title: Exendin-4 protects rat islets against loss of viability and function induced by brain death.
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.
authors.affiliation: Laboratory of Human Pancreatic Islet Biology, Endocrine Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil; Post-Graduate Program in Medical Sciences: Endocrinology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; School of Biomedical Sciences, CHIRI - Biosciences, Curtin University, Perth, Western Australia 6845, Australia.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Carlessi
authors.affiliation: Laboratory of Human Pancreatic Islet Biology, Endocrine Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil; Post-Graduate Program in Medical Sciences: Endocrinology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Natália E
authors.initials: NE
authors.lastname: Lemos
authors.affiliation: Laboratory of Human Pancreatic Islet Biology, Endocrine Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil.
authors.forename: Ana L
authors.initials: AL
authors.lastname: Dias
authors.affiliation: Laboratory of Human Pancreatic Islet Biology, Endocrine Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil.
authors.forename: Fernanda S
authors.initials: FS
authors.lastname: Oliveira
authors.affiliation: Laboratory of Human Pancreatic Islet Biology, Endocrine Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil; Post-Graduate Program in Medical Sciences: Endocrinology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Letícia A
authors.initials: LA
authors.lastname: Brondani
authors.affiliation: Laboratory of Human Pancreatic Islet Biology, Endocrine Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil; Post-Graduate Program in Medical Sciences: Endocrinology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Luis H
authors.initials: LH
authors.lastname: Canani
authors.affiliation: Laboratory of Human Pancreatic Islet Biology, Endocrine Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil.
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Bauer
authors.affiliation: Laboratory of Human Pancreatic Islet Biology, Endocrine Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil; Post-Graduate Program in Medical Sciences: Endocrinology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Cristiane B
authors.initials: CB
authors.lastname: Leitão
authors.affiliation: Laboratory of Human Pancreatic Islet Biology, Endocrine Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil; Post-Graduate Program in Medical Sciences: Endocrinology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. Electronic address: dcmoreira@hcpa.edu.br.
authors.forename: Daisy
authors.initials: D
authors.lastname: Crispim
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis; D001926:Brain Death / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019610:Cytoprotection; D000077270:Exenatide; D015870:Gene Expression; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000502:physiology*; D020935:MAP Kinase Signaling System; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D017208:Rats, Wistar; D013312:Stress, Physiological; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D000071246:Uncoupling Protein 2; D014688:Venoms / Q000494:pharmacology*; D000099156:Superoxide Dismutase 2; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D000893:Anti-Inflammatory Agents; D000077270:Exenatide; D006360:Heat-Shock Proteins; D007328:Insulin; D053583:Interleukin-1beta; D007473:Ion Channels; D024101:Mitochondrial Proteins; D010455:Peptides; D013482:Superoxide Dismutase; D051742:Transcription Factor CHOP; D014409:Tumor Necrosis Factor-alpha; D000071246:Uncoupling Protein 2; D014688:Venoms; D000099156:Superoxide Dismutase 2; C497251:Ddit3 protein, rat; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C000604389:UCP2 protein, human; C000604391:Ucp2 protein, rat
keywords: Brain death; ER stress; Exendin-4; Inflammation; Islet transplantation