The features of carbohydrate metabolism in children with cystic fi brosis: a 30-year-long history

Th e article presents a review on a cystic fibrosis-r elated diabetes, a severe complication of cystic fi brosis in children, which has acquired increasing importance and revealed to contribute in prognosis of the disease in recent years. Which include resent and historical epidemiology, pathophysiology, diagnostic methods, features of the course and the latest aspects of the targeted therapy effect on endocrine function of the pancreas. The authors presented a retrospective analysis of the carbohydrate metabolism condition in two groups of children with cystic fi brosis investigated in 1993 and 2021. These groups diff ered signifi cantly in baseline enzyme therapy, diet and nutritional support (the intake of supplementary medical nutrition). The study confi rmed that present-day patients have a lower percentage of impaired carbohydrate metabolism on the background of complete therapy. The authors proved that carbohydrate metabolism disorders occur earlier in nowadays children with cystic fi brosis, at the age before 10 years. This fi nding provides strong evidence that prediabetes is a period they should be diagnosed. These changes can be identifi ed only by a complete examination of the glycemic profi le of the patient, rather than, as previously thought, an oral glucose tolerance test. The study identifi ed that the indicator of continuous glucose monitoring — 6.42 mmol/l could be a predictor of the possible transition of prediabetic stage into cystic fi brosis related diabetes. The obtained results are confi rmed by the clinical case given by the authors.

1. Iafusco F., Maione G., Rosanio F. M., Mozzillo E., Franzese A., Tinto N. Cystic Fibrosis-R elated Diabetes (CFRD): Overview of Associated Genetic Factors. Diagnostics (Basel). 2021 Mar 22;11(3):572. doi: 10.3390/diagnostics11030572

2. Naehrig S., Chao C. M., Naehrlich L. Cystic Fibrosis. Dtsch Arztebl Int. 2017 Aug 21;114(33–34):564–574. doi: 10.3238/arztebl.2017.0564

3. Brown S.D., White R., Tobin P. Keep them breathing: Cystic fi brosis pathophysiology, diagnosis, and treatment. JAAPA. 2017 May;30(5):23–27. doi: 10.1097/01.JAA.0000515540.36581.92

4. Farrell P.M., White T. B., Ren C. L., et al. Diagnosis of Cystic Fibrosis: Consensus Guidelines from the Cystic Fibrosis Foundation. J Pediatr. 2017 Feb;181S: S4-S15.e1. doi: 10.1016/j.jpeds.2016.09.064. Erratum in: J Pediatr. 2017 May;184:243.

5. Kashirskaya N. Yu.,, Kapranova N. I., Kond rat iev a E. I. Cystic fi brosis. 2nd ed. Moscow. MedpraktikaM Publ., 2021, 680 P. Муковисцидоз. 2е изд., перераб. и доп. Под ред. Каширской НЮ, Капранова Н. И., Кондратьевой Е. И. М.: МедпрактикаМ, 2021, 680с.

6. Kashirskaya N. Yu., Kondratieva E. I., Krasovsky S. A., Star in ova M. A., Voronkova A. Yu., Amelina E. L. et al. Register of patients with cystic fi brosis in the Russian Federation. Moscow. Medpraktika- M Publ., 2021.

7. Alves C., Della-M anna T., Albuquerque C. T.M. Cystic fi brosis-r elated diabetes: an update on pathophysiology, diagnosis, and treatment. J Pediatr Endocrinol Metab. 2020;33(7):835–843. doi:10.1515/jpem-2019–0484

8. Atanesyan R.A., Kondratyeva E. I., Кrylova N. A., Klimov L. Ya., Dolbnya S. V. Cystic fi brosis- related diabetes. Medical News of North Caucasus. 2020;15(2):278–283. (In Russ.) doi: 10.14300/mnnc.2020.15068

9. Prentice B.J., Jaff e A., Hameed S., Verge C. F., Waters S., Widger J. Cystic fi brosis-r elated diabetes and lung disease: an update. Eur Respir Rev. 2021 Feb 16;30(159):200293. doi: 10.1183/16000617.0293–2020

10. Smirnov I.E., Tarasova O. V., Lukina O. F., Kustova O. V., Sorokina T. E., Simonova O. I. Structural and functional state of the lungs in cystic fi brosis in children. Russian pediatric journal. 2015; 18(2): 11–7. (in Russ.)

11. Cheney J., Vidmar S., Gailer N., Wainwright C., Douglas T. A.; Australasian Cystic Fibrosis Bronchoalveolar Lavage (ACFBAL) study group. Health-r elated quality-of-life in children with cystic fi brosis aged 5-years and associations with health outcomes. J Cyst Fibros. 2020 May;19(3):483–491. doi: 10.1016/j.jcf.2020.02.022. Epub 2020 Mar 9.

12. Baranov A. A., Namazova- Baranova L. S., Kutsev S. I., Avdeev S. N., Polevichenko E. V., Belevsky A. S. Cystic fi brosis (cystic fi brosis): clinical guidelines: (E84). 2021. Moscow. 2021. 225 P.

