Glucagon-like Peptide 1 Receptor Signaling in Acinar Cells Causes Growth-Dependent Release of Pancreatic Enzymes

• Published in: Cell reports (Cambridge) Vol. 17; no. 11; pp. 2845 - 2856
• Main Authors: Wewer Albrechtsen, Nicolai J., Albrechtsen, Reidar, Bremholm, Lasse, Svendsen, Berit, Kuhre, Rune E., Poulsen, Steen S., Christiansen, Charlotte B., Jensen, Elisa P., Janus, Charlotte, Hilsted, Linda, Deacon, Carolyn F., Hartmann, Bolette, Holst, Jens J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.12.2016
• Subjects: acinar cells; Acinar Cells - drug effects; Acinar Cells - enzymology; amylase; Amylases - genetics; Animals; Cell Line; Cell Proliferation - drug effects; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - enzymology; Forkhead Box Protein O1 - genetics; Gene Expression Regulation, Enzymologic; GLP-1; GLP-1R; Glucagon-Like Peptide 1 - administration & dosage; Glucagon-Like Peptide 1 - genetics; Glucagon-Like Peptide-1 Receptor - agonists; Glucagon-Like Peptide-1 Receptor - genetics; Humans; Incretins - therapeutic use; lipase; Lipase - genetics; Pancreas - enzymology; pancreatic enzymes; Pancreatitis - chemically induced; Pancreatitis - genetics; Pancreatitis - pathology; Signal Transduction; pancreatic enzymes; GLP-1; acinar cells; amylase; lipase; GLP-1R
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.11.051

Incretin-based therapies are widely used for type 2 diabetes and now also for obesity, but they are associated with elevated plasma levels of pancreatic enzymes and perhaps a modestly increased risk of acute pancreatitis. However, little is known about the effects of the incretin hormone glucagon-like peptide 1 (GLP-1) on the exocrine pancreas. Here, we identify GLP-1 receptors on pancreatic acini and analyze the impact of receptor activation in humans, rodents, isolated acini, and cell lines from the exocrine pancreas. GLP-1 did not directly stimulate amylase or lipase release. However, we saw that GLP-1 induces phosphorylation of the epidermal growth factor receptor and activation of Foxo1, resulting in cell growth with concomitant enzyme release. Our work uncovers GLP-1-induced signaling pathways in the exocrine pancreas and suggests that increases in amylase and lipase levels in subjects treated with GLP-1 receptor agonists reflect adaptive growth rather than early-stage pancreatitis. [Display omitted] •Glucagon-like peptide 1 does not acutely increase amylase and lipase levels•Glucagon-like peptide 1 induces mild c-Src-dependent acinar cell proliferation•This proliferation is associated with an increased constitutive release of enzymes•Enzyme increase during GLP-1 treatment does not reflect sub-clinical pancreatitis Glucagon-like peptide 1 (GLP-1)-based therapies are used to treat type 2 diabetes and obesity. Wewer Albrechtsen et al. detect GLP-1 receptor expression in pancreatic acinar cells and show that its activation leads to mild c-Src-dependent proliferation, increasing constitutive enzyme release. This enzyme increase during GLP-1 treatment does not reflect sub-clinical pancreatitis.