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Evidence for Loss in Identity, De-Differentiation, and Trans-Differentiation of Islet β-Cells in Type 2 Diabetes

The two main types of diabetes mellitus have distinct etiologies, yet a similar outcome: loss of islet β-cell function that is solely responsible for the secretion of the insulin hormone to reduce elevated plasma glucose toward euglycemic levels. Type 1 diabetes (T1D) has traditionally been characte...

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Autores principales: Hunter, Chad S., Stein, Roland W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372778/
https://www.ncbi.nlm.nih.gov/pubmed/28424732
http://dx.doi.org/10.3389/fgene.2017.00035
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author Hunter, Chad S.
Stein, Roland W.
author_facet Hunter, Chad S.
Stein, Roland W.
author_sort Hunter, Chad S.
collection PubMed
description The two main types of diabetes mellitus have distinct etiologies, yet a similar outcome: loss of islet β-cell function that is solely responsible for the secretion of the insulin hormone to reduce elevated plasma glucose toward euglycemic levels. Type 1 diabetes (T1D) has traditionally been characterized by autoimmune-mediated β-cell death leading to insulin-dependence, whereas type 2 diabetes (T2D) has hallmarks of peripheral insulin resistance, β-cell dysfunction, and cell death. However, a growing body of evidence suggests that, especially during T2D, key components of β-cell failure involves: (1) loss of cell identity, specifically proteins associated with mature cell function (e.g., insulin and transcription factors like MAFA, PDX1, and NKX6.1), as well as (2) de-differentiation, defined by regression to a progenitor or stem cell-like state. New technologies have allowed the field to compare islet cell characteristics from normal human donors to those under pathophysiological conditions by single cell RNA-Sequencing and through epigenetic analysis. This has revealed a remarkable level of heterogeneity among histologically defined “insulin-positive” β-cells. These results not only suggest that these β-cell subsets have different responses to insulin secretagogues, but that defining their unique gene expression and epigenetic modification profiles will offer opportunities to develop cellular therapeutics to enrich/maintain certain subsets for correcting pathological glucose levels. In this review, we will summarize the recent literature describing how β-cell heterogeneity and plasticity may be influenced in T2D, and various possible avenues of therapeutic intervention.
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spelling pubmed-53727782017-04-19 Evidence for Loss in Identity, De-Differentiation, and Trans-Differentiation of Islet β-Cells in Type 2 Diabetes Hunter, Chad S. Stein, Roland W. Front Genet Genetics The two main types of diabetes mellitus have distinct etiologies, yet a similar outcome: loss of islet β-cell function that is solely responsible for the secretion of the insulin hormone to reduce elevated plasma glucose toward euglycemic levels. Type 1 diabetes (T1D) has traditionally been characterized by autoimmune-mediated β-cell death leading to insulin-dependence, whereas type 2 diabetes (T2D) has hallmarks of peripheral insulin resistance, β-cell dysfunction, and cell death. However, a growing body of evidence suggests that, especially during T2D, key components of β-cell failure involves: (1) loss of cell identity, specifically proteins associated with mature cell function (e.g., insulin and transcription factors like MAFA, PDX1, and NKX6.1), as well as (2) de-differentiation, defined by regression to a progenitor or stem cell-like state. New technologies have allowed the field to compare islet cell characteristics from normal human donors to those under pathophysiological conditions by single cell RNA-Sequencing and through epigenetic analysis. This has revealed a remarkable level of heterogeneity among histologically defined “insulin-positive” β-cells. These results not only suggest that these β-cell subsets have different responses to insulin secretagogues, but that defining their unique gene expression and epigenetic modification profiles will offer opportunities to develop cellular therapeutics to enrich/maintain certain subsets for correcting pathological glucose levels. In this review, we will summarize the recent literature describing how β-cell heterogeneity and plasticity may be influenced in T2D, and various possible avenues of therapeutic intervention. Frontiers Media S.A. 2017-03-29 /pmc/articles/PMC5372778/ /pubmed/28424732 http://dx.doi.org/10.3389/fgene.2017.00035 Text en Copyright © 2017 Hunter and Stein. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Hunter, Chad S.
Stein, Roland W.
Evidence for Loss in Identity, De-Differentiation, and Trans-Differentiation of Islet β-Cells in Type 2 Diabetes
title Evidence for Loss in Identity, De-Differentiation, and Trans-Differentiation of Islet β-Cells in Type 2 Diabetes
title_full Evidence for Loss in Identity, De-Differentiation, and Trans-Differentiation of Islet β-Cells in Type 2 Diabetes
title_fullStr Evidence for Loss in Identity, De-Differentiation, and Trans-Differentiation of Islet β-Cells in Type 2 Diabetes
title_full_unstemmed Evidence for Loss in Identity, De-Differentiation, and Trans-Differentiation of Islet β-Cells in Type 2 Diabetes
title_short Evidence for Loss in Identity, De-Differentiation, and Trans-Differentiation of Islet β-Cells in Type 2 Diabetes
title_sort evidence for loss in identity, de-differentiation, and trans-differentiation of islet β-cells in type 2 diabetes
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372778/
https://www.ncbi.nlm.nih.gov/pubmed/28424732
http://dx.doi.org/10.3389/fgene.2017.00035
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