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Heterogeneous Development of β-Cell Populations in Diabetes-Resistant and -Susceptible Mice
Progressive dysfunction and failure of insulin-releasing β-cells are a hallmark of type 2 diabetes (T2D). To study mechanisms of β-cell loss in T2D, we performed islet single-cell RNA sequencing of two obese mouse strains differing in their diabetes susceptibility. With mice on a control diet, we id...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Diabetes Association
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9862397/ https://www.ncbi.nlm.nih.gov/pubmed/35771990 http://dx.doi.org/10.2337/db21-1030 |
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author | Gottmann, Pascal Speckmann, Thilo Stadion, Mandy Zuljan, Erika Aga, Heja Sterr, Michael Büttner, Maren Santos, Patrícia Martínez Jähnert, Markus Bornstein, Stefan R. Theis, Fabian J. Lickert, Heiko Schürmann, Annette |
author_facet | Gottmann, Pascal Speckmann, Thilo Stadion, Mandy Zuljan, Erika Aga, Heja Sterr, Michael Büttner, Maren Santos, Patrícia Martínez Jähnert, Markus Bornstein, Stefan R. Theis, Fabian J. Lickert, Heiko Schürmann, Annette |
author_sort | Gottmann, Pascal |
collection | PubMed |
description | Progressive dysfunction and failure of insulin-releasing β-cells are a hallmark of type 2 diabetes (T2D). To study mechanisms of β-cell loss in T2D, we performed islet single-cell RNA sequencing of two obese mouse strains differing in their diabetes susceptibility. With mice on a control diet, we identified six β-cell clusters with similar abundance in both strains. However, after feeding of a diabetogenic diet for 2 days, β-cell cluster composition markedly differed between strains. Islets of diabetes-resistant mice developed into a protective β-cell cluster (Beta4), whereas those of diabetes-prone mice progressed toward stress-related clusters with a strikingly different expression pattern. Interestingly, the protective cluster showed indications of reduced β-cell identity, such as downregulation of GLUT2, GLP1R, and MafA, and in vitro knockdown of GLUT2 in β-cells—mimicking its phenotype—decreased stress response and apoptosis. This might explain enhanced β-cell survival of diabetes-resistant islets. In contrast, β-cells of diabetes-prone mice responded with expression changes indicating metabolic pressure and endoplasmic reticulum stress, presumably leading to later β-cell loss. In conclusion, failure of diabetes-prone mice to adapt gene expression toward a more dedifferentiated state in response to rising blood glucose levels leads to β-cell failure and diabetes development. |
format | Online Article Text |
id | pubmed-9862397 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-98623972023-02-03 Heterogeneous Development of β-Cell Populations in Diabetes-Resistant and -Susceptible Mice Gottmann, Pascal Speckmann, Thilo Stadion, Mandy Zuljan, Erika Aga, Heja Sterr, Michael Büttner, Maren Santos, Patrícia Martínez Jähnert, Markus Bornstein, Stefan R. Theis, Fabian J. Lickert, Heiko Schürmann, Annette Diabetes Islet Studies Progressive dysfunction and failure of insulin-releasing β-cells are a hallmark of type 2 diabetes (T2D). To study mechanisms of β-cell loss in T2D, we performed islet single-cell RNA sequencing of two obese mouse strains differing in their diabetes susceptibility. With mice on a control diet, we identified six β-cell clusters with similar abundance in both strains. However, after feeding of a diabetogenic diet for 2 days, β-cell cluster composition markedly differed between strains. Islets of diabetes-resistant mice developed into a protective β-cell cluster (Beta4), whereas those of diabetes-prone mice progressed toward stress-related clusters with a strikingly different expression pattern. Interestingly, the protective cluster showed indications of reduced β-cell identity, such as downregulation of GLUT2, GLP1R, and MafA, and in vitro knockdown of GLUT2 in β-cells—mimicking its phenotype—decreased stress response and apoptosis. This might explain enhanced β-cell survival of diabetes-resistant islets. In contrast, β-cells of diabetes-prone mice responded with expression changes indicating metabolic pressure and endoplasmic reticulum stress, presumably leading to later β-cell loss. In conclusion, failure of diabetes-prone mice to adapt gene expression toward a more dedifferentiated state in response to rising blood glucose levels leads to β-cell failure and diabetes development. American Diabetes Association 2022-09 2022-06-30 /pmc/articles/PMC9862397/ /pubmed/35771990 http://dx.doi.org/10.2337/db21-1030 Text en © 2022 by the American Diabetes Association https://www.diabetesjournals.org/journals/pages/licenseReaders may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://www.diabetesjournals.org/journals/pages/license. |
spellingShingle | Islet Studies Gottmann, Pascal Speckmann, Thilo Stadion, Mandy Zuljan, Erika Aga, Heja Sterr, Michael Büttner, Maren Santos, Patrícia Martínez Jähnert, Markus Bornstein, Stefan R. Theis, Fabian J. Lickert, Heiko Schürmann, Annette Heterogeneous Development of β-Cell Populations in Diabetes-Resistant and -Susceptible Mice |
title | Heterogeneous Development of β-Cell Populations in Diabetes-Resistant and -Susceptible Mice |
title_full | Heterogeneous Development of β-Cell Populations in Diabetes-Resistant and -Susceptible Mice |
title_fullStr | Heterogeneous Development of β-Cell Populations in Diabetes-Resistant and -Susceptible Mice |
title_full_unstemmed | Heterogeneous Development of β-Cell Populations in Diabetes-Resistant and -Susceptible Mice |
title_short | Heterogeneous Development of β-Cell Populations in Diabetes-Resistant and -Susceptible Mice |
title_sort | heterogeneous development of β-cell populations in diabetes-resistant and -susceptible mice |
topic | Islet Studies |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9862397/ https://www.ncbi.nlm.nih.gov/pubmed/35771990 http://dx.doi.org/10.2337/db21-1030 |
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