diaendoСахарный диабетDiabetes mellitus2072-03512072-0378Endocrinology research centre10.14341/DM12955diaendo-12955Research ArticleОригинальные исследованияOriginal StudiesПрофиль островковых аутоантител и остаточная функция бета-клеток в зависимости от возраста манифестации сахарного диабета 1 типа у детейIslet autoantibodies and residual beta-cell function in children with type 1 diabetes depending on age of manifestationhttps://orcid.org/0000-0003-0123-8857РоманенковаЕ. М.RomanenkovaE. M.

Романенкова Елизавета Михайловна - Researcher ID: AAB-7186-2021; eLibrary SPIN: 6190-0118.

117036, Москва, ул. Дм. Ульянова, д. 11

Elizaveta M. Romanenkova - MD. Researcher ID: AAB-7186-2021; eLibrary SPIN: 6190-0118.

11 Dm. Ulyanova street, 117036 Moscow

romanenkovae@list.ruhttps://orcid.org/0000-0002-5463-0425ЗуфароваЮ. М.ZufarovaI. M.

Зуфарова Юлдуз Муроджоновна - Researcher ID: AGE-4004-2022; eLibrary SPIN: 7553-9512.

Москва

Iulduz M. Zufarova - MD; Researcher ID: AGE-4004-2022; eLibrary SPIN: 7553-9512.

Moscow

Iulduzzufarova@gmail.comhttps://orcid.org/0000-0001-9815-2309СорокинД. Ю.SorokinD. Y.

Сорокин Даниил Юрьевич - Researcher ID: HJY-5714-2023.

Москва

Daniil Y. Sorokin - MD; Researcher ID: HJY-5714-2023.

Moscow

daniilsorokin007@gmail.comhttps://orcid.org/0000-0001-7021-1151ЕреминаИ. А.EreminaI. A.

Еремина Ирина Александровна - кандидат медицинских наук; Researcher ID: S-3979-2016; Scopus Author ID: 6701334405.

Москва

Irina A. Eremina - MD, PhD; Researcher ID: S-3979-2016; Scopus Author ID: 6701334405.

Moscow

ieremina58@gmail.comhttps://orcid.org/0000-0002-8181-5572СечкоЕ. А.SechkoE. A.

Сечко Елена Александровна - кандидат медицинских наук; Researcher ID: S-4114-2016; Scopus Author ID: 55880018700.

Москва

Elena A. Sechko - MD, PhD; Researcher ID: S-4114-2016; Scopus Author ID: 55880018700.

Moscow

elena.sechko@bk.ruhttps://orcid.org/0000-0002-3199-4998НиканкинаЛ. В.NikankinaL. V.

Никанкина Лариса Вячеславовна - кандидат медицинских наук; Researcher ID: AAL-8725-2021; Scopus Author ID: 57190192821.

Москва

Larisa V. Nikankina - MD, PhD; Researcher ID: AAL-8725-2021; Scopus Author ID: 57190192821.

Moscow

Nikankina.Larisa@endocrincentr.ruhttps://orcid.org/0000-0002-5507-4627ПетерковаВ. А.PeterkovaV. A.

Петеркова Валентина Александровна - доктор медицинских наук, профессор, академик РАН.

Москва

Valentina A. Peterkova - PhD, professor, academician of Russian Academy of Medical Sciences.

Moscow

peterkovava@hotmail.comhttps://orcid.org/0000-0001-9621-5732БезлепкинаО. Б.BezlepkinaO. B.

Безлепкина Ольга Борисовна - доктор медицинских наук; Researcher ID: B-6627-2017; Scopus Author ID: 6507632848.

Москва

Olga B. Bezlepkina – PhD; Researcher ID: B-6627-2017; Scopus Author ID: 6507632848.

Moscow

olgabezlepkina@mail.ruhttps://orcid.org/0000-0002-4316-8546ЛаптевД. Н.LaptevD. N.

Лаптев Дмитрий Никитич - доктор медицинских наук ; Researcher ID: O-1826-2013; Scopus Author ID: 24341083800.

Москва

Dmitry N. Laptev, MD, PhD; Researcher ID: O-1826-2013; Scopus Author ID: 24341083800.

