School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia; Molecular and Integrative Cystic Fibrosis Research Centre, University of New South Wales, Sydney, NSW, Australia; School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia.
Department of Clinical Sciences, Unit of Islet Cell Exocytosis, Lund University Diabetes Centre, Scania University Hospital, Malmö, Scania, Sweden.
J Cyst Fibros. 2024 Sep;23(5):842-852. doi: 10.1016/j.jcf.2024.06.004. Epub 2024 Jun 18.
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.
囊性纤维化（CF）相关糖尿病（CFRD）是 CF 患者中普遍存在的合并症，显著影响发病率和死亡率。本文综述了 CFRD 分子机制的最新研究进展，包括 CFTR 蛋白、氧化应激、未折叠蛋白反应（UPR）和细胞内通讯的作用。CFRD 源自外分泌胰腺损伤和内在内分泌功能障碍的复杂相互作用，进一步复杂化的是错误折叠的 CFTR 蛋白对胰岛素分泌和作用的有害影响。研究表明，内质网应激和随后的 UPR 激活在胰腺外分泌和内分泌细胞功能障碍中发挥关键作用，导致β细胞丧失和胰岛素不足。此外，氧化应激和钙通量改变，加剧 CFTR 功能障碍，损害β细胞的存活和功能，强调了抗氧化途径在 CFRD 发病机制中的重要性。新出现的证据强调了外泌体 microRNAs（miRNAs）在介导炎症和应激反应中的重要性，为 CFRD 的分子图谱提供了新的见解。尽管胰岛素治疗仍然是 CFRD 管理的基石，但对 CFTR 调节剂反应的变异性突出表明需要采用个性化的治疗方法。本文综述提倡进一步研究非 CFTR 治疗靶点，强调需要解决 CFRD 的多方面病理生理学。深入了解 CFRD 的复杂机制将为创新治疗铺平道路，超越胰岛素治疗，针对疾病的根本原因，并改善 CF 患者的生活质量。
