diaendoСахарный диабетDiabetes mellitus2072-03512072-0378Endocrinology research centre10.14341/DM12819diaendo-12819Research ArticleОригинальные исследованияOriginal StudiesНеиммунный сахарный диабет у детей, обусловленный гетерозиготными мутациями в гене глюкокиназы (GCK-MODY): анализ данных 144 пациентовNon-immune diabetes mellitus in children due to heterozygous mutations in the glucokinase gene (GCK-MODY): data of 144 patientshttps://orcid.org/0000-0002-8181-5572СечкоЕ. А.SechkoE. A.

Сечко Елена Александровна, кандидат медицинских наук

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

eLibrary SPIN: 4608-565

Elena A. Sechko, MD, PhD

11 Dm. Ulyanova street, Moscow 117036

eLibrary SPIN: 4608-565

elena.sechko@bk.ruhttps://orcid.org/0000-0003-4950-3920КураеваТ. Л.KuraevaT. L.

Кураева Тамара Леонидовна, доктор медицинских наук, проф.

Москва

eLibrary SPIN: 8206-0406

Tamara L. Kuraeva, MD, PhD, Professor

Moscow

eLibrary SPIN: 8206-0406

diabetkuraeva@mail.ruhttps://orcid.org/0000-0002-0316-8314ЗильберманЛ. И.ZilbermanL. I.

Зильберман Любовь Иосифовна, кандидат медицинских наук

Москва

eLibrary SPIN: 4488-7724

Lubov I. Zilberman, MD, PhD

Moscow

eLibrary SPIN: 4488-7724

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

Лаптев Дмитрий Никитич, доктор медицинских наук

Москва

eLibrary SPIN: 2419-4019

Dmitry N. Laptev, MD, PhD

Moscow

eLibrary SPIN: 2419-4019

laptevdn@ya.ruhttps://orcid.org/0000-0001-9621-5732БезлепкинаО. Б.BezlepkinaO. B.

Безлепкина Ольга Борисовна, доктор медицинских наук, профессор

Москва

eLibrary SPIN: 3884-0945

Olga B. Bezlepkina, MD, PhD, Professor

Moscow

eLibrary SPIN: 3884-0945

Olgabezlepkina@mail.ruПетерковаВ. А.PeterkovaV. A.

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

Москва

eLibrary SPIN: 4009-2463

Valentina A. Peterkova, PhD, Professor, Academician of RAS

Moscow

eLibrary SPIN: 4009-2463

peterkovava@hotmail.comНациональный медицинский исследовательский центр эндокринологииРоссияEndocrinology Research CentreRussian Federation202225032022252145154Copyright © Сечко Е.А., Кураева Т.Л., Зильберман Л.И., Лаптев Д.Н., Безлепкина О.Б., Петеркова В.А., 20222022Сечко Е.А., Кураева Т.Л., Зильберман Л.И., Лаптев Д.Н., Безлепкина О.Б., Петеркова В.А.Sechko E.A., Kuraeva T.L., Zilberman L.I., Laptev D.N., Bezlepkina O.B., Peterkova V.A.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/12819ОБОСНОВАНИЕ

ОБОСНОВАНИЕ. Моногенный сахарный диабет (МСД) — это редкая форма сахарного диабета (СД), причиной которого является наличие одной или более мутаций в одном из генов, приводящих к дисфункции β-клеток поджелудочной железы. Несмотря на достаточную известность наиболее распространенных подтипов MODY, случаи МСД остаются недиагностированными и классифицируются как СД 1 и 2 типов.

ЦЕЛЬ

ЦЕЛЬ. Изучить клинические, лабораторные характеристики, а также возрастные особенности GCK-MODY у детей.

МАТЕРИАЛЫ И МЕТОДЫ

МАТЕРИАЛЫ И МЕТОДЫ. Изучаемая популяция — пациенты с GCK-MODY в возрасте до 18 лет. Диагноз подтвержден результатом молекулярно-генетического исследования — выявление гетерозиготной мутации в гене GCK.

