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Alpha1-antitrypsin ameliorates islet amyloid-induced glucose intolerance and β-cell dysfunction
OBJECTIVE: Pancreatic β-cell failure is central to the development and progression of type 2 diabetes (T2D). The aggregation of human islet amyloid polypeptide (hIAPP) has been associated with pancreatic islet inflammation and dysfunction in T2D. Alpha1-antitrypsin (AAT) is a circulating protease in...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186564/ https://www.ncbi.nlm.nih.gov/pubmed/32229246 http://dx.doi.org/10.1016/j.molmet.2020.100984 |
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author | Rodríguez-Comas, Júlia Moreno-Vedia, Juan Obach, Mercè Castaño, Carlos de Pablo, Sara Alcarraz-Vizán, Gema Díaz-Catalán, Daniela Mestre, Anna Horrillo, Raquel Costa, Montserrat Novials, Anna Servitja, Joan-Marc |
author_facet | Rodríguez-Comas, Júlia Moreno-Vedia, Juan Obach, Mercè Castaño, Carlos de Pablo, Sara Alcarraz-Vizán, Gema Díaz-Catalán, Daniela Mestre, Anna Horrillo, Raquel Costa, Montserrat Novials, Anna Servitja, Joan-Marc |
author_sort | Rodríguez-Comas, Júlia |
collection | PubMed |
description | OBJECTIVE: Pancreatic β-cell failure is central to the development and progression of type 2 diabetes (T2D). The aggregation of human islet amyloid polypeptide (hIAPP) has been associated with pancreatic islet inflammation and dysfunction in T2D. Alpha1-antitrypsin (AAT) is a circulating protease inhibitor with anti-inflammatory properties. Here, we sought to investigate the potential therapeutic effect of AAT treatment in a mouse model characterized by hIAPP overexpression in pancreatic β-cells. METHODS: Mice overexpressing hIAPP (hIAPP-Tg) in pancreatic β-cells were used as a model of amyloid-induced β-cell dysfunction. Glucose homeostasis was evaluated by glucose tolerance tests and insulin secretion assays. Apoptosis and amyloid formation was assessed in hIAPP-Tg mouse islets cultured at high glucose levels. Dissociated islet cells were cocultured with macrophages obtained from the peritoneal cavity. RESULTS: Nontreated hIAPP-Tg mice were glucose intolerant and exhibited impaired insulin secretion. Interestingly, AAT treatment improved glucose tolerance and restored the insulin secretory response to glucose in hIAPP-Tg mice. Moreover, AAT administration normalized the expression of the essential β-cell genes MafA and Pdx1, which were downregulated in pancreatic islets from hIAPP-Tg mice. AAT prevented the formation of amyloid deposits and apoptosis in hIAPP-Tg islets cultured at high glucose concentrations. Since islet macrophages mediate hIAPP-induced β-cell dysfunction, we investigated the effect of AAT in cocultures of macrophages and islet cells. AAT prevented hIAPP-induced β-cell apoptosis in these cocultures without reducing the hIAPP-induced secretion of IL-1β by macrophages. Remarkably, AAT protected β-cells against the cytotoxic effects of conditioned medium from hIAPP-treated macrophages. Similarly, AAT also abrogated the cytotoxic effects of exogenous proinflammatory cytokines on pancreatic β-cells. CONCLUSIONS: These results demonstrate that treatment with AAT improves glucose homeostasis in mice overexpressing hIAPP and protects pancreatic β-cells from the cytotoxic actions of hIAPP mediated by macrophages. These results support the use of AAT-based therapies to recover pancreatic β-cell function for the treatment of T2D. |
format | Online Article Text |
