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Am J Pathol. 2015 Jan;185(1):139-50. doi: 10.1016/j.ajpath.2014.09.009. Epub 2014 Nov 6.

Chronic continuous exenatide infusion does not cause pancreatic inflammation and ductal hyperplasia in non-human primates.

Author information

1
Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas; Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy.
2
Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas.
3
Department of Surgery, Transplant Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
4
Department of Pathology, Ospedale di Circolo and Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy.
5
Department of Pharmacology and Biomolecular Science, Universitádegli Studi di Milano, Milan, Italy.
6
Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas; Department of Biomedical Sciences for Health, Universitádegli Studi di Milano, Milan, Italy.
7
Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
8
Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
9
Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas; Department of Internal and Specialized Medicine, Ospedale San Raffaele, Milan, Italy.
10
Department of Pediatrics, Children's Hospital Harvard Medical School, Boston, Massachusetts.
11
Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas; Division of Health Sciences, Department of Medicine and Nutrition, University of Guanajuato, Campus León, México, and the Research Department, Hospital Regional de Alta Especialidad del Bajío, León, Mexico.
12
Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas.
13
Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas; Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas; Faculdade de Ciencias Medicas (FCM), Departamento de Clinica Medica, Obesity and Comorbidities Research Center (O.C.R.C.), Universidade Estadual de Campinas (UNICAMP), Campinas, Brazil. Electronic address: folli@uthscsa.edu.

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.

PMID:
25447052
PMCID:
PMC4278248
DOI:
10.1016/j.ajpath.2014.09.009
[Indexed for MEDLINE]
Free PMC Article

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