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Gene Delivery of Manf to Beta-Cells of the Pancreatic Islets Protects NOD Mice from Type 1 Diabetes Development
In type 1 diabetes, dysfunctional glucose regulation occurs due to the death of insulin-producing beta-cells in the pancreatic islets. Initiation of this process is caused by the inheritance of an adaptive immune system that is predisposed to responding to beta-cell antigens, most notably to insulin...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9599570/ https://www.ncbi.nlm.nih.gov/pubmed/36291702 http://dx.doi.org/10.3390/biom12101493 |
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author | Singh, Kailash Bricard, Orian Haughton, Jeason Björkqvist, Mikaela Thorstensson, Moa Luo, Zhengkang Mascali, Loriana Pasciuto, Emanuela Mathieu, Chantal Dooley, James Liston, Adrian |
author_facet | Singh, Kailash Bricard, Orian Haughton, Jeason Björkqvist, Mikaela Thorstensson, Moa Luo, Zhengkang Mascali, Loriana Pasciuto, Emanuela Mathieu, Chantal Dooley, James Liston, Adrian |
author_sort | Singh, Kailash |
collection | PubMed |
description | In type 1 diabetes, dysfunctional glucose regulation occurs due to the death of insulin-producing beta-cells in the pancreatic islets. Initiation of this process is caused by the inheritance of an adaptive immune system that is predisposed to responding to beta-cell antigens, most notably to insulin itself, coupled with unknown environmental insults priming the autoimmune reaction. While autoimmunity is a primary driver in beta-cell death, there is growing evidence that cellular stress participates in the loss of beta-cells. In the beta-cell fragility model, partial loss of islet mass requires compensatory upregulation of insulin production in the remaining islets, driving a cellular stress capable of triggering apoptosis in the remaining cells. The Glis3-Manf axis has been identified as being pivotal to the relative fragility or robustness of stressed islets, potentially operating in both type 1 and type 2 diabetes. Here, we have used an AAV-based gene delivery system to enhance the expression of the anti-apoptotic protein Manf in the beta-cells of NOD mice. Gene delivery substantially lowered the rate of diabetes development in treated mice. Manf-treated mice demonstrated minimal insulitis and superior preservation of insulin production. Our results demonstrating the therapeutic potential of Manf delivery to enhance beta-cell robustness and avert clinical diabetes. |
format | Online Article Text |
id | pubmed-9599570 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-95995702022-10-27 Gene Delivery of Manf to Beta-Cells of the Pancreatic Islets Protects NOD Mice from Type 1 Diabetes Development Singh, Kailash Bricard, Orian Haughton, Jeason Björkqvist, Mikaela Thorstensson, Moa Luo, Zhengkang Mascali, Loriana Pasciuto, Emanuela Mathieu, Chantal Dooley, James Liston, Adrian Biomolecules Article In type 1 diabetes, dysfunctional glucose regulation occurs due to the death of insulin-producing beta-cells in the pancreatic islets. Initiation of this process is caused by the inheritance of an adaptive immune system that is predisposed to responding to beta-cell antigens, most notably to insulin itself, coupled with unknown environmental insults priming the autoimmune reaction. While autoimmunity is a primary driver in beta-cell death, there is growing evidence that cellular stress participates in the loss of beta-cells. In the beta-cell fragility model, partial loss of islet mass requires compensatory upregulation of insulin production in the remaining islets, driving a cellular stress capable of triggering apoptosis in the remaining cells. The Glis3-Manf axis has been identified as being pivotal to the relative fragility or robustness of stressed islets, potentially operating in both type 1 and type 2 diabetes. Here, we have used an AAV-based gene delivery system to enhance the expression of the anti-apoptotic protein Manf in the beta-cells of NOD mice. Gene delivery substantially lowered the rate of diabetes development in treated mice. Manf-treated mice demonstrated minimal insulitis and superior preservation of insulin production. Our results demonstrating the therapeutic potential of Manf delivery to enhance beta-cell robustness and avert clinical diabetes. MDPI 2022-10-16 /pmc/articles/PMC9599570/ /pubmed/36291702 http://dx.doi.org/10.3390/biom12101493 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Singh, Kailash Bricard, Orian Haughton, Jeason Björkqvist, Mikaela Thorstensson, Moa Luo, Zhengkang Mascali, Loriana Pasciuto, Emanuela Mathieu, Chantal Dooley, James Liston, Adrian Gene Delivery of Manf to Beta-Cells of the Pancreatic Islets Protects NOD Mice from Type 1 Diabetes Development |
title | Gene Delivery of Manf to Beta-Cells of the Pancreatic Islets Protects NOD Mice from Type 1 Diabetes Development |
title_full | Gene Delivery of Manf to Beta-Cells of the Pancreatic Islets Protects NOD Mice from Type 1 Diabetes Development |
title_fullStr | Gene Delivery of Manf to Beta-Cells of the Pancreatic Islets Protects NOD Mice from Type 1 Diabetes Development |
title_full_unstemmed | Gene Delivery of Manf to Beta-Cells of the Pancreatic Islets Protects NOD Mice from Type 1 Diabetes Development |
title_short | Gene Delivery of Manf to Beta-Cells of the Pancreatic Islets Protects NOD Mice from Type 1 Diabetes Development |
title_sort | gene delivery of manf to beta-cells of the pancreatic islets protects nod mice from type 1 diabetes development |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9599570/ https://www.ncbi.nlm.nih.gov/pubmed/36291702 http://dx.doi.org/10.3390/biom12101493 |
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