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

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.