The Effect of Cystic Fibrosis Transmembrane Conductance Regulator Modulators on Impaired Glucose Tolerance and Cystic Fibrosis Related Diabetes

Overview

Journal J Clin Transl Endocrinol

Specialty Endocrinology

Date 2022 Jun 24

PMID 35746945

Authors

Sana Hasan

Mohammad Salman Khan

M Cecilia Lansang

Affiliations

Soon will be listed here.

Abstract

Cystic fibrosis (CF) is an autosomal recessive disorder, with a prevalence of 1 in 2,500 live births. It is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. With the significant advancement in CFTR-directed therapies, life expectancy of CF patients has steadily increased. With improved survival, CF related co-morbidities have become more apparent. The most common endocrine complication includes Cystic fibrosis related diabetes (CFRD). Impaired glucose tolerance and insulin deficiency in CFRD leads to a decline in pulmonary function in CF patients. Here we review the underlying mechanisms involved in the pathogenesis of CFRD, focusing on the role of CFTR in the regulation of insulin secretion from the β-cell. We then discuss CFTR modulators and their effect on impaired glucose tolerance and CFRD.

Citing Articles

Changes in immunofluorescence staining during islet regeneration in a cystic fibrosis-related diabetes (CFRD) ferret model.

Mohammed S, Bone R, Aquino J, Mirmira R, Evans-Molina C, Ismail H Islets. 2024; 16(1):2436696.

PMID: 39641365 PMC: 11633224. DOI: 10.1080/19382014.2024.2436696.

An Update in Cystic Fibrosis-Related Diabetes in Children and Adolescents.

Anton-Paduraru D, Murgu A, Donos M, Trofin F, Azoicai A, Popovici P Children (Basel). 2023; 10(12).

PMID: 38136081 PMC: 10741586. DOI: 10.3390/children10121879.

The Effects of Elexacaftor, Tezacaftor, and Ivacaftor (ETI) on Blood Glucose in Patients With Cystic Fibrosis: A Systematic Review.

Salazar-Barragan M, Taub D Cureus. 2023; 15(7):e41697.

PMID: 37575762 PMC: 10413995. DOI: 10.7759/cureus.41697.

Evolving Nutritional Needs in Cystic Fibrosis.

Frantzen T, Barsky S, LaVecchia G, Marowitz M, Wang J Life (Basel). 2023; 13(7).

PMID: 37511806 PMC: 10381916. DOI: 10.3390/life13071431.

References

White M, Maheshwari R, Anderson S, Berlinguer-Palmini R, Jones C, Richardson S . In Situ Analysis Reveals That CFTR Is Expressed in Only a Small Minority of β-Cells in Normal Adult Human Pancreas. J Clin Endocrinol Metab. 2019; 105(5). PMC: 7341165. DOI: 10.1210/clinem/dgz209. View

Moran A, Dunitz J, Nathan B, Saeed A, Holme B, Thomas W . Cystic fibrosis-related diabetes: current trends in prevalence, incidence, and mortality. Diabetes Care. 2009; 32(9):1626-31. PMC: 2732133. DOI: 10.2337/dc09-0586. View

NTimbane T, Comte B, Mailhot G, Berthiaume Y, Poitout V, Prentki M . Cystic fibrosis-related diabetes: from CFTR dysfunction to oxidative stress. Clin Biochem Rev. 2009; 30(4):153-77. PMC: 2791770. View

Guo J, Chen H, Ruan Y, Zhang X, Zhang X, Fok K . Glucose-induced electrical activities and insulin secretion in pancreatic islet β-cells are modulated by CFTR. Nat Commun. 2014; 5:4420. PMC: 4104438. DOI: 10.1038/ncomms5420. View

Misgault B, Chatron E, Reynaud Q, Touzet S, Abely M, Melly L . Effect of one-year lumacaftor-ivacaftor treatment on glucose tolerance abnormalities in cystic fibrosis patients. J Cyst Fibros. 2020; 19(5):712-716. DOI: 10.1016/j.jcf.2020.03.002. View

Soejima K, LANDING B . Pancreatic islets in older patients with cystic fibrosis with and without diabetes mellitus: morphometric and immunocytologic studies. Pediatr Pathol. 1986; 6(1):25-46. DOI: 10.3109/15513818609025923. View

