Proglucagon-Derived Peptides Do Not Significantly Affect Acute Exocrine Pancreas in Rats

Abstract

Objectives: Reports have suggested a link between treatment with glucagon-like peptide 1 (GLP-1) analogs and an increased risk of pancreatitis. Oxyntomodulin, a dual agonist of both GLP-1 and glucagon receptors, is currently being investigated as a potential antiobesity therapy, but little is known about its pancreatic safety. The aim of the study was to investigate the acute effect of oxyntomodulin and other proglucagon-derived peptides on the rat exocrine pancreas.

Methods: Glucagon-like peptide 1, oxyntomodulin, glucagon, and exendin-4 were infused into anesthetized rats to measure plasma amylase concentration changes. In addition, the effect of each peptide on both amylase release and proliferation in rat pancreatic acinar (AR42J) and primary isolated ductal cells was determined.

Results: Plasma amylase did not increase postpeptide infusion, compared with vehicle and cholecystokinin; however, oxyntomodulin inhibited plasma amylase when coadministered with cholecystokinin. None of the peptides caused a significant increase in proliferation rate or amylase secretion from acinar and ductal cells.

Conclusions: The investigated peptides do not have an acute effect on the exocrine pancreas with regard to proliferation and plasma amylase, when administered individually. Oxyntomodulin seems to be a potent inhibitor of amylase release, potentially making it a safer antiobesity agent regarding pancreatitis, compared with GLP-1 agonists.

Fig. 1a, b

Amylase secretion (unit/ l) post GLP-1, glucagon (GCG), oxyntomodulin (OXM) and exendin-4 (Ex-4) bolus 30nmol intravenous injection. A dose of 2.4nmol/ rat cholecystokinin (CCK) was infused intravenously. Student t-test with Bonferroni correction was used to evaluate differences across time points vs. time 0. Values are shown as mean ± S.E.M. ** p < 0.01, *** p < 0.001 vs. time 0 basal sample (n= 4-5).

Fig. 1a, b

Amylase secretion (unit/ l) post GLP-1, glucagon (GCG), oxyntomodulin (OXM) and exendin-4 (Ex-4) bolus 30nmol intravenous injection. A dose of 2.4nmol/ rat cholecystokinin (CCK) was infused intravenously. Student t-test with Bonferroni correction was used to evaluate differences across time points vs. time 0. Values are shown as mean ± S.E.M. ** p < 0.01, *** p < 0.001 vs. time 0 basal sample (n= 4-5).

Fig. 2a, b

Amylase secretion (unit/ l) post peptide and CCK intravenous co-administration as a single bolus injection. GLP-1, glucagon (GCG), oxyntomodulin (OXM) and exendin-4 (EX-4) were co-administered at 30nmol with 2.4nmol CCK. Student t-test with Bonferroni correction was used between groups at individual time points vs. CCK. Values are shown as mean ± S.E.M. # p < 0.05, ## p < 0.01 vs. CCK (n= 4-5).

Fig. 2a, b

Amylase secretion (unit/ l) post peptide and CCK intravenous co-administration as a single bolus injection. GLP-1, glucagon (GCG), oxyntomodulin (OXM) and exendin-4 (EX-4) were co-administered at 30nmol with 2.4nmol CCK. Student t-test with Bonferroni correction was used between groups at individual time points vs. CCK. Values are shown as mean ± S.E.M. # p < 0.05, ## p < 0.01 vs. CCK (n= 4-5).

Fig. 3

Amylase release from AR42J cells post GLP-1, glucagon, oxyntomodulin, exendin-4 and CCK treatment at ascending concentrations for 50 min (n=5) a. GLP-1 b. Glucagon c. Oxyntomodulin d. Exendin-4 e. CCK. Amylase is expressed as a percentage of the secreted amylase into the medium over the total amylase content of the cells (100%). One way ANOVA with Tukey’s post-hoc test was used. Values are shown as mean ± S.E.M. *** p < 0.001 vs. untreated cells (0).

Fig. 4

Amylase release from AR42J cells post peptide (10nM)/ CCK (1nM) treatment for 50 min (n=5). Amylase is expressed as a percentage of the secreted amylase into the medium over the total activity of the cells (100%). Student t-test with Bonferroni correction was used between CCK and peptides. Values are shown as mean ± S.E.M. # p < 0.05, ## p < 0.01, ### p < 0.001 vs. CCK

Fig. 5

Relative Ki67 mRNA expression in a. AR42J cells and b. Billiopancreatic ductal cells treated with GLP-1, glucagon (GCG), oxyntomodulin (OXM) and exendin-4 (Ex-4) for 18hr (n=3-4). Student t-test with Bonferroni correction was used between untreated control group and peptides. Values are shown as mean ± S.E.M.

Fig. 5

Relative Ki67 mRNA expression in a. AR42J cells and b. Billiopancreatic ductal cells treated with GLP-1, glucagon (GCG), oxyntomodulin (OXM) and exendin-4 (Ex-4) for 18hr (n=3-4). Student t-test with Bonferroni correction was used between untreated control group and peptides. Values are shown as mean ± S.E.M.