Beyond insulin : Unraveling the complex interplay of ER stress, oxidative damage, and CFTR modulation in CFRD
Umashankar, Bala ; Eliasson, Lena LU
; Ooi, Chee Y.
; Kim, Ki Wook
; Shaw, James A.M.
and Waters, Shafagh A.
(2024)
In Journal of Cystic Fibrosis
- Abstract
CF-related diabetes (CFRD) is a prevalent comorbidity in people with Cystic Fibrosis (CF), significantly impacting morbidity and mortality rates. This review article critically evaluates the current understanding of CFRD molecular mechanisms, including the role of CFTR protein, oxidative stress, unfolded protein response (UPR) and intracellular communication. CFRD manifests from a complex interplay between exocrine pancreatic damage and intrinsic endocrine dysfunction, further complicated by the deleterious effects of misfolded CFTR protein on insulin secretion and action. Studies indicate that ER stress and subsequent UPR activation play critical roles in both exocrine and endocrine pancreatic cell dysfunction, contributing to β-cell... (More)
CF-related diabetes (CFRD) is a prevalent comorbidity in people with Cystic Fibrosis (CF), significantly impacting morbidity and mortality rates. This review article critically evaluates the current understanding of CFRD molecular mechanisms, including the role of CFTR protein, oxidative stress, unfolded protein response (UPR) and intracellular communication. CFRD manifests from a complex interplay between exocrine pancreatic damage and intrinsic endocrine dysfunction, further complicated by the deleterious effects of misfolded CFTR protein on insulin secretion and action. Studies indicate that ER stress and subsequent UPR activation play critical roles in both exocrine and endocrine pancreatic cell dysfunction, contributing to β-cell loss and insulin insufficiency. Additionally, oxidative stress and altered calcium flux, exacerbated by CFTR dysfunction, impair β-cell survival and function, highlighting the significance of antioxidant pathways in CFRD pathogenesis. Emerging evidence underscores the importance of exosomal microRNAs (miRNAs) in mediating inflammatory and stress responses, offering novel insights into CFRD's molecular landscape. Despite insulin therapy remaining the cornerstone of CFRD management, the variability in response to CFTR modulators underscores the need for personalized treatment approaches. The review advocates for further research into non-CFTR therapeutic targets, emphasizing the need to address the multifaceted pathophysiology of CFRD. Understanding the intricate mechanisms underlying CFRD will pave the way for innovative treatments, moving beyond insulin therapy to target the disease's root causes and improve the quality of life for individuals with CF.
(Less)
- author
- Umashankar, Bala
; Eliasson, Lena
LU
; Ooi, Chee Y.
; Kim, Ki Wook
; Shaw, James A.M.
and Waters, Shafagh A.
- organization
- publishing date
- 2024
- type
- Contribution to journal
- publication status
- in press
- subject
- keywords
- CFRD, ER stress, Exosomes, miRNA, Oxidative stress
- in
- Journal of Cystic Fibrosis
- publisher
- Elsevier
- external identifiers
-
- scopus:85196352885
- ISSN
- 1569-1993
- DOI
- 10.1016/j.jcf.2024.06.004
- language
- English
- LU publication?
- yes
- additional info
- Publisher Copyright: © 2024 The Author(s)
- id
- c4b8c3de-eb5a-40f6-aaed-b5c2cfd6d542
- date added to LUP
- 2024-09-11 14:32:42
- date last changed
- 2024-09-11 14:33:49
@article{c4b8c3de-eb5a-40f6-aaed-b5c2cfd6d542,
abstract = {{<p>CF-related diabetes (CFRD) is a prevalent comorbidity in people with Cystic Fibrosis (CF), significantly impacting morbidity and mortality rates. This review article critically evaluates the current understanding of CFRD molecular mechanisms, including the role of CFTR protein, oxidative stress, unfolded protein response (UPR) and intracellular communication. CFRD manifests from a complex interplay between exocrine pancreatic damage and intrinsic endocrine dysfunction, further complicated by the deleterious effects of misfolded CFTR protein on insulin secretion and action. Studies indicate that ER stress and subsequent UPR activation play critical roles in both exocrine and endocrine pancreatic cell dysfunction, contributing to β-cell loss and insulin insufficiency. Additionally, oxidative stress and altered calcium flux, exacerbated by CFTR dysfunction, impair β-cell survival and function, highlighting the significance of antioxidant pathways in CFRD pathogenesis. Emerging evidence underscores the importance of exosomal microRNAs (miRNAs) in mediating inflammatory and stress responses, offering novel insights into CFRD's molecular landscape. Despite insulin therapy remaining the cornerstone of CFRD management, the variability in response to CFTR modulators underscores the need for personalized treatment approaches. The review advocates for further research into non-CFTR therapeutic targets, emphasizing the need to address the multifaceted pathophysiology of CFRD. Understanding the intricate mechanisms underlying CFRD will pave the way for innovative treatments, moving beyond insulin therapy to target the disease's root causes and improve the quality of life for individuals with CF.</p>}},
author = {{Umashankar, Bala and Eliasson, Lena and Ooi, Chee Y. and Kim, Ki Wook and Shaw, James A.M. and Waters, Shafagh A.}},
issn = {{1569-1993}},
keywords = {{CFRD; ER stress; Exosomes; miRNA; Oxidative stress}},
language = {{eng}},
publisher = {{Elsevier}},
series = {{Journal of Cystic Fibrosis}},
title = {{Beyond insulin : Unraveling the complex interplay of ER stress, oxidative damage, and CFTR modulation in CFRD}},
url = {{http://dx.doi.org/10.1016/j.jcf.2024.06.004}},
doi = {{10.1016/j.jcf.2024.06.004}},
year = {{2024}},
}