A human antibody against pathologic IAPP aggregates protects beta cells in type 2 diabetes models

In patients with type 2 diabetes, pancreatic beta cells progressively degenerate and gradually lose their ability to produce insulin and regulate blood glucose. Beta cell dysfunction and loss is associated with an accumulation of aggregated forms of islet amyloid polypeptide (IAPP) consisting of sol...

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Autores principales: Wirth, Fabian, Heitz, Fabrice D., Seeger, Christine, Combaluzier, Ioana, Breu, Karin, Denroche, Heather C., Thevenet, Julien, Osto, Melania, Arosio, Paolo, Kerr-Conte, Julie, Verchere, C. Bruce, Pattou, François, Lutz, Thomas A., Donath, Marc Y., Hock, Christoph, Nitsch, Roger M., Grimm, Jan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10562398/
https://www.ncbi.nlm.nih.gov/pubmed/37813862
http://dx.doi.org/10.1038/s41467-023-41986-0
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author Wirth, Fabian
Heitz, Fabrice D.
Seeger, Christine
Combaluzier, Ioana
Breu, Karin
Denroche, Heather C.
Thevenet, Julien
Osto, Melania
Arosio, Paolo
Kerr-Conte, Julie
Verchere, C. Bruce
Pattou, François
Lutz, Thomas A.
Donath, Marc Y.
Hock, Christoph
Nitsch, Roger M.
Grimm, Jan
author_facet Wirth, Fabian
Heitz, Fabrice D.
Seeger, Christine
Combaluzier, Ioana
Breu, Karin
Denroche, Heather C.
Thevenet, Julien
Osto, Melania
Arosio, Paolo
Kerr-Conte, Julie
Verchere, C. Bruce
Pattou, François
Lutz, Thomas A.
Donath, Marc Y.
Hock, Christoph
Nitsch, Roger M.
Grimm, Jan
author_sort Wirth, Fabian
collection PubMed
description In patients with type 2 diabetes, pancreatic beta cells progressively degenerate and gradually lose their ability to produce insulin and regulate blood glucose. Beta cell dysfunction and loss is associated with an accumulation of aggregated forms of islet amyloid polypeptide (IAPP) consisting of soluble prefibrillar IAPP oligomers as well as insoluble IAPP fibrils in pancreatic islets. Here, we describe a human monoclonal antibody selectively targeting IAPP oligomers and neutralizing IAPP aggregate toxicity by preventing membrane disruption and apoptosis in vitro. Antibody treatment in male rats and mice transgenic for human IAPP, and human islet-engrafted mouse models of type 2 diabetes triggers clearance of IAPP oligomers resulting in beta cell protection and improved glucose control. These results provide new evidence for the pathological role of IAPP oligomers and suggest that antibody-mediated removal of IAPP oligomers could be a pharmaceutical strategy to support beta cell function in type 2 diabetes.
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spelling pubmed-105623982023-10-11 A human antibody against pathologic IAPP aggregates protects beta cells in type 2 diabetes models Wirth, Fabian Heitz, Fabrice D. Seeger, Christine Combaluzier, Ioana Breu, Karin Denroche, Heather C. Thevenet, Julien Osto, Melania Arosio, Paolo Kerr-Conte, Julie Verchere, C. Bruce Pattou, François Lutz, Thomas A. Donath, Marc Y. Hock, Christoph Nitsch, Roger M. Grimm, Jan Nat Commun Article In patients with type 2 diabetes, pancreatic beta cells progressively degenerate and gradually lose their ability to produce insulin and regulate blood glucose. Beta cell dysfunction and loss is associated with an accumulation of aggregated forms of islet amyloid polypeptide (IAPP) consisting of soluble prefibrillar IAPP oligomers as well as insoluble IAPP fibrils in pancreatic islets. Here, we describe a human monoclonal antibody selectively targeting IAPP oligomers and neutralizing IAPP aggregate toxicity by preventing membrane disruption and apoptosis in vitro. Antibody treatment in male rats and mice transgenic for human IAPP, and human islet-engrafted mouse models of type 2 diabetes triggers clearance of IAPP oligomers resulting in beta cell protection and improved glucose control. These results provide new evidence for the pathological role of IAPP oligomers and suggest that antibody-mediated removal of IAPP oligomers could be a pharmaceutical strategy to support beta cell function in type 2 diabetes. Nature Publishing Group UK 2023-10-09 /pmc/articles/PMC10562398/ /pubmed/37813862 http://dx.doi.org/10.1038/s41467-023-41986-0 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Wirth, Fabian
Heitz, Fabrice D.
Seeger, Christine
Combaluzier, Ioana
Breu, Karin
Denroche, Heather C.
Thevenet, Julien
Osto, Melania
Arosio, Paolo
Kerr-Conte, Julie
Verchere, C. Bruce
Pattou, François
Lutz, Thomas A.
Donath, Marc Y.
Hock, Christoph
Nitsch, Roger M.
Grimm, Jan
A human antibody against pathologic IAPP aggregates protects beta cells in type 2 diabetes models
title A human antibody against pathologic IAPP aggregates protects beta cells in type 2 diabetes models
title_full A human antibody against pathologic IAPP aggregates protects beta cells in type 2 diabetes models
title_fullStr A human antibody against pathologic IAPP aggregates protects beta cells in type 2 diabetes models
title_full_unstemmed A human antibody against pathologic IAPP aggregates protects beta cells in type 2 diabetes models
title_short A human antibody against pathologic IAPP aggregates protects beta cells in type 2 diabetes models
title_sort human antibody against pathologic iapp aggregates protects beta cells in type 2 diabetes models
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10562398/
https://www.ncbi.nlm.nih.gov/pubmed/37813862
http://dx.doi.org/10.1038/s41467-023-41986-0
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