13. Management of cystic fi brosisrelated diabetes mellitus. Report of the UK Cystic Fibrosis Trust Diabetes Working Group; Cystic Fibrosis Trust, 2004.

14. Milla C.E., Billings J., Moran A. Diabetes is associated with dramatically decreased survival in female but not male subjects with cystic fi brosis. Diabetes Care. 2005 Sep;28(9):2141–4. doi: 10.2337/diacare.28.9.2141

15. Moran A., Brunzell C., Cohen R. C., et al. Clinical care guidelines for cystic fi brosis- related diabetes: A position statement of the american diabetes association and a clinical practice guideline of the cystic fi brosis foundation, endorsed by the pediatric endocrine society. Diabetes care. 2010;33(12):2697-708. doi: 102337/dc10–1768

16. Olesen H.V., Drevinek P., Gulmans V. A., Hatziagorou E., Jung A., Mei-Z ahav M., Stojnic N., Th omas M., Zolin A.; ECFSPR Steering Group. Cystic fi brosis related diabetes in Europe: Prevalence, risk factors and outcome; Olesen, et al. J Cyst Fibros. 2020 Mar;19(2):321–327. doi: 10.1016/j.jcf.2019.10.009. Epub 2019 Oct 31.

17. Kondratieva E.I., Kashirskaya N. Yu., Kapranova N. I. Cystic fi brosis: defi nition, diagnostic criteria, therapy. National consensus (2nd edition). Moscow. LLC “Company BORGES” Publ., 2018, 356 P.

18. Coderre L., Debieche L., Plourde J., Rabasa-L horet R., Lesage S. The Potential Causes of Cystic Fibrosis- Related Diabetes. Front Endocrinol (Lausanne). 2021 Jul 30;12:702823. doi: 10.3389/fendo.2021.702823

19. Beju D., Knox D., Yates D., et al. Th e ultrastructure of langergans islets in cystic fi brosis. Pediatric Pulmonology. 1992, no.9, Suppl 8, 313 P.

20. Hundrieser I., Bremer S., et al. Frequency of _F508 deletion in the CF gene in Turkish cystic fi brosis patients. Hum. Gen. 1990, Vol.85, no. 4, pp.409–410.

21. Kashirskaya N. Yu. Clinical and prognostic signifi cance of indicators of carbohydrate and fat metabolism in children and adolescents with cystic fi brosis: Abstract of the thesis. can. Sciences. Moscow, Nerey LLP Publ., 1995. 24 P.

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

23. Samoilenko V. A. Carbohydrate disorders and diabetes mellitus in adult patients with cystic fi brosis. Abstract dis… cand. med. Sciences. Moscow, 2014.

24. Perano S., Rayner C. K., Couper J., Martin J., Horowitz M. Cystic fi brosis related diabetes – a new perspective on the optimal management of postprandial glycemia. J Diabetes Complications. 2014 Nov-D ec;28(6):904–11. doi: 10.1016/j.jdiacomp.2014.06.012. Epub 2014 Jun 21.

25. Schwarzenberg S.J., Th omas W., Olsen T. W., Grover T., Walk D., Milla C., Moran A. Microvascular complications in cystic fi brosis- related diabetes. Diabetes Care. 2007 May;30(5):1056–61. doi: 10.2337/dc06–1576

26. Doan L.V., Madison L. D. Cystic Fibrosis Related Diabetes. 2021 Aug 30. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan. PMID: 31424776.

27. Castellani C., Duff A. J.A., Bell S. C., Heijerman H. G.M., et al. ECFS best practice guidelines: the 2018 revision. J Cyst Fibros. 2018 Mar;17(2):153–178. doi: 10.1016/j.jcf.2018.02.006

28. Yi Y., Norris A. W., Wang K., Sun X., Uc A., Moran A., Engelhardt J. F., Ode K. L. Abnormal Glucose Tolerance in Infants and Young Children with Cystic Fibrosis. Am J Respir Crit Care Med. 2016 Oct 15;194(8):974–980. doi: 10.1164/rccm.201512–2518OC. PMID: 27447840; PMCID: PMC5067820.

29. Prentice B., Hameed S., Verge C. F., Ooi C. Y., Jaff e A., Widger J. Diagnosing cystic fi brosis- related diabetes: current methods and challenges. Expert Rev Respir Med. 2016 Jul;10(7):799–811. doi: 10.1080/17476348.2016.1190646

30. Blanquer M., Clainche L. L., Bismuth E., Storey C., Gerardin M., Houdouin V. Very early glucose tolerance abnormalities in children with cystic fibrosis. J Cyst Fibros. 2021 Sep;20(5):792–795. doi: 10.1016/j.jcf.2021.08.001

31. Theocharous K., Prentice B., Verge C. F., Jaffé A., Hameed S. Detection and Management of Early Glucose Abnormalities in Cystic Fibrosis / Cystic Fibrosis – Facts, Management and Advances, edited by Prashant Mohite, Anna Reed, André Simon. London: IntechOpen. 2020 doi: 10.5772/intechopen.92847

