Abstract

Background Clinical reports link use of the 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 anti-diabetic agents exendin-4 or liraglutide or the DPP-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 exendin-4 when administered prior to or following the initiation of caerulein-induced experimental pancreatitis was 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 exendin-4 increased expression of egr-1 and c-fos in the exocrine pancreas. Administration of exendin-4 or liraglutide for 1 week increased pancreas weight, and induced expression of mRNA transcripts encoding the anti-inflammatory proteins PAP (RegIIIβ) and RegIIIα. Chronic exendin-4 treatment of high fat fed mice increased expression of PAP and reduced pancreatic expression of mRNA transcripts encoding for the proinflammatory proteins MCP-1, TNFα and STAT3. Sitagliptin and metformin did not significantly change pancreatic gene expression profiles. Exendin-4 administered prior to or following caerulein, did not modify the severity of experimental pancreatitis and levels of pancreatic edema and serum amylase were comparable in caerulein-treated Glp1r−/− vs. 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.