The release of GLP-1 from gut L cells is inhibited by low extracellular pH.

Abstract

The intestinal luminal pH profile varies from stomach to rectum and becomes disrupted in diseases. However, little is known about the pH dependence of incretin hormone secretion, with most in vitro studies having failed to consider this modulatory factor or having used nonphysiological buffer systems. Here, we report the extracellular pH (pHe) dependence of glucagon-like peptide-1 (GLP-1) exocytosis from L cells. The pHe dependence of GLP-1 release from GLUTag cells and murine ex vivo primary gut cultures was detected by ELISA. GLP-1 release was measured over a range of pHe under a physiological (CO₂/HCO₃ ^-) buffering regime and in its absence (HEPES buffer). The relationship between intracellular pH (pHi) and pHe was mapped given that at least some component of pH sensitivity is likely to be intracellular. GLP-1 secretion from L cells was pHe-dependent and stimulated under alkaline conditions. In the absence of glucose or extracellular calcium, secretion remained at a pHe-insensitive baseline. pHi followed changes in pHe, but the relationship was offset to more alkaline levels in the absence of CO₂/HCO₃ ^- buffer and became shallower if [Cl^-] changes that normally accompany [HCO₃ ^-] changes were compensated iso-osmotically with gluconate. GLP-1 secretion is sensitive to pHe and the buffer present. Exploiting this mechanism therapeutically may benefit patients with obesity.