Hasan Sana, Soltman Sarah, Wood Colleen, Blackman Scott M
Department of Endocrinology and Metabolism, Cleveland Clinic Foundation, Cleveland, OH, USA.
Oregon Health & Science University Division of Endocrinology, Diabetes and Clinical Nutrition, USA.
J Clin Transl Endocrinol. 2021 Dec 10;27:100287. doi: 10.1016/j.jcte.2021.100287. eCollection 2022 Mar.
Cystic fibrosis related diabetes (CFRD) generally reflects insufficient and/or delayed production of insulin, developing slowly over years to decades. Multiple mechanisms have been implicated in the pathogenesis of CFRD. CFTR function itself is a strong determinant of CFRD risk. Variants in CFTR that result in residual CFTR function and exocrine pancreatic sufficiency reduce the risk of CFRD by ten to twenty fold. Two groups of hypotheses have been proposed for the mechanism of CFTR impairing insulin secretion in CFRD: (1) β-cell dysfunction results from β cell intrinsic CFTR-dependent mechanisms of insulin secretion. (2) β-cell dysfunction results from factors outside the β cell. Genome-wide association studies have identified multiple susceptibility genes for type 2 diabetes, including as containing genetic modifiers of CFRD. These findings support the presence of intrinsic β cell defects playing a role in CFRD pathogenesis. Oxidative stress and inflammation are β cell-extrinsic mechanisms involved with CFRD. CFTR mutations render β cells more susceptible to oxidative stress and also leads to defects in α-cell function, resulting in reduced suppression of glucagon secretion. Furthermore, CFRD is characterized by β cell loss secondary to intra-islet inflammation. Recent studies have demonstrated the presence of multiple inflammatory mediators within the human CF islet. This review presents a concise overview of the current understanding of genetic modifiers of CFRD, oxidative stress, islet inflammation, and the controversies about the role of CFTR in the islet.
囊性纤维化相关糖尿病（CFRD）通常反映胰岛素分泌不足和/或延迟，在数年至数十年间缓慢发展。CFRD的发病机制涉及多种机制。CFTR功能本身是CFRD风险的一个重要决定因素。导致CFTR残余功能和外分泌胰腺功能正常的CFTR变异可使CFRD风险降低10至20倍。关于CFTR在CFRD中损害胰岛素分泌的机制，已提出两组假说：（1）β细胞功能障碍源于β细胞内在的依赖CFTR的胰岛素分泌机制。（2）β细胞功能障碍源于β细胞外部的因素。全基因组关联研究已确定了2型糖尿病的多个易感基因，包括作为CFRD遗传修饰因子的基因。这些发现支持内在β细胞缺陷在CFRD发病机制中起作用。氧化应激和炎症是与CFRD有关的β细胞外部机制。CFTR突变使β细胞更容易受到氧化应激的影响，还会导致α细胞功能缺陷，从而减少对胰高血糖素分泌的抑制。此外，CFRD的特征是胰岛内炎症继发β细胞丢失。最近的研究表明，在人类囊性纤维化胰岛中存在多种炎症介质。本文综述了目前对CFRD遗传修饰因子、氧化应激、胰岛炎症以及CFTR在胰岛中作用的争议的理解。