Moscow

laptevdn@ya.ruГНЦ РФ ФГБУ «Национальный медицинский исследовательский центр эндокринологии»РоссияEndocrinology Research CentreRussian Federation202314072023263204212Copyright © Романенкова Е.М., Зуфарова Ю.М., Сорокин Д.Ю., Еремина И.А., Сечко Е.А., Никанкина Л.В., Петеркова В.А., Безлепкина О.Б., Лаптев Д.Н., 20232023Романенкова Е.М., Зуфарова Ю.М., Сорокин Д.Ю., Еремина И.А., Сечко Е.А., Никанкина Л.В., Петеркова В.А., Безлепкина О.Б., Лаптев Д.Н.Romanenkova E.M., Zufarova I.M., Sorokin D.Y., Eremina I.A., Sechko E.A., Nikankina L.V., Peterkova V.A., Bezlepkina O.B., Laptev D.N.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.dia-endojournals.ru/jour/article/view/12955ОБОСНОВАНИЕ

ОБОСНОВАНИЕ. Сахарный диабет 1 типа (СД1) — хроническое заболевание, сопровождающееся деструкцией β-клеток и прогрессирующим снижением секреции инсулина в результате аутоиммунного процесса. Специфические островковые аутоантитела (ААт) являются основным диагностическим маркером СД1. Клинически важным показателем в исследовании течения СД1 является уровень С-пептида, отражающий остаточную секрецию инсулина β-клетками.

ЦЕЛЬ

ЦЕЛЬ. Исследовать частоту и уровень остаточной секреции С-пептида и персистирования островковых ААт у детей с разной длительностью заболевания в зависимости от возраста манифестации.

МАТЕРИАЛЫ И МЕТОДЫ

МАТЕРИАЛЫ И МЕТОДЫ. Проанализированы данные уровней С-пептида и специфических островковых ААт к ZnT8 (транспортеру цинка 8), ААт к IA-2 (тирозинфосфатазе), ААт к GAD (глутаматдекарбоксилазе), IAA (ААт к инсулину) у 1333 детей с СД1. Пациенты распределены на 3 группы в зависимости от длительности (1-я — <1 года, 2-я — от 1 до 5 лет, 3-я — >5 лет) и возраста манифестации (А — допубертат и Б — пубертат) СД1.

РЕЗУЛЬТАТЫ

РЕЗУЛЬТАТЫ. Медиана длительности СД1 — 1,8 [0,8; 3,9], частота серопозитивности — 76,3%, частота определяемого уровня С-пептида — 40%. С увеличением продолжительности заболевания отмечается снижение ААт+ до: 1-я группа — 74%, 2-я— 69%, 3-я— 48%. При начале СД1 в допубертатном возрасте частота ААт+ значимо ниже при любой длительности заболевания. В первый год заболевания наиболее выявляемыми ААт в обеих группах являются ZnT8A и GADA. IA-2A встречаются с той же частотой в группе подростков. Серопозитивность по IAA более характерна при диагностике СД1 в допубертатном возрасте. Неопределяемый уровень С-пептида чаще наблюдался при манифестации СД1 в допубертатном возрасте (p<0,05): 1А — 13% и 1Б — 5%, 2А — 51% и 2Б — 14%, 3А — 82% и 3Б — 50%, а нормальный уровень С-пептида — у детей с началом СД1 в пубертатном возрасте (p<0,05): 1А — 6% и 1Б — 44%, 2А — 2% и 2Б — 25%, 3А — 2% и 3Б — 11%.

ЗАКЛЮЧЕНИЕ

ЗАКЛЮЧЕНИЕ. У детей наблюдается высокая частота выявления ААт — около половины детей с длительностью СД1 более 5 лет являются серопозитивными. Наиболее информативными ААт в начале СД1 являются GADA и ZnT8A. Уровень С-пептида зависит от возраста манифестации СД1.

BACKGROUND

BACKGROUND: Type 1 diabetes mellitus (T1D) is an autoimmune disorder that leads to pancreatic β-cells destruction and progressive decrease of insulin secretion. Specific islet autoantibodies (AAbs) are the main diagnostic marker of T1D. Residual β-cell function, as measured by C-peptide, has repeatedly been demonstrated to be clinically important.