РЕЗУЛЬТАТЫ

РЕЗУЛЬТАТЫ. MODY-GCK верифицирован у 144 пациентов (131 пробанда и 13 сибсов) в возрасте до 18 лет. В 80,2% случаев (n=105) были выявлены миссенс-мутации. В 59,6% случаев мутации выявлены однократно. Наиболее часто встречались миссенс-мутации p.G261R (n=7) и p.G258C (n=6). Возраст диагностики нарушений углеводного обмена составил 7,6 года [4,0; 11,2]. В 72,2% случаев нарушения углеводного обмена были диагностированы случайно, в 16,7% — обследование проведено по поводу отягощенной наследственности по СД, в 11,1% — отмечались клинические симптомы СД. Гликемия натощак при диагностике составила 6,8 ммоль/л [6,4; 7,3], уровень гликированного гемоглобина (HbA1c) — 6,4% [6,1; 6,7]. При обследовании уровень гликемии натощак соответствовал нормальным значениям у 16,4% пациентов, нарушенной гликемии натощак — у 57,8%, диабетическим значениям — 25,8%. На 120-й минуте при проведении орального глюкозотолерантного теста у 62,3% пациентов уровень гликемии соответствовал нарушенной толерантности к глюкозе, у 18,9% — диабетическим значениям, у 11,7% пациентов — нормальным показателям гликемии. Выявлена умеренная положительная корреляция между возрастом обследования и уровнями гликемии натощак (r=0,347; p<0,01), С-пептида (r=0,656; p<0,001) и инсулина (r=0,531; p<0,001). Инсулинорезистентность (ИР) по индексу НОМА выявлена у 21 пациента (14,5%), экзогенно-конституциональное ожирение — у 6 пациентов (4,2%). У 9 пациентов (6,25%) выявлено умеренное повышение титра специфических панкреатических антител (АТ). Наличие ИР, ожирения, АТ не оказывало влияния на уровень HbA1c. В 92,3% случаев компенсации углеводного обмена удавалось достичь на фоне диеты, в 4,2% был назначен инсулин, 2,1% — метформин, 1,4% — препараты сульфонилмочевины.

ЗАКЛЮЧЕНИЕ

ЗАКЛЮЧЕНИЕ. У детей нарушения углеводного обмена при GCK-MODY диагностируются чаще всего случайно, асимптоматически в любом возрасте, в том числе с рождения, характеризуются сочетанием нарушения гликемии натощак и нарушения толерантности к глюкозе и, как правило, не требуют назначения сахароснижающей терапии.

BACKGROUND

BACKGROUND: Monogenic diabetes mellitus (MDM) is a rare form of diabetes mellitus (DM) which caused by one or more mutations in one of the genes that cause pancreatic β-cell dysfunction. Despite the sufficient knowledge of the most common subtypes of MODY, cases of MDM are undiagnosed and classified as type 1 diabetes mellitus and type 2 diabetes mellitus.

AIM

AIM: To study the clinical, laboratory characteristics, as well as age-related features of GCK-MODY in children.

MATERIALS AND METHODS

MATERIALS AND METHODS: The studied population is patients with GCK-MODY under the age of 18 years. The diagnosis was confirmed by genetic test, a heterozygous mutation was identificated in the GCK gene.

RESULTS

RESULTS: MODY-GCK was verified in 144 patients (131 probands and 13 siblings) under the age of 18 years. Missense mutations were detected in 80.2% (n=105). Mutation was detected in one case in 59.6%. The most common missense mutations were p.G261R (n=7) and p.G258C (n=6). The age of diagnosis of carbohydrate metabolism disorders was 7.6 years [4.0; 11.2]. In 72.2% carbohydrate metabolism disorders were diagnosed accidentally, in 16.7% the examination was provided due to a family history of diabetes, 11.1% had clinical symptoms of diabetes. Fasting glycemia at diagnosis was 6.8 mmol / l [6.4; 7.3], HbA1c — 6.4% [6.1; 6.7]. At examination, the level of fasting glycemia corresponded to normal values in 16.4% of patients, impaired fasting glycemia — in 57.8%, diabetic — in 25.8%. In 62.3% of patients was impaired glucose tolerance, in 18.9% — to diabetic values, and in 11.7% of patients — to a normal level at 120 minutes during the oral glucose tolerance test. A moderate positive correlation was found between the age of examination and the levels of fasting glycemia (r=0.347, p<0.01), C-peptide (r=0.656, p<0.001), and insulin (r=0.531, p<0.001). Insulin resistance (IR) (HOMA index) was detected in 21 patients (14.5%), obesity — in 6 patients (4.2%). In 9 patients (6.25%) was revealed a moderate increase in the titer of specific pancreatic antibodies (AT). The presence of IR, obesity, AT did not affect the level of HbA1c. In 92.3% diet was priscribed, in 4.2% insulin was prescribed, 2.1% — metformin, 1.4% — sulfonylureas.

