Present address: Innovation Center China, AstraZeneca Global R&D, 898 Halei Road, Shanghai, 201203.
Agonists at GPR119 mediate secretion of GLP-1 from mouse enteroendocrine cells through glucose-independent pathways
Article first published online: 23 MAR 2012
© 2011 Merck Sharp & Dohme Corp. British Journal of Pharmacology © 2011 The British Pharmacological Society
British Journal of Pharmacology
Special Issue: Themed Section: Cannabinoids in Biology and Medicine, Part II. Guest Editors: Itai Bab and Steve Alexander
Volume 165, Issue 8, pages 2799–2807, April 2012
How to Cite
Lan, H., Lin, H., Wang, C., Wright, M., Xu, S., Kang, L., Juhl, K., Hedrick, J. and Kowalski, T. (2012), Agonists at GPR119 mediate secretion of GLP-1 from mouse enteroendocrine cells through glucose-independent pathways. British Journal of Pharmacology, 165: 2799–2807. doi: 10.1111/j.1476-5381.2011.01754.x
- Issue published online: 23 MAR 2012
- Article first published online: 23 MAR 2012
- Accepted manuscript online: 26 OCT 2011 06:29AM EST
- Received; 19 August 2011; Revised; 7 October 2011; Accepted; 13 October 2011
- calcium influx
BACKGROUND AND PURPOSE The G protein-coupled receptor 119 (GPR119) mediates insulin secretion from pancreatic β cells and glucagon-like peptide 1 (GLP-1) release from intestinal L cells. While GPR119-mediated insulin secretion is glucose dependent, it is not clear whether or not GPR119-mediated GLP-1 secretion similarly requires glucose. This study was designed to address the glucose-dependence of GPR119-mediated GLP-1 secretion, and to explore the cellular mechanisms of hormone secretion in L cells versus those in β cells.
EXPERIMENTAL APPROACH GLP-1 secretion in response to GPR119 agonists and ion channel modulators, with and without glucose, was analysed in the intestinal L cell line GLUTag, in primary intestinal cell cultures and in vivo. Insulin secretion from Min6 cells, a pancreatic β cell line, was analysed for comparison.
KEY RESULTS In GLUTag cells, GPR119 agonists stimulated GLP-1 secretion both in the presence and in the absence of glucose. In primary mouse colon cultures, GPR119 agonists stimulated GLP-1 secretion under glucose-free conditions. Moreover, a GPR119 agonist increased plasma GLP-1 in mice without a glucose load. However, in Min6 cells, GPR119-mediated insulin secretion was glucose-dependent. Among the pharmacological agents tested in this study, nitrendipine, an L-type voltage-dependent calcium channel blocker, dose-dependently reduced GLP-1 secretion from GLUTag cells, but had no effect in Min6 cells in the absence of glucose.
CONCLUSIONS AND IMPLICATIONS Unlike that in pancreatic β cells, GPR119-mediated GLP-1 secretion from intestinal L cells was glucose-independent in vitro and in vivo, probably because of a higher basal calcium tone in the L cells.