Kelly A, De Leon D, Sheikh S, Camburn D, Kubrak C, Peleckis A . Islet Hormone and Incretin Secretion in Cystic Fibrosis after Four Months of Ivacaftor Therapy. Am J Respir Crit Care Med. 2018; 199(3):342-351. PMC: 6835076. DOI: 10.1164/rccm.201806-1018OC. View

Lanng S, Thorsteinsson B, Roder M, Orskov C, Holst J, Nerup J . Pancreas and gut hormone responses to oral glucose and intravenous glucagon in cystic fibrosis patients with normal, impaired, and diabetic glucose tolerance. Acta Endocrinol (Copenh). 1993; 128(3):207-14. DOI: 10.1530/acta.0.1280207. View

Lopes-Pacheco M . CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine. Front Pharmacol. 2020; 10:1662. PMC: 7046560. DOI: 10.3389/fphar.2019.01662. View

10.

Christian F, Thierman A, Shirley E, Allen K, Cross C, Jones K . Sustained Glycemic Control With Ivacaftor in Cystic Fibrosis-Related Diabetes. J Investig Med High Impact Case Rep. 2019; 7:2324709619842898. PMC: 6480995. DOI: 10.1177/2324709619842898. View

11.

Bellin M, Laguna T, Leschyshyn J, Regelmann W, Dunitz J, Billings J . Insulin secretion improves in cystic fibrosis following ivacaftor correction of CFTR: a small pilot study. Pediatr Diabetes. 2013; 14(6):417-21. PMC: 3804832. DOI: 10.1111/pedi.12026. View

12.

Sun X, Yi Y, Xie W, Liang B, Winter M, He N . CFTR Influences Beta Cell Function and Insulin Secretion Through Non-Cell Autonomous Exocrine-Derived Factors. Endocrinology. 2017; 158(10):3325-3338. PMC: 5659686. DOI: 10.1210/en.2017-00187. View

13.

Fontes G, Ghislain J, Benterki I, Zarrouki B, Trudel D, Berthiaume Y . The ΔF508 Mutation in the Cystic Fibrosis Transmembrane Conductance Regulator Is Associated With Progressive Insulin Resistance and Decreased Functional β-Cell Mass in Mice. Diabetes. 2015; 64(12):4112-22. PMC: 4876763. DOI: 10.2337/db14-0810. View

14.

Wainwright C, Elborn J, Ramsey B, Marigowda G, Huang X, Cipolli M . Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. N Engl J Med. 2015; 373(3):220-31. PMC: 4764353. DOI: 10.1056/NEJMoa1409547. View

15.

Olivier A, Yi Y, Sun X, Sui H, Liang B, Hu S . Abnormal endocrine pancreas function at birth in cystic fibrosis ferrets. J Clin Invest. 2012; 122(10):3755-68. PMC: 3534166. DOI: 10.1172/JCI60610. View

16.

Manderson Koivula F, McClenaghan N, Harper A, Kelly C . Islet-intrinsic effects of CFTR mutation. Diabetologia. 2016; 59(7):1350-1355. PMC: 4901107. DOI: 10.1007/s00125-016-3936-1. View

17.

Huang W, Guo J, Zhang X, Yu M, Chung Y, Ruan Y . Glucose-Sensitive CFTR Suppresses Glucagon Secretion by Potentiating KATP Channels in Pancreatic Islet α Cells. Endocrinology. 2017; 158(10):3188-3199. DOI: 10.1210/en.2017-00282. View

18.

Yi Y, Sun X, Gibson-Corley K, Xie W, Liang B, He N . A Transient Metabolic Recovery from Early Life Glucose Intolerance in Cystic Fibrosis Ferrets Occurs During Pancreatic Remodeling. Endocrinology. 2016; 157(5):1852-65. PMC: 4870869. DOI: 10.1210/en.2015-1935. View

19.

Iannucci A, Mukai K, Johnson D, Burke B . Endocrine pancreas in cystic fibrosis: an immunohistochemical study. Hum Pathol. 1984; 15(3):278-84. DOI: 10.1016/s0046-8177(84)80191-4. View

20.

Hart N, Aramandla R, Poffenberger G, Fayolle C, Thames A, Bautista A . Cystic fibrosis-related diabetes is caused by islet loss and inflammation. JCI Insight. 2018; 3(8). PMC: 5931120. DOI: 10.1172/jci.insight.98240. View