id | pubmed-7186564 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-71865642020-05-04 Alpha1-antitrypsin ameliorates islet amyloid-induced glucose intolerance and β-cell dysfunction Rodríguez-Comas, Júlia Moreno-Vedia, Juan Obach, Mercè Castaño, Carlos de Pablo, Sara Alcarraz-Vizán, Gema Díaz-Catalán, Daniela Mestre, Anna Horrillo, Raquel Costa, Montserrat Novials, Anna Servitja, Joan-Marc Mol Metab Original Article OBJECTIVE: Pancreatic β-cell failure is central to the development and progression of type 2 diabetes (T2D). The aggregation of human islet amyloid polypeptide (hIAPP) has been associated with pancreatic islet inflammation and dysfunction in T2D. Alpha1-antitrypsin (AAT) is a circulating protease inhibitor with anti-inflammatory properties. Here, we sought to investigate the potential therapeutic effect of AAT treatment in a mouse model characterized by hIAPP overexpression in pancreatic β-cells. METHODS: Mice overexpressing hIAPP (hIAPP-Tg) in pancreatic β-cells were used as a model of amyloid-induced β-cell dysfunction. Glucose homeostasis was evaluated by glucose tolerance tests and insulin secretion assays. Apoptosis and amyloid formation was assessed in hIAPP-Tg mouse islets cultured at high glucose levels. Dissociated islet cells were cocultured with macrophages obtained from the peritoneal cavity. RESULTS: Nontreated hIAPP-Tg mice were glucose intolerant and exhibited impaired insulin secretion. Interestingly, AAT treatment improved glucose tolerance and restored the insulin secretory response to glucose in hIAPP-Tg mice. Moreover, AAT administration normalized the expression of the essential β-cell genes MafA and Pdx1, which were downregulated in pancreatic islets from hIAPP-Tg mice. AAT prevented the formation of amyloid deposits and apoptosis in hIAPP-Tg islets cultured at high glucose concentrations. Since islet macrophages mediate hIAPP-induced β-cell dysfunction, we investigated the effect of AAT in cocultures of macrophages and islet cells. AAT prevented hIAPP-induced β-cell apoptosis in these cocultures without reducing the hIAPP-induced secretion of IL-1β by macrophages. Remarkably, AAT protected β-cells against the cytotoxic effects of conditioned medium from hIAPP-treated macrophages. Similarly, AAT also abrogated the cytotoxic effects of exogenous proinflammatory cytokines on pancreatic β-cells. CONCLUSIONS: These results demonstrate that treatment with AAT improves glucose homeostasis in mice overexpressing hIAPP and protects pancreatic β-cells from the cytotoxic actions of hIAPP mediated by macrophages. These results support the use of AAT-based therapies to recover pancreatic β-cell function for the treatment of T2D. Elsevier 2020-03-27 /pmc/articles/PMC7186564/ /pubmed/32229246 http://dx.doi.org/10.1016/j.molmet.2020.100984 Text en © 2020 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Original Article Rodríguez-Comas, Júlia Moreno-Vedia, Juan Obach, Mercè Castaño, Carlos de Pablo, Sara Alcarraz-Vizán, Gema Díaz-Catalán, Daniela Mestre, Anna Horrillo, Raquel Costa, Montserrat Novials, Anna Servitja, Joan-Marc Alpha1-antitrypsin ameliorates islet amyloid-induced glucose intolerance and β-cell dysfunction |
title | Alpha1-antitrypsin ameliorates islet amyloid-induced glucose intolerance and β-cell dysfunction |
title_full | Alpha1-antitrypsin ameliorates islet amyloid-induced glucose intolerance and β-cell dysfunction |
title_fullStr | Alpha1-antitrypsin ameliorates islet amyloid-induced glucose intolerance and β-cell dysfunction |
title_full_unstemmed | Alpha1-antitrypsin ameliorates islet amyloid-induced glucose intolerance and β-cell dysfunction |
title_short | Alpha1-antitrypsin ameliorates islet amyloid-induced glucose intolerance and β-cell dysfunction |
title_sort | alpha1-antitrypsin ameliorates islet amyloid-induced glucose intolerance and β-cell dysfunction |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186564/ https://www.ncbi.nlm.nih.gov/pubmed/32229246 http://dx.doi.org/10.1016/j.molmet.2020.100984 |
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