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Insulin Therapy for Pre-Hyperglycemic Beta-Cell Endoplasmic Reticulum Crowding
Insulin therapy improves β-cell function in early stages of diabetes by mechanisms that may exceed alleviation of glucotoxicity. In advance type 2 diabetes, hyperglycemia causes β-cell damage and ultimately β-cell loss. At such an advanced stage, therapeutic modalities are often inadequate. Growing...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567120/ https://www.ncbi.nlm.nih.gov/pubmed/23408938 http://dx.doi.org/10.1371/journal.pone.0054351 |
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author | Absood, Afaf Gandomani, Benjamin Zaki, Anthony Nasta, Vlad Michail, Andrew Habib, Peter M. W. Hodish, Israel |
author_facet | Absood, Afaf Gandomani, Benjamin Zaki, Anthony Nasta, Vlad Michail, Andrew Habib, Peter M. W. Hodish, Israel |
author_sort | Absood, Afaf |
collection | PubMed |
description | Insulin therapy improves β-cell function in early stages of diabetes by mechanisms that may exceed alleviation of glucotoxicity. In advance type 2 diabetes, hyperglycemia causes β-cell damage and ultimately β-cell loss. At such an advanced stage, therapeutic modalities are often inadequate. Growing evidence indicates that in early stages of type-2 diabetes and some types of monogenic diabetes linked with malfunctioning endoplasmic-reticulum (ER), the β-cell ER fails to process sufficient proinsulin once it becomes overloaded. These changes manifest with ER distention (ER-crowding) and deficiency of secretory granules. We hypothesize that insulin therapy may improves β-cell function by alleviating ER-crowding. To support this hypothesis, we investigated pre-diabetic β-cell changes in hProC(A7)Y-CpepGFP transgenic mice that develop prolonged pre-diabetes due to proinsulin dysmaturation and ER-crowding. We attenuated the β-cell ER proinsulin synthesis with a treat-to-target insulin therapy while avoiding hypoglycemia and weight gain. Alleviation of ER-crowding resulted in temporary improvement in proinsulin maturation, insulin secretion and glucose tolerance. Our observations suggest that alleviation of pre-diabetic ER-crowding using a treat-to-target insulin therapy may improve β-cell function and may prevent further metabolic deterioration. |
format | Online Article Text |
id | pubmed-3567120 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-35671202013-02-13 Insulin Therapy for Pre-Hyperglycemic Beta-Cell Endoplasmic Reticulum Crowding Absood, Afaf Gandomani, Benjamin Zaki, Anthony Nasta, Vlad Michail, Andrew Habib, Peter M. W. Hodish, Israel PLoS One Research Article Insulin therapy improves β-cell function in early stages of diabetes by mechanisms that may exceed alleviation of glucotoxicity. In advance type 2 diabetes, hyperglycemia causes β-cell damage and ultimately β-cell loss. At such an advanced stage, therapeutic modalities are often inadequate. Growing evidence indicates that in early stages of type-2 diabetes and some types of monogenic diabetes linked with malfunctioning endoplasmic-reticulum (ER), the β-cell ER fails to process sufficient proinsulin once it becomes overloaded. These changes manifest with ER distention (ER-crowding) and deficiency of secretory granules. We hypothesize that insulin therapy may improves β-cell function by alleviating ER-crowding. To support this hypothesis, we investigated pre-diabetic β-cell changes in hProC(A7)Y-CpepGFP transgenic mice that develop prolonged pre-diabetes due to proinsulin dysmaturation and ER-crowding. We attenuated the β-cell ER proinsulin synthesis with a treat-to-target insulin therapy while avoiding hypoglycemia and weight gain. Alleviation of ER-crowding resulted in temporary improvement in proinsulin maturation, insulin secretion and glucose tolerance. Our observations suggest that alleviation of pre-diabetic ER-crowding using a treat-to-target insulin therapy may improve β-cell function and may prevent further metabolic deterioration. Public Library of Science 2013-02-07 /pmc/articles/PMC3567120/ /pubmed/23408938 http://dx.doi.org/10.1371/journal.pone.0054351 Text en © 2013 Absood et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Absood, Afaf Gandomani, Benjamin Zaki, Anthony Nasta, Vlad Michail, Andrew Habib, Peter M. W. Hodish, Israel Insulin Therapy for Pre-Hyperglycemic Beta-Cell Endoplasmic Reticulum Crowding |
title | Insulin Therapy for Pre-Hyperglycemic Beta-Cell Endoplasmic Reticulum Crowding |
title_full | Insulin Therapy for Pre-Hyperglycemic Beta-Cell Endoplasmic Reticulum Crowding |
title_fullStr | Insulin Therapy for Pre-Hyperglycemic Beta-Cell Endoplasmic Reticulum Crowding |
title_full_unstemmed | Insulin Therapy for Pre-Hyperglycemic Beta-Cell Endoplasmic Reticulum Crowding |
title_short | Insulin Therapy for Pre-Hyperglycemic Beta-Cell Endoplasmic Reticulum Crowding |
title_sort | insulin therapy for pre-hyperglycemic beta-cell endoplasmic reticulum crowding |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567120/ https://www.ncbi.nlm.nih.gov/pubmed/23408938 http://dx.doi.org/10.1371/journal.pone.0054351 |
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