AIM

AIM: To study the frequency and levels of residual C-peptide secretion and persistence of pancreatic AAbs in children with T1D with different duration and age of manifestation of the disease.

MATERIALS AND METHODS

MATERIALS AND METHODS: The levels of C-peptide and AAbs to ZnT8 (zinc transporter 8), AAbs to IA-2 (Insulinoma Antigen 2), AAbs to GAD (Glutamate Decarboxylase), IAA (insulin autoantibodies) were measured. Patients were divided into 3 groups depending on the duration of T1D (1st — <1 year, 2nd — from 1 to 5 years, 3rd — >5 years) and age of manifestation (A — prepubertal and B — puberty).

RESULTS

RESULTS: The median duration of T1D was 1.8 [0,8;3,9], 76.3% out of 1333 patients were seropositive, 40% had residual levels of C-peptide. With disease duration there were a decrease in AAbs+: 1st group 74%, 2nd group 69%, and 3rd group 48%. In all groups, percentage of patients with positive levels of one or more AAbs was significantly higher in children with T1D manifestation at puberty. GADA and ZnT8A were more common in the first year of the disease. IA-2A were observed with the same frequency in the group of adolescents. IAA were more common in patients at prepubertal age. An undetectable level of C-peptide was observed significantly higher in children with T1D manifestation in prepubertal age (p<0.05): 1А — 13% and 1B — 5%, 2А — 51% and 2B — 14%, 3А — 82% and 3B — 50%, reference range of C-peptide was observed in adolescents (p<0,05): 1А — 6% and 1B — 44%, 2А — 2% and 2b — 25%, 3А — 2% and 3B — 11%.

CONCLUSION

CONCLUSION: AAbs+ is relatively common in children with T1D and about half of them are seropositive in more than 5 years after manifestation. GADA and ZnT8A have high specificity for patients with new-onset T1D. C-peptide secretion depends on the age of the disease manifestation.