CONCLUSION

CONCLUSION: In children, disorders of carbohydrate metabolism in GCK-MODY are diagnosed accidentally, asymptomatically at any age from birth, and are characterized by a combination of impaired fasting glycemia and impaired glucose tolerance and, as a rule, do not require antihyperglycemic therapy

ген GCKмоногенный сахарный диабетMODYгипергликемия у детейсахарный диабет у детей и подростковGCK genemonogenic diabetes mellitusMODYhyperglycemia in childrendiabetes mellitus in children and adolescentsИсследование выполнено в рамках государственного задания «Персонализированный подход к прогнозированию развития и дифференциальной диагностике сахарного диабета 1 типа у детей и подростков», регистрационный номер АААА-А20-120012190131-9ReferencesHattersley AT, Greeley SAW, Polak M, et al. ISPAD Clinical Practice Consensus Guidelines 2018: The diagnosis and management of monogenic diabetes in children and adolescents. Pediatr Diabetes. 2018;19(S27):47-63. doi: https://doi.org/10.1111/pedi.12772Hattersley AT, Greeley SAW, Polak M, et al. ISPAD Clinical Practice Consensus Guidelines 2018: The diagnosis and management of monogenic diabetes in children and adolescents. Pediatr Diabetes. 2018;19(S27):47-63. doi: https://doi.org/10.1111/pedi.12772Tattersall RB, Fajans SS. A difference between the inheritance of classical juvenile-onset and maturity-onset type diabetes of young people. Diabetes. 1975;24(1):44-53. doi: https://doi.org/10.2337/diab.24.1.44Tattersall RB, Fajans SS. A difference between the inheritance of classical juvenile-onset and maturity-onset type diabetes of young people. Diabetes. 1975;24(1):44-53. doi: https://doi.org/10.2337/diab.24.1.44Yamagata K, Furuta H, Oda N, et al. Mutations in the hepatocyte nuclear factor-4α gene in maturity-onset diabetes of the young (MODY1). Nature. 1996;384:458-460. doi: https://doi.org/10.1038/384458a0Yamagata K, Furuta H, Oda N, et al. Mutations in the hepatocyte nuclear factor-4α gene in maturity-onset diabetes of the young (MODY1). Nature. 1996;384:458-460. doi: https://doi.org/10.1038/384458a0Mozzillo E, Salzano G, Barbetti F, et al. Survey on etiological diagnosis of diabetes in 1244 Italian diabetic children and adolescents: impact of access to genetic testing. Diabetes Res Clin Pract. 2015;107(3):e15-e18. doi: https://doi.org/10.1016/j.diabres.2015.01.003Mozzillo E, Salzano G, Barbetti F, et al. Survey on etiological diagnosis of diabetes in 1244 Italian diabetic children and adolescents: impact of access to genetic testing. Diabetes Res Clin Pract. 2015;107(3):e15-e18. doi: https://doi.org/10.1016/j.diabres.2015.01.003Fendler W, Borowiec M, Baranowska-Jazwiecka A, et al. Prevalence of monogenic diabetes amongst Polish children after a nationwide genetic screening campaign. Diabetologia. 2012;55(10):2631-2635. doi: https://doi.org/10.1007/s00125-012-2621-2Fendler W, Borowiec M, Baranowska-Jazwiecka A, et al. Prevalence of monogenic diabetes amongst Polish children after a nationwide genetic screening campaign. Diabetologia. 2012;55(10):2631-2635. doi: https://doi.org/10.1007/s00125-012-2621-2Chakera AJ, Spyer G, Vincent N, et al. The 0.1% of the population with glucokinase monogenic diabetes can be recognized by clinical characteristics in pregnancy: the Atlantic Diabetes in Pregnancy cohort. Diabetes Care. 2014;37(5):1230-1236. doi: https://doi.org/10.2337/dc13-2248Chakera AJ, Spyer G, Vincent N, et al. The 0.1% of the population with glucokinase monogenic diabetes can be recognized by clinical characteristics in pregnancy: the Atlantic Diabetes in Pregnancy cohort. Diabetes Care. 2014;37(5):1230-1236. doi: https://doi.org/10.2337/dc13-2248Кураева Т.