title: 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.
authors.affiliation: 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.
authors.forename: Teresa Vanessa
authors.initials: TV
authors.lastname: Fiorentino
authors.affiliation: Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas.
authors.forename: Michael
authors.initials: M
authors.lastname: Owston
authors.affiliation: Department of Surgery, Transplant Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Gregory
authors.initials: G
authors.lastname: Abrahamian
authors.affiliation: Department of Pathology, Ospedale di Circolo and Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: La Rosa
authors.affiliation: Department of Pathology, Ospedale di Circolo and Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Marando
authors.affiliation: Department of Pharmacology and Biomolecular Science, Universitádegli Studi di Milano, Milan, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Perego
authors.affiliation: Department of Pharmacology and Biomolecular Science, Universitádegli Studi di Milano, Milan, Italy.
authors.forename: Eliana S
authors.initials: ES
authors.lastname: Di Cairano
authors.affiliation: Department of Pathology, Ospedale di Circolo and Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Finzi
authors.affiliation: Department of Pathology, Ospedale di Circolo and Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Capella
authors.affiliation: Department of Pathology, Ospedale di Circolo and Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy.
authors.forename: Fausto
authors.initials: F
authors.lastname: Sessa
authors.affiliation: 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.
authors.forename: Francesca
authors.initials: F
authors.lastname: Casiraghi
authors.affiliation: Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Ana
authors.initials: A
authors.lastname: Paez
authors.affiliation: Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Ashwin
authors.initials: A
authors.lastname: Adivi
authors.affiliation: 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.
authors.forename: Alberto
authors.initials: A
authors.lastname: Davalli
authors.affiliation: Department of Pediatrics, Children's Hospital Harvard Medical School, Boston, Massachusetts.
authors.forename: Paolo
authors.initials: P
authors.lastname: Fiorina
authors.affiliation: 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.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Guardado Mendoza
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas.
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Comuzzie
authors.affiliation: Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas.
authors.forename: Mark
authors.initials: M
authors.lastname: Sharp
authors.affiliation: Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Ralph A
authors.initials: RA
authors.lastname: DeFronzo
authors.affiliation: Department of Surgery, Transplant Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Glenn
authors.initials: G
authors.lastname: Halff
authors.affiliation: Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Dick
authors.affiliation: 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.
authors.forename: Franco
authors.initials: F
authors.lastname: Folli
mesh_terms: D000681:Amylases / Q000097:blood; D000818:Animals; D017209:Apoptosis; D000077270:Exenatide; D005260:Female; D006965:Hyperplasia; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology*; D007262:Infusions, Intravenous; D007333:Insulin Resistance; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008856:Microscopy, Fluorescence; D046790:Pancreas, Exocrine / Q000378:metabolism / Q000473:pathology*; D010183:Pancreatic Ducts / Q000166:cytology / Q000473:pathology*; D010215:Papio; D010455:Peptides / Q000008:administration & dosage* / Q000009:adverse effects; D010641:Phenotype; D014688:Venoms / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D007004:Hypoglycemic Agents; D019394:Ki-67 Antigen; D010455:Peptides; D014688:Venoms; D000077270:Exenatide; D000681:Amylases