Cystic fibrosis–related diabetes onset can be predicted using biomarkers measured at birth

Lin, Yu Chung; Keenan, Katherine; Gong, Jiafen; Panjwani, Naim; Avolio, Julie; Fan, Lin; Adam, Damien; Barrett, P. K. M.; Bégin, Stéphanie; Berthiaume, Yves; Bilodeau, Lara; Bjornson, Candice; Brusky, Janna; Burgess, Caroline; Chilvers, Mark; Consunji-Araneta, Raquel; Côté-Maurais, Guillaume; Dale, Andrea; Donnelly, Christine; Fairservice, Lori; Griffin, Katie; Henderson, Natalie; Hillaby, Angela; Hughes, Daniel; Iqbal, Shaikh; Itterman, Jennifer; Jackson, Mary; Karlsen, Emma; Kosteniuk, Lorna; Lazosky, Lynda; Leung, Winnie; Lévesque, Valérie; Maillé, Émilie; Mateos-Corral, Dimas; McMahon, V.; Merjaneh, M.; Morrison, Nancy; Parkins, Michael D.; Pike, Jennifer; Price, April; Quon, Bradley S.; Reisman, Joe; Smith, Clare; Smith, Mary Jane; Vadeboncoeur, Nathalie; Veniott, Danny; Viczko, Terry; Wilcox, Pearce; Wylick, Richard van; Cutting, Garry R.; Tullis, Elizabeth; Ratjen, Félix; Rommens, Johanna M.; Sun, Lei; Solomon, Melinda; Stephenson, Anne L.; Brochiero, Emmanuelle; Blackman, Scott M.; Corvol, Harriet; Strug, Lisa J.

doi:10.1038/s41436-020-01073-x

Cited by 19 publications

(16 citation statements)

References 38 publications

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“…Moreover, they have difficulties with higher-level processes known as “executive function”, which demand greater cognitive load and recruit the prefrontal cortex [ 23 ]. CFRD is associated with poor prognosis in individuals with CF, while early diagnosis and aggressive treatment contribute to improvement in survival [ 24 , 25 ]. Additionally, pubertal stage in patients with CFRD was more delayed than in controls [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Cystic Fibrosis-Related Diabetes in Poland

Rachel

Biesiadecki

Galiniak

2022

IJERPH

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Cystic fibrosis (CF) is the most common autosomal recessive inherited monogenic disease in Caucasians. As medical technology progresses and the quality of patient care improves, the survival time of patients with CF has increased, which results in more frequent comorbidities such as cystic fibrosis-related diabetes (CFRD). CFRD is the result of abnormal glucose metabolism characterized primarily by insulin deficiency, exacerbated periodically by insulin resistance. The aim of our study was to analyze the epidemiology of patients with CFRD in Poland on the basis of data collected from six CF treatment centers. Analyses were performed on 1157 CF patients who were treated at one of the six CF care centers. CFRD was diagnosed according to standard criteria. All data including demographics, types of CFTR mutations, CFRD duration, and microorganisms in the sputum were obtained from the patients’ medical history. Our study indicates that the prevalence of CFRD in Poland is 12.9%. CFRD was most often diagnosed between the ages of 11 and 20 (60% of patients), while 23% of patients were diagnosed between 21 and 30 years of age. Furthermore, we observed that approximately 3–5% of patients under the age of 10 had CFRD. We found out that the type of mutation did not affect the frequency of CFRD development. Factors that increased the risk of developing CFRD include underweight and chronic Pseudomonas aeruginosa infection. Due to the extended lifespan of CF patients, the number of CFRD patients is currently increasing. We believe that the results of our study may complement information from other studies or may be useful in planning health policy in Poland.

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Section: Discussionmentioning

confidence: 99%

Cystic Fibrosis-Related Diabetes in Poland

Rachel

Biesiadecki

Galiniak

2022

IJERPH

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“…It has long been noted that the severity of CFTR mutation seems to be correlated with the likelihood of developing CFRD. In a recent article by Lin et al, the strongest predictors of detecting early or late onset of CFRD included sex, CFTR severity score, and several genetic variants [6] . More severe CFTR gene mutations result in phenotypes with more significant exocrine pancreatic disease, thereby causing increased scarring and destruction of beta cells.…”

Section: Genetic Modifiersmentioning

confidence: 99%

The role of genetic modifiers, inflammation and CFTR in the pathogenesis of Cystic fibrosis related diabetes

Hasan

Soltman

Wood

et al. 2022

Journal of Clinical & Translational Endocrinology

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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 TCF7L2, CDKN2A/B, CDKAL1, and IGF2BP2, 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.

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“…There is a close physical connection between the ductal system and pancreatic islets, as well as a strong association between markers of exocrine pancreatic damage, such as circulating immunoreactive trypsinogen, and the risk of developing CFRD (101). Recently, this association has been strengthened by the identification of genetic variants, including PRSS1 and SLC26A9, coding for cationic trypsinogen and a chloride channel, respectively, as predictors of CFRD (102). This suggests that the destruction of the exocrine pancreas and the resulting inflammation and fibrosis may contribute to disorganization, dysfunction, and destruction of the endocrine tissue (Figure 2).…”

Section: Indirect Effects Of Cftr Mutation On B-cell Functionmentioning

confidence: 99%

The Potential Causes of Cystic Fibrosis-Related Diabetes

et al. 2021

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Cystic fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). Cystic fibrosis-related diabetes (CFRD) is the most common comorbidity, affecting more than 50% of adult CF patients. Despite this high prevalence, the etiology of CFRD remains incompletely understood. Studies in young CF children show pancreatic islet disorganization, abnormal glucose tolerance, and delayed first-phase insulin secretion suggesting that islet dysfunction is an early feature of CF. Since insulin-producing pancreatic β-cells express very low levels of CFTR, CFRD likely results from β-cell extrinsic factors. In the vicinity of β-cells, CFTR is expressed in both the exocrine pancreas and the immune system. In the exocrine pancreas, CFTR mutations lead to the obstruction of the pancreatic ductal canal, inflammation, and immune cell infiltration, ultimately causing the destruction of the exocrine pancreas and remodeling of islets. Both inflammation and ductal cells have a direct effect on insulin secretion and could participate in CFRD development. CFTR mutations are also associated with inflammatory responses and excessive cytokine production by various immune cells, which infiltrate the pancreas and exert a negative impact on insulin secretion, causing dysregulation of glucose homeostasis in CF adults. In addition, the function of macrophages in shaping pancreatic islet development may be impaired by CFTR mutations, further contributing to the pancreatic islet structural defects as well as impaired first-phase insulin secretion observed in very young children. This review discusses the different factors that may contribute to CFRD.

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Cystic fibrosis–related diabetes onset can be predicted using biomarkers measured at birth

Cited by 19 publications

References 38 publications

Cystic Fibrosis-Related Diabetes in Poland

Cystic Fibrosis-Related Diabetes in Poland

The role of genetic modifiers, inflammation and CFTR in the pathogenesis of Cystic fibrosis related diabetes

The Potential Causes of Cystic Fibrosis-Related Diabetes

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