Exendin-4 protects rat islets against loss of viability and function induced by brain death. (5th September 2015)

• Record Type: Journal Article
• Authors: Carlessi, Rodrigo; Lemos, Natália E.; Dias, Ana L.; Oliveira, Fernanda S.; Brondani, Letícia A.; Canani, Luis H.; Bauer, Andrea C.; Leitão, Cristiane B.; Crispim, Daisy
• Is Part Of: Molecular and cellular endocrinology. Volume 412(2015)
• Page Start: 239
• Page End: 250
• Publication Date: 2015-09-05
• Subjects: Brain death -- Islet transplantation -- Exendin-4 -- Inflammation -- ER stress; Actb β-actin -- BD brain death -- Hspa5/Bip Immunoglobulin heavy-chain binding protein -- Ccl2 Chemokine (C–C motif) ligand 2 -- Chop C/EBP homologous protein -- CREB cAMP response element-binding protein -- DAB diaminobenzidine tetrahydrochloride -- DAPI 4′, 6-diamidino-2-phenylindole, dilactate -- eIF2α Eukaryotic initiation factor 2 -- ER endoplasmic reticulum -- ERK1/2 Extracellular signal-regulated kinases 1 and 2 -- Ex-4 exendin-4 -- FDA fluorescein diacetate -- GLP1 Glucagon-like peptide-1 -- GSIS glucose-stimulated insulin secretion -- HMGB1 High mobility group box 1 -- HRP horseradish peroxidase -- IBMIR instant blood-mediated inflammatory reaction -- IEQ islet equivalents -- IL-1β Interleukin-1 beta -- IRE-1α Inositol-requiring enzyme 1 -- KRB Krebs–Ringer-bicarbonate buffer -- MAPK Mitogen-activated protein kinase -- PI propidium iodide -- PKA Protein kinase A -- ROS reactive oxygen species -- Sod2 Superoxide dismutase 2 -- Tf Tissue factor -- TNFα Tumor necrosis factor -- TRITC tetramethylrhodamine -- TUNEL Terminal deoxynucleotidyl transferase dUTP nick end labeling -- Ucp2 Uncoupling protein 2 -- Xbp-1 X-box binding protein 1; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2015.05.009
• Languages: English
• ISSNs: 0303-7207

Abstract

Highlights: Exendin-4 treatment prevents loss of islet viability induced by brain death. Impairment in GSIS induced by brain death is minimized by Exendin-4 treatment. Exendin-4 protects against brain death-induced increase in pancreatic IL-1β expression. ER stress related genes are augmented in islets following brain death. Brain death-induced loss of islet viability is not elicited by classic apoptosis. Abstract: Islet quality loss after isolation from brain-dead donors still hinders the implementation of human islet transplantation for treatment of type 1 diabetes. In this scenario, systemic inflammation elicited by donor brain death (BD) is among the main factors influencing islet viability and functional impairment. Exendin-4 is largely recognized to promote anti-inflammatory and cytoprotective effects on β-cells. Therefore, we hypothesized that administration of exendin-4 to brain-dead donors might improve islet survival and insulin secretory capabilities. Here, using a rat model of BD, we demonstrate that exendin-4 administration to the brain-dead donors increases both islet viability and glucose-stimulated insulin secretion. In this model, exendin-4 treatment produced a significant decrease in interleukin-1β expression in the pancreas. Furthermore, exendin-4 treatment increased the expression of superoxide dismutase-2 and prevented BD-induced elevation in uncoupling protein-2 expression. Such observations were accompanied by a reduction in gene expression of two genes often associated with endoplasmic reticulum (ER) stress response in freshly isolated islets from treated animals, C/EBP homologous protein and immunoglobulin heavy-chain binding protein . As ER stress response has been shown to be triggered by and to participate in cytokine-induced β-cell death, we suggest that exendin-4 might exert its beneficial effects through alleviation of pancreatic inflammation and oxidative stress, which in turn could prevent islet ER stress and β-cell death. Our findings might unveil a novel strategy to preserve islet quality from brain-dead donors. After testing in the human pancreatic islet transplantation setting, this approach might sum to the ongoing effort to achieve consistent and successful single-donor islet transplantation.