| Abstract: | In this study, we aimed to evaluate the effects of exenatide (EXE) treatment on exocrine pancreas of nonhuman primates. To this end, 52 baboons (Papio hamadryas) underwent partial pancreatectomy, followed by continuous infusion of EXE or saline (SAL) for 14 weeks. Histological analysis, immunohistochemistry, Computer Assisted Stereology Toolbox morphometry, and immunofluorescence staining were performed at baseline and after treatment. The EXE treatment did not induce pancreatitis, parenchymal or periductal inflammatory cell accumulation, ductal hyperplasia, or dysplastic lesions/pancreatic intraepithelial neoplasia. At study end, Ki-67–positive (proliferating) acinar cell number did not change, compared with baseline, in either group. Ki-67–positive ductal cells increased after EXE treatment (P = 0.04). However, the change in Ki-67–positive ductal cell number did not differ significantly between the EXE and SAL groups (P = 0.13). M-30–positive (apoptotic) acinar and ductal cell number did not change after SAL or EXE treatment. No changes in ductal density and volume were observed after EXE or SAL. Interestingly, by triple-immunofluorescence staining, we detected c-kit (a marker of cell transdifferentiation) positive ductal cells co-expressing insulin in ducts only in the EXE group at study end, suggesting that EXE may promote the differentiation of ductal cells toward a β-cell phenotype. In conclusion, 14 weeks of EXE treatment did not exert any negative effect on exocrine pancreas, by inducing either pancreatic inflammation or hyperplasia/dysplasia in nonhuman primates.Glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-IV (DPP-IV) inhibitors represent new classes of therapeutic agents for type 2 diabetes mellitus treatment acting by augmenting β-cell function while decreasing food intake and body weight.1–7Isolated cases of pancreatitis have been reported in diabetic patients treated with GLP-1 receptor agonists and DPP-IV inhibitors, prompting the US Food and Drug Administration to issue alerts on possible adverse effects.8 Acute pancreatitis is a severe clinical condition characterized by pancreatic pathological changes and increased serum amylase and lipase levels. Obstructive gallstone disease, alcohol abuse, hypertriglyceridemia, obesity, and type 2 diabetes mellitus are the most common risk factors for pancreatitis and pancreatic cancer.9–11Although pancreatitis and pancreatic cancer have been suggested to be more frequent in diabetic patients treated with GLP-1–based therapies, the methodologically heterogeneous literature available does not support a firm conclusion on whether GLP-1 receptor agonists or DPP-IV inhibitors are directly implicated in pancreatitis or pancreatic cancer.8,12–25 Animal studies designed to examine the effect of GLP-1–based therapies on exocrine pancreas have also yielded conflicting results.26–31In this study, we directly evaluated whether the GLP-1 receptor agonist exenatide (EXE) can promote inflammation/pancreatitis and hyperplasia/dysplasia in exocrine pancreas of baboons. Baboons have interesting genetic and physiological similarity to humans, develop similar pathological features, and represent a valuable model to study human diseases, such as insulin resistance, obesity, and type 2 diabetes mellitus.32–38 |
