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Background: Clinical reports have suggested the potential link of Glucagon-Like Peptide 1 Receptor Agonists (GLP-1RAs) with the development of pancreatitis. We investigated the effects of long-term exposure of Exendin-4 (Ex-4), a kind of GLP-1RA, on biochemical, histological and genetic markers of pancreatitis in High-Fat Diet (HFD) induced mice. Methodology: HFD induced mice received subcutaneous twice-daily injections of Ex-4 (3 and 30 μg/kg/d) or vehicle for 12 w. Pancreatitis was induced with Caerulein (CRN) in Ex-4 treated mice or wild mice. Changes in body weight, food consumption, serum amylase, serum lipase, glucose, and insulin concentrations were measured in each group. An extended histopathological and ultralstructural by transmission electron microscopy evaluation of exocrine pancreas was performed. The expressions of pancreatitis-associated microRNAs and genes were assessed by real-time PCR. Results: Ex-4 improved physical condition, glucose concentrations, decreased food intake, and increased serum insulin sensitivity in HFD induced mice. No deleterious effects on serum amylase and lipase were observed after Ex-4 treatment. The histopathological and ultralstructural findings did not reveal adverse effects of Ex-4. Ex-4 administration did not significantly modify the level of pancreatitisassociated microRNAs (miR-181, miR-148, miR-210 and miR-216a) or pancreatitis-associated genes (RegIII, MCP-1 and IL-6). However, we noted slightly pancreatitis ultralstructural changes in one mouse from 30 μg/kg/d Ex-4-treated group. Conclusion: Ex-4 does not affect biochemical, histopathological or genetic markers of pancreatitis in HFD induced mice. However, surveillance for a possible increased risk of pancreatitis under excess GLP-1RAs administration is warranted to ensure at least benefits far outweigh potential risks.

Exendin-4 dose not evoke pancreatitis or pancreatitis-associated histopathological and genetic changes in high-fat diet induced diabetic mice