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Setting the Stage for Insulin Granule Dysfunction during Type-1-Diabetes: Is ER Stress the Culprit?

Type-1-diabetes (T1D) is a multifactorial disorder with a global incidence of about 8.4 million individuals in 2021. It is primarily classified as an autoimmune disorder, where the pancreatic β-cells are unable to secrete sufficient insulin. This leads to elevated blood glucose levels (hyperglycemia...

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Autores principales: Makam, Aishwarya A., Biswas, Anusmita, Kothegala, Lakshmi, Gandasi, Nikhil R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9687317/
https://www.ncbi.nlm.nih.gov/pubmed/36359215
http://dx.doi.org/10.3390/biomedicines10112695
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author Makam, Aishwarya A.
Biswas, Anusmita
Kothegala, Lakshmi
Gandasi, Nikhil R.
author_facet Makam, Aishwarya A.
Biswas, Anusmita
Kothegala, Lakshmi
Gandasi, Nikhil R.
author_sort Makam, Aishwarya A.
collection PubMed
description Type-1-diabetes (T1D) is a multifactorial disorder with a global incidence of about 8.4 million individuals in 2021. It is primarily classified as an autoimmune disorder, where the pancreatic β-cells are unable to secrete sufficient insulin. This leads to elevated blood glucose levels (hyperglycemia). The development of T1D is an intricate interplay between various risk factors, such as genetic, environmental, and cellular elements. In this review, we focus on the cellular elements, such as ER (endoplasmic reticulum) stress and its consequences for T1D pathogenesis. One of the major repercussions of ER stress is defective protein processing. A well-studied example is that of islet amyloid polypeptide (IAPP), which is known to form cytotoxic amyloid plaques when misfolded. This review discusses the possible association between ER stress, IAPP, and amyloid formation in β-cells and its consequences in T1D. Additionally, ER stress also leads to autoantigen generation. This is driven by the loss of Ca(++) ion homeostasis. Imbalanced Ca(++) levels lead to abnormal activation of enzymes, causing post-translational modification of β-cell proteins. These modified proteins act as autoantigens and trigger the autoimmune response seen in T1D islets. Several of these autoantigens are also crucial for insulin granule biogenesis, processing, and release. Here, we explore the possible associations between ER stress leading to defects in insulin secretion and ultimately β-cell destruction.
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spelling pubmed-96873172022-11-25 Setting the Stage for Insulin Granule Dysfunction during Type-1-Diabetes: Is ER Stress the Culprit? Makam, Aishwarya A. Biswas, Anusmita Kothegala, Lakshmi Gandasi, Nikhil R. Biomedicines Review Type-1-diabetes (T1D) is a multifactorial disorder with a global incidence of about 8.4 million individuals in 2021. It is primarily classified as an autoimmune disorder, where the pancreatic β-cells are unable to secrete sufficient insulin. This leads to elevated blood glucose levels (hyperglycemia). The development of T1D is an intricate interplay between various risk factors, such as genetic, environmental, and cellular elements. In this review, we focus on the cellular elements, such as ER (endoplasmic reticulum) stress and its consequences for T1D pathogenesis. One of the major repercussions of ER stress is defective protein processing. A well-studied example is that of islet amyloid polypeptide (IAPP), which is known to form cytotoxic amyloid plaques when misfolded. This review discusses the possible association between ER stress, IAPP, and amyloid formation in β-cells and its consequences in T1D. Additionally, ER stress also leads to autoantigen generation. This is driven by the loss of Ca(++) ion homeostasis. Imbalanced Ca(++) levels lead to abnormal activation of enzymes, causing post-translational modification of β-cell proteins. These modified proteins act as autoantigens and trigger the autoimmune response seen in T1D islets. Several of these autoantigens are also crucial for insulin granule biogenesis, processing, and release. Here, we explore the possible associations between ER stress leading to defects in insulin secretion and ultimately β-cell destruction. MDPI 2022-10-25 /pmc/articles/PMC9687317/ /pubmed/36359215 http://dx.doi.org/10.3390/biomedicines10112695 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 Review
Makam, Aishwarya A.
Biswas, Anusmita
Kothegala, Lakshmi
Gandasi, Nikhil R.
Setting the Stage for Insulin Granule Dysfunction during Type-1-Diabetes: Is ER Stress the Culprit?
title Setting the Stage for Insulin Granule Dysfunction during Type-1-Diabetes: Is ER Stress the Culprit?
title_full Setting the Stage for Insulin Granule Dysfunction during Type-1-Diabetes: Is ER Stress the Culprit?
title_fullStr Setting the Stage for Insulin Granule Dysfunction during Type-1-Diabetes: Is ER Stress the Culprit?
title_full_unstemmed Setting the Stage for Insulin Granule Dysfunction during Type-1-Diabetes: Is ER Stress the Culprit?
title_short Setting the Stage for Insulin Granule Dysfunction during Type-1-Diabetes: Is ER Stress the Culprit?
title_sort setting the stage for insulin granule dysfunction during type-1-diabetes: is er stress the culprit?
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9687317/
https://www.ncbi.nlm.nih.gov/pubmed/36359215
http://dx.doi.org/10.3390/biomedicines10112695
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