сахарный диабет 1 типадетиманифестацияC-пептидаутоантителаtype 1 diabeteschildrenmanifestationC-peptideautoantibodiesИсследование выполнено в рамках исполнения государственного задания № 123021000040-9ReferencesKeenan HA, Sun JK, Levine J, et al. Residual insulin production and pancreatic ß-cell turnover after 50 years of diabetes: Joslin Medalist Study. Diabetes. 2010;59(11):2846-2853. doi: https://doi.org/10.2337/db10-0676Keenan HA, Sun JK, Levine J, et al. Residual insulin production and pancreatic ß-cell turnover after 50 years of diabetes: Joslin Medalist Study. Diabetes. 2010;59(11):2846-2853. doi: https://doi.org/10.2337/db10-0676Meier JJ, Bhushan A, Butler AE, et al. Sustained beta cell apoptosis in patients with long-standing type 1 diabetes: indirect evidence for islet regeneration? Diabetologia. 2005;48(11):2221-2228. doi: https://doi.org/10.1007/s00125-005-1949-2Meier JJ, Bhushan A, Butler AE, et al. Sustained beta cell apoptosis in patients with long-standing type 1 diabetes: indirect evidence for islet regeneration? Diabetologia. 2005;48(11):2221-2228. doi: https://doi.org/10.1007/s00125-005-1949-2Wang L, Lovejoy NF, Faustman DL. Persistence of prolonged C-peptide production in type 1 diabetes as measured with an ultrasensitive C-peptide assay. Diabetes Care. 2012;35(3):465-470. doi: https://doi.org/10.2337/dc11-1236Wang L, Lovejoy NF, Faustman DL. Persistence of prolonged C-peptide production in type 1 diabetes as measured with an ultrasensitive C-peptide assay. Diabetes Care. 2012;35(3):465-470. doi: https://doi.org/10.2337/dc11-1236Davis AK, DuBose SN, Haller MJ, et al. Prevalence of detectable C-peptide according to age at diagnosis and duration of type 1 diabetes. Diabetes Care. 2015;38(3):476-481. doi: https://doi.org/10.2337/dc14-1952Davis AK, DuBose SN, Haller MJ, et al. Prevalence of detectable C-peptide according to age at diagnosis and duration of type 1 diabetes. Diabetes Care. 2015;38(3):476-481. doi: https://doi.org/10.2337/dc14-1952Lachin JM, McGee P, Palmer JP. Impact of C-Peptide Preservation on Metabolic and Clinical Outcomes in the Diabetes Control and Complications Trial. Diabetes. 2014;63(2):739-748. doi: https://doi.org/10.2337/db13-0881Lachin JM, McGee P, Palmer JP. Impact of C-Peptide Preservation on Metabolic and Clinical Outcomes in the Diabetes Control and Complications Trial. Diabetes. 2014;63(2):739-748. doi: https://doi.org/10.2337/db13-0881Jeyam A, Colhoun H, McGurnaghan S, et al. Clinical impact of residual c-peptide secretion in type 1 diabetes on glycemia and microvascular complications [published correction appears in Diabetes Care. 2021 Feb 5] [published correction appears in Diabetes Care. 2021;44(4):1072]. Diabetes Care. 2021;44(2):390-398. doi: https://doi.org/10.2337/dc20-0567Jeyam A, Colhoun H, McGurnaghan S, et al. Clinical impact of residual c-peptide secretion in type 1 diabetes on glycemia and microvascular complications [published correction appears in Diabetes Care. 2021 Feb 5] [published correction appears in Diabetes Care. 2021;44(4):1072]. Diabetes Care. 2021;44(2):390-398. doi: https://doi.org/10.2337/dc20-0567Yu MG, Keenan HA, Shah HS, et al. Residual β cell function and monogenic variants in long-duration type 1 diabetes patients. J Clin Invest. 2019;129(8):3252-3263. doi: https://doi.org/10.1172/JCI127397Yu MG, Keenan HA, Shah HS, et al. Residual β cell function and monogenic variants in long-duration type 1 diabetes patients. J Clin Invest. 2019;129(8):3252-3263. doi: https://doi.org/10.1172/JCI127397Atkinson MA, Eisenbarth GS, Michels AW. Type 1 diabetes. Lancet. 2014;383(9911):69-82. doi: https://doi.org/10.1016/S0140-6736(13)60591-7Atkinson MA, Eisenbarth GS, Michels AW. Type 1 diabetes. Lancet. 2014;383(9911):69-82. doi: https://doi.org/10.1016/S0140-6736(13)60591-7Сечко Е.А., Кураева Т.Л., Зильберман Л.И., и др. Неиммунный сахарный диабет у детей, обусловленный гетерозиготными мутациями в гене глюкокиназы (GCK-MODY): анализ данных 144 пациентов // Сахарный диабет. — 2022. — Т. 25. — №2. — С. 145-154. doi: https://doi.org/10.14341/DM12819Sechko EA, Kuraeva TL, Zilberman LI, et al. Non-immune diabetes mellitus in children due to heterozygous mutations in the glucokinase gene (GCK-MODY): data of 144 patients. Diabetes mellitus. 