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. 2021 Dec 7:27:100286.
doi: 10.1016/j.jcte.2021.100286. eCollection 2022 Mar.

The role of modulators in cystic fibrosis related diabetes

Lina Merjaneh  1 , Sana Hasan  2 , Nader Kasim  3 , Katie Larson Ode  4
Affiliations

The role of modulators in cystic fibrosis related diabetes

Lina Merjaneh et al. J Clin Transl Endocrinol. .

Abstract

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.

Keywords: CFRD; Insulin; Modulator therapy.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
The mutation classes of the CFTR gene leading to CFTR dysfunction.
Fig. 2
Fig. 2
The possible mechanisms in which highly effective modulator therapy (HEMT) might affect glucose metabolism in CF.
See this image and copyright information in PMC

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