Merjaneh Lina, Hasan Sana, Kasim Nader, Ode Katie Larson
Division of Endocrinology, Department of Pediatrics, Seattle Children's Hospital, Seattle, WA, USA.
Department of Endocrinology and Metabolism, Cleveland Clinic Foundation, Cleveland, OH.
J Clin Transl Endocrinol. 2021 Dec 7;27:100286. doi: 10.1016/j.jcte.2021.100286. eCollection 2022 Mar.
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.
调节剂疗法的发展和引入彻底改变了囊性纤维化（CF）的治疗模式。高效的调节剂疗法已使CF患者的肺功能、病情加重率、体重和生活质量得到显著改善。然而，它们对CF相关糖尿病（CFRD）的影响尚未明确界定。CF跨膜传导调节因子（CFTR）在CFRD发病机制中的作用尚未得到充分了解，旨在解读CFRD潜在机制的研究仍在不断发展。在本综述中，我们总结了关于CFTR调节剂对CFRD影响的已知情况。在门控突变中使用依伐卡托单药治疗的小型研究显示胰岛素分泌、糖耐量有所改善和/或胰岛素需求减少。然而，鲁马卡托/依伐卡托的研究（主要针对ΔF508纯合子）并未显示CFRD或糖耐量有显著改善。关于高效三联疗法（依列卡托/替扎卡托/依伐卡托）对CFRD或胰岛素分泌的影响尚无研究。CFTR调节剂可能通过多种机制影响CFRD的发展或进展，包括通过直接纠正CFTR缺陷来改善胰岛素分泌、改善导管功能、减轻胰岛炎症、改善肠促胰岛素分泌，或通过减轻全身炎症和改善肺功能及生活质量带动身体活动增加来提高胰岛素敏感性。另一方面，它们可刺激食欲并改善胃肠功能，导致热量摄入和吸收增加，促使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，那么在较年轻时开始使用CFTR调节剂可能有助于预防CFRD。尽管CF管理取得了进展，但CFRD仍然是一项挑战，相关知识也在不断发展。未来的研究将有助于更好地理解高效CFTR调节剂在CFRD中的作用。
