Chronic Continuous Exenatide Infusion Does Not Cause Pancreatic Inflammation and Ductal Hyperplasia in Non-Human Primates

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 receptor agonist exenatide has no acute effect on MRI‐measured exocrine pancreatic function in patients with type 2 diabetes: a randomized trial

“…An increasing amount of evidence suggests pancreatic safety with GLP‐1 receptor agonists. A recent controlled study with exenatide demonstrated no effect on exocrine pancreatic histology (in baboons) . Moreover, the largest case–control study to date found no adverse effects of exenatide .…”

Immunohistochemical assessment of glucagon‐like peptide 1 receptor (GLP‐1R) expression in the pancreas of patients with type 2 diabetes

“…A recent histology study by Ueberberg et al in a distinct donor cohort including patients with and without history of incretin based‐treatment (1 GLP‐1R agonist and 6 DPP‐4 inhibitor treated), also found no advanced PanIN lesions in any of the samples studied . Another study showed that continuous, 14‐week infusion of exenatide in non‐human primates does not alter PanIN prevalence . For the present study samples, the average age within the cohort of 7 DPP‐4 inhibitor donors combined with a single GLP‐1R agonist‐treated donor is significantly higher than their non‐incretin‐based counterparts (58.0 ± 10.2 vs 42.3 ± 13.7; P = .0052).…”

“…primates does not alter PanIN prevalence. 23 For the present study In the present study, the frequency of GLP-1R-positive cells located within or in close proximity to the ductal epithelium was quantitated. The area of this population of cells with respect to ductal epithelial cells was calculated to be approximately 4%.…”

Pancreas Volume and Fat Deposition in Diabetes and Normal Physiology: Consideration of the Interplay Between Endocrine and Exocrine Pancreas

“…However, since the start of incretin-based medicine several case reports on the development of acute pancreatitis have been published, and the US Food and Drug Administration (FDA) has issued a "black box warning" for these drugs [81]. Incretin-induced pancreatitis and subsequent oncogenesis have been suggested by some animal studies [82][83][84][85], but the results are conflicting [86][87][88][89][90]. It has also been shown that the GLP-1 receptor is expressed in some but not all pancreatic exocrine cells [91], while DPP-4 is expressed in some (~30%) duct cells [92].…”