Glucagon-like peptide-1 receptor activation modulates pancreatitis-associated gene expression but does not modify the susceptibility to experimental pancreatitis in mice.
OBJECTIVE
Clinical reports link use of the glucagon-like peptide-1 receptor (GLP-1R) agonists exenatide and liraglutide to pancreatitis. However, whether these agents act on the exocrine pancreas is poorly understood.


METHODS
We assessed whether the antidiabetic agents exendin (Ex)-4, liraglutide, the dipeptidyl peptidase-4 inhibitor sitagliptin, or the biguanide metformin were associated with changes in expression of genes associated with the development of experimental pancreatitis. The effects of Ex-4 when administered before or after the initiation of caerulein-induced experimental pancreatitis were determined. The importance of endogenous GLP-1R signaling for gene expression in the exocrine pancreas and the severity of pancreatitis was assessed in Glp1r(-/-) mice.


RESULTS
Acute administration of Ex-4 increased expression of egr-1 and c-fos in the exocrine pancreas. Administration of Ex-4 or liraglutide for 1 week increased pancreas weight and induced expression of mRNA transcripts encoding the anti-inflammatory proteins pancreatitis-associated protein (PAP) (RegIIIbeta) and RegIIIalpha. Chronic Ex-4 treatment of high-fat-fed mice increased expression of PAP and reduced pancreatic expression of mRNA transcripts encoding for the proinflammatory monocyte chemotactic protein-1, tumor necrosis factor-alpha, and signal transducer and activator of transcription-3. Sitagliptin and metformin did not significantly change pancreatic gene expression profiles. Ex-4 administered before or after caerulein did not modify the severity of experimental pancreatitis, and levels of pancreatic edema and serum amylase were comparable in caerulein-treated Glp1r(-/-) versus Glp1r(+/+) mice.


CONCLUSIONS
These findings demonstrate that GLP-1 receptor activation increases pancreatic mass and selectively modulates the expression of genes associated with pancreatitis. However, activation or genetic elimination of GLP-1R signaling does not modify the severity of experimental pancreatitis in mice.
Koehler
Jacqueline A
JA
Department of Medicine, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Ontario, Canada.
Baggio
Laurie L
LL
Lamont
Benjamin J
BJ
Ali
Safina
S
Drucker
Daniel J
DJ
D000818:Animals; D002108:Ceruletide / Q000633:toxicity; D004041:Dietary Fats / Q000494:pharmacology; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1 / Q000235:genetics; D000077270:Exenatide; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D016762:Genes, fos / Q000502:physiology; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives / Q000378:metabolism* / Q000633:toxicity; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents / Q000633:toxicity; D000069450:Liraglutide; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D046790:Pancreas, Exocrine / Q000187:drug effects / Q000502:physiology; D010195:Pancreatitis / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology*; D000073718:Pancreatitis-Associated Proteins; D010455:Peptides / Q000633:toxicity; D018027:Receptors, Glucagon / Q000235:genetics* / Q000378:metabolism*; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014688:Venoms / Q000633:toxicity
D004041:Dietary Fats; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D000073718:Pancreatitis-Associated Proteins; D010455:Peptides; C000612141:REG3A protein, human; D018027:Receptors, Glucagon; D014688:Venoms; D000069450:Liraglutide; D002108:Ceruletide; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide