Agonists at GPR119 mediate secretion of GLP-1 from mouse enteroendocrine cells through glucose-independent pathways.
OBJECTIVE
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.


METHODS
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.


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
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.
Diabetes and Endocrinology, Merck Research Laboratories, Rahway, NJ, USA             Biologics, Merck Research Laboratories, Rahway, NJ, USA.
H
H
Lan
H V
HV
Lin
C F
CF
Wang
M J
MJ
Wright
S
S
Xu
L
L
Kang
K
K
Juhl
J A
JA
Hedrick
T J
TJ
Kowalski
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D003106:Colon / Q000166:cytology; D063388:Endocannabinoids; D019858:Enteroendocrine Cells / Q000187:drug effects* / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009829:Oleic Acids / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*
D063388:Endocannabinoids; C516207:Gpr119 protein, mouse; D009829:Oleic Acids; D043562:Receptors, G-Protein-Coupled; D005576:Colforsin; C488250:oleoylethanolamide; D052216:Glucagon-Like Peptide 1; D005947:Glucose; D002118:Calcium