Lina Merjaneh , Sana Hasan , Nader Kasim , Katie Larson Ode
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Small studies using ivacaftor monotherapy in gating mutations have revealed improvement in insulin secretion, glucose tolerance and/or decrease in insulin requirement. However, lumacaftor/ivacaftor studies (primarily in delta F 508 homozygous) have not revealed significant improvement in CFRD or glucose tolerance. No studies are yet available regarding the effect of the highly effective triple therapy (elexacaftor/tezacaftor/ivacaftor) on CFRD or insulin secretion. CFTR modulators might affect development or progression of CFRD through many mechanisms including improving insulin secretion by correcting the CFTR defect directly, improving ductal function, reducing islet inflammation, and improving incretin secretion or by enhancing insulin sensitivity via reduced systemic inflammation and increased physical activity driven by improved lung function and quality of life. On the other hand, they can stimulate appetite and improve gastrointestinal function resulting in increased caloric intake and absorption, driving excessive weight gain and potentially increased insulin resistance. If the defect in insulin secretion is reversible then it is possible that initiation of CFTR modulators at a younger age might help prevent CFRD. Despite the advances in CF management, CFRD remains a challenge and knowledge continues to evolve. 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Highly effective modulator therapies have driven marked improvements in lung function, exacerbation rate, weight and quality of life in CF patients.<!--> <!-->However, their effect on CF related diabetes (CFRD) is not well delineated. The role of CF transmembrane conductance regulator (CFTR) in CFRD pathogenesis is inadequately understood and research aimed at deciphering the underlying mechanisms of CFRD continues to evolve. In this review, we summarize what is known regarding the effect of CFTR modulators on CFRD. Small studies using ivacaftor monotherapy in gating mutations have revealed improvement in insulin secretion, glucose tolerance and/or decrease in insulin requirement. However, lumacaftor/ivacaftor studies (primarily in delta F 508 homozygous) have not revealed significant improvement in CFRD or glucose tolerance. No studies are yet available regarding the effect of the highly effective triple therapy (elexacaftor/tezacaftor/ivacaftor) on CFRD or insulin secretion. 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引用次数: 18
摘要
调节剂疗法的发展和引入已经完全改变了治疗囊性纤维化(CF)的范式。高效的调节疗法显著改善了CF患者的肺功能、加重率、体重和生活质量。然而,它们对CF相关性糖尿病(CFRD)的影响尚未得到很好的描述。CF跨膜传导调节因子(CFTR)在CFRD发病机制中的作用尚不清楚,旨在破译CFRD潜在机制的研究仍在继续发展。在这篇综述中,我们总结了关于CFTR调制器对CFRD的影响。使用ivacaftor单药治疗门控突变的小型研究显示胰岛素分泌、葡萄糖耐量和/或胰岛素需要量的改善。然而,lumacaftor/ivacaftor研究(主要是在delta F 508纯合子中)并未显示CFRD或葡萄糖耐量的显着改善。目前还没有关于高效三联疗法(elexaftor /tezacaftor/ivacaftor)对CFRD或胰岛素分泌的影响的研究。CFTR调节剂可能通过多种机制影响CFRD的发生或进展,包括通过直接纠正CFTR缺陷改善胰岛素分泌、改善导管功能、减少胰岛炎症和改善肠促胰岛素分泌,或通过减少全身炎症和增加肺功能和生活质量驱动的体力活动来增强胰岛素敏感性。另一方面,它们可以刺激食欲,改善胃肠道功能,从而增加热量的摄入和吸收,导致体重过度增加,并可能增加胰岛素抵抗。如果胰岛素分泌缺陷是可逆的,那么在年轻时开始使用CFTR调节剂可能有助于预防CFRD。尽管CF管理取得了进步,但CFRD仍然是一个挑战,知识仍在不断发展。未来的研究将推动对高效CFTR调制剂在CFRD中的作用的更好理解。
The role of modulators in cystic fibrosis related diabetes
The development and introduction of modulator therapies have completely shifted the paradigm for the treatment of cystic fibrosis (CF). Highly effective modulator therapies have driven marked improvements in lung function, exacerbation rate, weight and quality of life in CF patients. However, their effect on CF related diabetes (CFRD) is not well delineated. The role of CF transmembrane conductance regulator (CFTR) in CFRD pathogenesis is inadequately understood and research aimed at deciphering the underlying mechanisms of CFRD continues to evolve. In this review, we summarize what is known regarding the effect of CFTR modulators on CFRD. Small studies using ivacaftor monotherapy in gating mutations have revealed improvement in insulin secretion, glucose tolerance and/or decrease in insulin requirement. However, lumacaftor/ivacaftor studies (primarily in delta F 508 homozygous) have not revealed significant improvement in CFRD or glucose tolerance. No studies are yet available regarding the effect of the highly effective triple therapy (elexacaftor/tezacaftor/ivacaftor) on CFRD or insulin secretion. CFTR modulators might affect development or progression of CFRD through many mechanisms including improving insulin secretion by correcting the CFTR defect directly, improving ductal function, reducing islet inflammation, and improving incretin secretion or by enhancing insulin sensitivity via reduced systemic inflammation and increased physical activity driven by improved lung function and quality of life. On the other hand, they can stimulate appetite and improve gastrointestinal function resulting in increased caloric intake and absorption, driving excessive weight gain and potentially increased insulin resistance. If the defect in insulin secretion is reversible then it is possible that initiation of CFTR modulators at a younger age might help prevent CFRD. Despite the advances in CF management, CFRD remains a challenge and knowledge continues to evolve. Future studies will drive better understanding of the role of highly effective CFTR modulators in CFRD.