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Hyperglycemia-Induced Dysregulated Fusion Intermediates in Insulin-Secreting Cells Visualized by Super-Resolution Microscopy
Impaired insulin release is a hallmark of type 2 diabetes and is closely related to chronically elevated glucose concentrations, known as “glucotoxicity.” However, the molecular mechanisms by which glucotoxicity impairs insulin secretion remain poorly understood. In addition to known kiss-and-run an...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083903/ https://www.ncbi.nlm.nih.gov/pubmed/33937248 http://dx.doi.org/10.3389/fcell.2021.650167 |
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author | Yang, Guoyi Li, Liuju Liu, Yanmei Liang, Kuo Wei, Lisi Chen, Liangyi |
author_facet | Yang, Guoyi Li, Liuju Liu, Yanmei Liang, Kuo Wei, Lisi Chen, Liangyi |
author_sort | Yang, Guoyi |
collection | PubMed |
description | Impaired insulin release is a hallmark of type 2 diabetes and is closely related to chronically elevated glucose concentrations, known as “glucotoxicity.” However, the molecular mechanisms by which glucotoxicity impairs insulin secretion remain poorly understood. In addition to known kiss-and-run and kiss-and-stay fusion events in INS-1 cells, ultrafast Hessian structured illumination microscopy (Hessian SIM) enables full fusion to be categorized according to the newly identified structures, such as ring fusion (those with enlarged pores) or dot fusion (those without apparent pores). In addition, we identified four fusion intermediates during insulin exocytosis: initial pore opening, vesicle collapse, enlarged pore formation, and final pore dilation. Long-term incubation in supraphysiological doses of glucose reduced exocytosis in general and increased the occurrence of kiss-and-run events at the expense of reduced full fusion. In addition, hyperglycemia delayed pore opening, vesicle collapse, and enlarged pore formation in full fusion events. It also reduced the size of apparently enlarged pores, all of which contributed to the compromised insulin secretion. These phenotypes were mostly due to the hyperglycemia-induced reduction in syntaxin-1A (Stx-1A) and SNAP-25 protein, since they could be recapitulated by the knockdown of endogenous Stx-1A and SNAP-25. These findings suggest essential roles for the vesicle fusion type and intermediates in regulating insulin secretion from pancreatic beta cells in normal and disease conditions. |
format | Online Article Text |
id | pubmed-8083903 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-80839032021-04-30 Hyperglycemia-Induced Dysregulated Fusion Intermediates in Insulin-Secreting Cells Visualized by Super-Resolution Microscopy Yang, Guoyi Li, Liuju Liu, Yanmei Liang, Kuo Wei, Lisi Chen, Liangyi Front Cell Dev Biol Cell and Developmental Biology Impaired insulin release is a hallmark of type 2 diabetes and is closely related to chronically elevated glucose concentrations, known as “glucotoxicity.” However, the molecular mechanisms by which glucotoxicity impairs insulin secretion remain poorly understood. In addition to known kiss-and-run and kiss-and-stay fusion events in INS-1 cells, ultrafast Hessian structured illumination microscopy (Hessian SIM) enables full fusion to be categorized according to the newly identified structures, such as ring fusion (those with enlarged pores) or dot fusion (those without apparent pores). In addition, we identified four fusion intermediates during insulin exocytosis: initial pore opening, vesicle collapse, enlarged pore formation, and final pore dilation. Long-term incubation in supraphysiological doses of glucose reduced exocytosis in general and increased the occurrence of kiss-and-run events at the expense of reduced full fusion. In addition, hyperglycemia delayed pore opening, vesicle collapse, and enlarged pore formation in full fusion events. It also reduced the size of apparently enlarged pores, all of which contributed to the compromised insulin secretion. These phenotypes were mostly due to the hyperglycemia-induced reduction in syntaxin-1A (Stx-1A) and SNAP-25 protein, since they could be recapitulated by the knockdown of endogenous Stx-1A and SNAP-25. These findings suggest essential roles for the vesicle fusion type and intermediates in regulating insulin secretion from pancreatic beta cells in normal and disease conditions. Frontiers Media S.A. 2021-04-15 /pmc/articles/PMC8083903/ /pubmed/33937248 http://dx.doi.org/10.3389/fcell.2021.650167 Text en Copyright © 2021 Yang, Li, Liu, Liang, Wei and Chen. https://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) and the copyright owner(s) 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 | Cell and Developmental Biology Yang, Guoyi Li, Liuju Liu, Yanmei Liang, Kuo Wei, Lisi Chen, Liangyi Hyperglycemia-Induced Dysregulated Fusion Intermediates in Insulin-Secreting Cells Visualized by Super-Resolution Microscopy |
title | Hyperglycemia-Induced Dysregulated Fusion Intermediates in Insulin-Secreting Cells Visualized by Super-Resolution Microscopy |
title_full | Hyperglycemia-Induced Dysregulated Fusion Intermediates in Insulin-Secreting Cells Visualized by Super-Resolution Microscopy |
title_fullStr | Hyperglycemia-Induced Dysregulated Fusion Intermediates in Insulin-Secreting Cells Visualized by Super-Resolution Microscopy |
title_full_unstemmed | Hyperglycemia-Induced Dysregulated Fusion Intermediates in Insulin-Secreting Cells Visualized by Super-Resolution Microscopy |
title_short | Hyperglycemia-Induced Dysregulated Fusion Intermediates in Insulin-Secreting Cells Visualized by Super-Resolution Microscopy |
title_sort | hyperglycemia-induced dysregulated fusion intermediates in insulin-secreting cells visualized by super-resolution microscopy |
topic | Cell and Developmental Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083903/ https://www.ncbi.nlm.nih.gov/pubmed/33937248 http://dx.doi.org/10.3389/fcell.2021.650167 |
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