2022;25(2):145-154. (In Russ.). doi: https://doi.org/10.14341/DM12819Mayer-Davis EJ, Kahkoska AR, Jefferies C, et al. ISPAD Clinical Practice Consensus Guidelines 2018: Definition, epidemiology, and classification of diabetes in children and adolescents. Pediatr Diabetes. 2018;19(S27):7-19. doi: https://doi.org/10.1111/pedi.12773Mayer-Davis EJ, Kahkoska AR, Jefferies C, et al. ISPAD Clinical Practice Consensus Guidelines 2018: Definition, epidemiology, and classification of diabetes in children and adolescents. Pediatr Diabetes. 2018;19(S27):7-19. doi: https://doi.org/10.1111/pedi.12773Российская ассоциация эндокринологов. Клинические рекомендации. Сахарный диабет 1 типа у детей. М.: Министерство здравоохранения Российской Федерации; 2021.Rossijskaja associacija jendokrinologov. Klinicheskie rekomendacii. Saharnyj diabet 1 tipa u detej. Moscow: Ministerstvo Zdravoohranenija Rossijskoj Federacii; 2021. (In Russ.).Patel SK, Ma CS, Fourlanos S, Greenfield JR. Autoantibody-negative type 1 diabetes: A neglected subtype. Trends Endocrinol Metab. 2021;32(5):295-305. doi: https://doi.org/10.1016/j.tem.2021.02.001Patel SK, Ma CS, Fourlanos S, Greenfield JR. Autoantibody-negative type 1 diabetes: A neglected subtype. Trends Endocrinol Metab. 2021;32(5):295-305. doi: https://doi.org/10.1016/j.tem.2021.02.001Vipin VP, Zaidi G, Watson K, et al. High prevalence of idiopathic (islet antibody-negative) type 1 diabetes among Indian children and adolescents [published correction appears in Pediatr Diabetes. 2022;23(4):527]. Pediatr Diabetes. 2021;22(1):47-51. doi: https://doi.org/10.1111/pedi.13066Vipin VP, Zaidi G, Watson K, et al. High prevalence of idiopathic (islet antibody-negative) type 1 diabetes among Indian children and adolescents [published correction appears in Pediatr Diabetes. 2022;23(4):527]. Pediatr Diabetes. 2021;22(1):47-51. doi: https://doi.org/10.1111/pedi.13066Ziegler AG, Rewers M, Simell O, et al. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA. 2013;309(23):2473-2479. doi: https://doi.org/10.1001/jama.2013.6285Ziegler AG, Rewers M, Simell O, et al. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA. 2013;309(23):2473-2479. doi: https://doi.org/10.1001/jama.2013.6285Bravis V, Kaur A, Walkey HC, et al. Relationship between islet autoantibody status and the clinical characteristics of children and adults with incident type 1 diabetes in a UK cohort. BMJ Open. 2018;8(4):e020904. doi: https://doi.org/10.1136/bmjopen-2017-020904Bravis V, Kaur A, Walkey HC, et al. Relationship between islet autoantibody status and the clinical characteristics of children and adults with incident type 1 diabetes in a UK cohort. BMJ Open. 2018;8(4):e020904. doi: https://doi.org/10.1136/bmjopen-2017-020904Głowińska-Olszewska B, Michalak J, Łuczyński W, et al. Organ-specific autoimmunity in relation to clinical characteristics in children with long-lasting type 1 diabetes. J Pediatr Endocrinol Metab. 2016;29(6):69-82. doi: https://doi.org/10.1515/jpem-2015-0190Głowińska-Olszewska B, Michalak J, Łuczyński W, et al. Organ-specific autoimmunity in relation to clinical characteristics in children with long-lasting type 1 diabetes. J Pediatr Endocrinol Metab. 2016;29(6):69-82. doi: https://doi.org/10.1515/jpem-2015-0190Decochez K, Tits J, Coolens JL, et al. High frequency of persisting or increasing islet-specific autoantibody levels after diagnosis of type 1 diabetes presenting before 40 years of age. The Belgian Diabetes Registry. Diabetes Care. 2000;23(6):838-844. doi: https://doi.org/10.2337/diacare.23.6.838Decochez K, Tits J, Coolens JL, et al. High frequency of persisting or increasing islet-specific autoantibody levels after diagnosis of type 1 diabetes presenting before 40 years of age. The Belgian Diabetes Registry. Diabetes Care. 2000;23(6):838-844. doi: https://doi.org/10.2337/diacare.23.6.838Wilmot-Roussel H, Lévy D-J, Carette C, et al. Factors associated with the presence of glutamic acid decarboxylase and islet antigen-2 autoantibodies in patients with long-standing type 1 diabetes. Diabetes Metab. 