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

Abstract

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.

Adaptive changes in pancreas post Roux‐en‐Y gastric bypass induced weight loss

“…No further increase suggesting GLP-1-mediated increased constitutive release of enzymes nor subclinical pancreatitis was seen. 11 Therefore, our present observations might reflect hyperlipidaemia-associated pancreatic injury with increased lipase enzyme activity in obesity.…”

“…In in vitro studies and animal models, GLP‐1 has been shown to increase beta‐cell mass through beta‐cell regeneration, proliferation, and neogenesis in immature islets, whereas fully differentiated adult human beta‐cells appear unable to proliferate, . Little is known about the effects of GLP‐1 on the exocrine pancreas, and its impact on the release of pancreatic lipase levels is controversially discussed …”

“…In in vitro studies and animal models, GLP-1 has been shown to increase beta-cell mass through beta-cell regeneration, proliferation, and neogenesis in immature islets, whereas fully differentiated adult human beta-cells appear unable to proliferate, 9.10 Little is known about the effects of GLP-1 on the exocrine pancreas, and its impact on the release of pancreatic lipase levels is controversially discussed. 11 Therefore, in the present study, we addressed the following questions: (1) Does pancreatic parenchymal and fat volume decrease following weight loss after RYGB, (2) does estimated beta-cell mass decrease after RYGB, and (3) is this associated with changes in insulin secretion, insulin sensitivity or GLP-1 release? 2 | MATERIALS AND METHODS…”

Efficacy and safety of dulaglutide monotherapy compared with glimepiride in East‐Asian patients with type 2 diabetes in a multicentre, double‐blind, randomized, parallel‐arm, active comparator, phase III trial

“…The most common drug‐related AEs reported in the present study were gastrointestinal (eg, diarrhoea or nausea), which were transient and rarely led to treatment discontinuation. A similar pattern of pancreatic enzyme increase associated with dulaglutide and the GLP‐1RA class of drugs was also observed in the present study. Small elevations in the mean concentration of pancreatic enzymes within a normal range were observed over time.…”

Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development

“…"Clearly, the development of the first antagonists with (subtype) selectivity for EPAC represents another research milestone to ascribe biologic responses to EPAC" (915). Indeed, these selective EPAC2 inhibitors are becoming effective tools in probing isoform-specific EPAC functions (18,47,130,175,226,250,302,411,463,565,682,743,841,896,961,1114).…”