, albeit similar effects on plasma insulin and somatostatin concentrations. The effect of LY315902 on motor control is mediated through the GLP-1 receptor and seems partly dependent on the L-arginine/NO pathway.