2013;39(3):244-249. doi: https://doi.org/10.1016/j.diabet.2013.01.002Wilmot-Roussel H, Lévy D-J, Carette C, et al. Factors associated with the presence of glutamic acid decarboxylase and islet antigen-2 autoantibodies in patients with long-standing type 1 diabetes. Diabetes Metab. 2013;39(3):244-249. doi: https://doi.org/10.1016/j.diabet.2013.01.002Umpaichitra V, Banerji MA, Castells S. Autoantibodies in children with type 2 diabetes mellitus. J Pediatr Endocrinol Metab. 2002;15(S1):525-530.Umpaichitra V, Banerji MA, Castells S. Autoantibodies in children with type 2 diabetes mellitus. J Pediatr Endocrinol Metab. 2002;15(S1):525-530.Тимофеев А.В., Горст К.А., Уваров В.Ю., и др. Диагностическая ценность применяющихся в России методов исследования антител к антигенам β-клеток. Классический иммунофлюоресцентный метод определения антител к островковым клеткам, радиоиммунный метод определения антител к глутаматдекарбоксилазе и иммуноферментные методы определения антител к тирозинфосфатазе и инсулину // Сахарный диабет. — 2016. Т. 19. — №4. — С. 331-340. doi: https://doi.org/10.14341/DM8032Timofeev AV, Gorst KA, Uvarov VY, et al. Diagnostic value of islet autoantibody assays practised in Russia. Classic immunofluorescence islet cell antibody assay, immunoradiometric glutamic acid decarboxylase antibody assay, and ELISA tyrosine phosphatase antibody and insulin antibody assays. Diabetes mellitus. 2016;19(4):331-340. (In Russ.). doi: https://doi.org/10.14341/DM8032Zanone MM, Catalfamo E, Pietropaolo SL, et al. Glutamic acid decarboxylase and ICA512/IA-2 autoantibodies as disease markers and relationship to residual β-cell function and glycemic control in young type 1 diabetic patients. Metabolism. 2003;52(1):25-29. doi: https://doi.org/10.1053/meta.2003.50003Zanone MM, Catalfamo E, Pietropaolo SL, et al. Glutamic acid decarboxylase and ICA512/IA-2 autoantibodies as disease markers and relationship to residual β-cell function and glycemic control in young type 1 diabetic patients. Metabolism. 2003;52(1):25-29. doi: https://doi.org/10.1053/meta.2003.50003Cheng BW, Lo FS, Wang AM, et al. Autoantibodies against islet cell antigens in children with type 1 diabetes mellitus. Oncotarget. 2018;9(23):16275-16283. doi: https://doi.org/10.18632/oncotarget.24527Cheng BW, Lo FS, Wang AM, et al. Autoantibodies against islet cell antigens in children with type 1 diabetes mellitus. Oncotarget. 2018;9(23):16275-16283. doi: https://doi.org/10.18632/oncotarget.24527Романенкова Е.М., Еремина И.А., Титович Е.В., и др. Уровень С-пептида и распространенность панкреатических аутоантител у детей с сахарным диабетом 1 типа при разной длительности заболевания // Сахарный диабет. — 2022. — Т. 25. — №2. — С. 155-165. doi: https://doi.org/10.14341/DM12843Romanenkova EM, Eremina IA, Titovich EV, et al. C-peptide levels and the prevalence of islets autoantibodies in children with type 1 diabetes mellitus with different duration of the disease. Diabetes mellitus. 2022;25(2):155-165. (In Russ.). doi: https://doi.org/10.14341/DM12843Tsai EB, Sherry NA, Palmer JP, Herold KC. The rise and fall of insulin secretion in type 1 diabetes mellitus. Diabetologia. 2006;49(2):261-270. doi: https://doi.org/10.1007/s00125-005-0100-8Tsai EB, Sherry NA, Palmer JP, Herold KC. The rise and fall of insulin secretion in type 1 diabetes mellitus. Diabetologia. 2006;49(2):261-270. doi: https://doi.org/10.1007/s00125-005-0100-8Hao W, Gitelman S, DiMeglio LA, et al. Fall in C-peptide during first 4 years from diagnosis of type 1 diabetes: Variable relation to age, HbA1c, and insulin dose. Diabetes Care. 2016;39(10):1664-1670. doi: https://doi.org/10.2337/dc16-0360Hao W, Gitelman S, DiMeglio LA, et al. Fall in C-peptide during first 4 years from diagnosis of type 1 diabetes: Variable relation to age, HbA1c, and insulin dose. Diabetes Care. 2016;39(10):1664-1670. doi: https://doi.org/10.2337/dc16-0360

The authors declare that there are no conflicts of interest present.