32. Brodsky J., Dougherty S., Makani R., Rubenstein R. C., Kelly A. Elevation of 1-hour plasma glucose during oral glucose tolerance testing is associated with worse pulmonary function in cystic fi brosis. Diabetes Care. 2011 Feb;34(2):292–5. doi: 10.2337/dc10–1604

33. Prentice B.J., Chelliah A., Ooi C. Y., Hameed S., Verge C. F., Plush L., Widger J. Peak OGTT glucose is associated with lower lung function in young children with cystic fi brosis. J Cyst Fibros. 2020 Mar;19(2):305–309. doi: 10.1016/j.jcf.2019.05.005

34. Cano Megías M., González Albarrán O., Guisado Vasco P., Lamas Ferreiro A., Máiz Carro L. Insulin resistance, β-cell dysfunction and diff erences in curves of plasma glucose and insulin in the intermediate points of the standard glucose tolerance test in adults with cysticfi brosis. Endocrinol Nutr. 2015 Feb;62(2):91–9. English, Spanish. doi: 10.1016/j.endonu.2014.08.002

35. Roberts K., Liu I, Jaff e A., Verge C. F., Th omas P. S. Markers of pancreatic function in the breath. J Breath Res. 2014 Nov 24;8(4):046009. doi: 10.1088/1752–7155/8/4/046009

36. Granados A., Chan C. L., Ode K. L., Moheet A., Moran A., Holl R. Cystic fi brosis related diabetes: Pathophysiology, screening and diagnosis. J Cyst Fibros. 2019 Oct;18 Suppl 2: S3-S9. doi: 10.1016/j.jcf.2019.08.016

37. O’Riordan S.M., Hindmarsh P., Hill N. R., et al. Valid ation of continuous glucose monitoring in children and adolescents with cystic fi brosis: a prospective cohort study. Diabetes Care. 2009 Jun;32(6):1020–2. doi: 10.2337/dc08–1925. Epub 2009 Mar 11.

38. Dedov I.I., Shestakova M. V., Mayorova A. Yu. Algorithms of specialized medical care for patients with diabetes mellitus. Moscow. 2021. doi: 10.14341/DM12802

39. Medtronic iPro2. User Guide. 2010. USA. Medtronic iPro2. Руководство пользователей – 2010. USA.

40. Guardian® REAL-Time. Continuous glucose monitoring system. User Manual. 2006. USA. Guardian® REAL-Time. Система постоянного измерения уровня глюкозы. Руководство пользователя – 2006. USA.

41. Elidottir H., Diemer S., Eklund E., Hansen C. R. Abnormal glucose tolerance and lung function in children with cystic fi brosis. Comparing oral glucose tolerance test and continuous glucose monitoring. J Cyst Fibros. 2021 Sep;20(5):779–784. doi: 10.1016/j.jcf.2021.01.002

42. Chan C.L., Ode K. L., Granados A., Moheet A., Moran A., Hameed S. Continuous glucose monitoring in cystic fi brosis – A practical guide. J Cyst Fibros. 2019 Oct;18 Suppl 2: S25-S31. doi: 10.1016/j.jcf.2019.08.025

43. Kulcu E., Tamada J. A., Reach G., Potts R. O., Lesho M. J. Physiological Diff erences Between Interstitial Glucose and Blood Glucose Measured in Human Subjects. Diabetes Care. Aug 2003;26(8):2405–9 https://doi.org/. doi: 10.2337/diacare.26.8.2405

44. Sandouk Z., Khan F., Khare S., Moran A. Cystic fi brosis related diabetes (CFRD) prognosis. J Clin Transl Endocrinol. 2021;26:100278. Published 2021 Nov 19. doi:10.1016/j.jcte.2021.100278

45. Bellin M.D., Laguna T., Leschyshyn J., Regelmann W., Dunitz J., Billings J., Moran A. Insulin secretion improves in cystic fi brosis following ivacaft or correction of CFTR: a small pilot study. Pediatr Diabetes. 2013 Sep;14(6):417-21. doi: 10.1111/pedi.12026

46. Gaines H., Jones K. R., Lim J., Medhi N. F., Chen S., Scofi eld R. H. Eff ect of CFTR modulator therapy on cystic fi brosis- related diabetes. J Diabetes Complications. 2021 Jun;35(6):107845. doi: 10.1016/j.jdiacomp.2020.107845

47. Merjaneh L., Hasan S., Kasim N., Ode K. L. Th e role of modulators in cystic fi brosis related diabetes. J Clin Transl Endocrinol. 2021 Dec 7;27:100286. doi: 10.1016/j.jcte.2021.100286

48. Simonova O.I., Roslavtseva E. A. Features of enzyme replacement therapy in cystic fi brosis in children: the benefi ts of high-tech enzyme preparations. Questions of modern pediatrics. 2011; 10(5), 152–156. (in Russ.)

49. Peterkova V. A. Diabetes mellitus in children and adolescents: ISPAD clinical practice consensus: 2014/trans. from English. Moscow. GEOTAR-Media Pubmed., 2016. 656 P.