Л., Сечко Е.А., Зильберман Л.И., и др. Молекулярно-генетические и клинические варианты MODY2 и MODY3 у детей в России // Проблемы эндокринологии. — 2015. — Т. 61. — №5. — С. 14-25. doi: https://doi.org/10.14341/probl201561514-25Kuraeva TL, Sechko EA, Zilberman LI, et al. Molecular genetic and clinical variants MODY2 and MODY3 in children in Russia. Problems of Endocrinology. 2015;61(5):14-25. (In Russ.). doi: https://doi.org/10.14341/probl201561514-25Зубкова Н.А., Гиоева О.А., Тихонович Ю.В., и др. Клиническая и молекулярно-генетическая характеристика случаев MODY1-3 в Российской Федерации, выявленных по результатам NGS // Проблемы эндокринологии. — 2017. — Т. 63. — №6. — С. 369-378. doi: https://doi.org/10.14341/probl2017636369-378Zubkova NA, Gioeva OA, Tikhonovich YuV, et al. Clinical and molecular genetic characteristics of MODY1—3 cases in the Russian Federation as shown by NGS. Problems of Endocrinology. 2017;63(6):369-378. (In Russ.). doi: https://doi.org/10.14341/probl2017636369-378Glotov OS, Serebryakova EA, Turkunova ME, et al. Whole-exome sequencing in Russian children with non-type 1 diabetes mellitus reveals a wide spectrum of genetic variants in MODY-related and unrelated genes. Mol Med Rep. 2019;20(6):4905-4914. doi: https://doi.org/10.3892/mmr.2019.10751Glotov OS, Serebryakova EA, Turkunova ME, et al. Whole-exome sequencing in Russian children with non-type 1 diabetes mellitus reveals a wide spectrum of genetic variants in MODY-related and unrelated genes. Mol Med Rep. 2019;20(6):4905-4914. doi: https://doi.org/10.3892/mmr.2019.10751Matschinsky FM. Regulation of pancreatic beta-cell glucokinase: from basics to therapeutics. Diabetes. 2002;51(S3):S394-S404. doi: https://doi.org/10.2337/diabetes.51.2007.s394Matschinsky FM. Regulation of pancreatic beta-cell glucokinase: from basics to therapeutics. Diabetes. 2002;51(S3):S394-S404. doi: https://doi.org/10.2337/diabetes.51.2007.s394Stride A, Vaxillaire M, Tuomi T, et al. The genetic abnormality in the beta cell determines the response to an oral glucose load. Diabetologia. 2002;45(3):427-435. doi: https://doi.org/10.1007/s00125-001-0770-9Stride A, Vaxillaire M, Tuomi T, et al. The genetic abnormality in the beta cell determines the response to an oral glucose load. Diabetologia. 2002;45(3):427-435. doi: https://doi.org/10.1007/s00125-001-0770-9Stride A, Shields B, Gill-Carey O, et al. Cross-sectional and longitudinal studies suggest pharmacological treatment used in patients with glucokinase mutations does not alter glycaemia. Diabetologia. 2014;57(1):54-56. doi: https://doi.org/10.1007/s00125-013-3075-xStride A, Shields B, Gill-Carey O, et al. Cross-sectional and longitudinal studies suggest pharmacological treatment used in patients with glucokinase mutations does not alter glycaemia. Diabetologia. 2014;57(1):54-56. doi: https://doi.org/10.1007/s00125-013-3075-xFeigerlová E, Pruhová S, Dittertová L, et al. Aetiological heterogeneity of asymptomatic hyperglycaemia in children and adolescents. Eur J Pediatr. 2006;165(7):446-452. doi: https://doi.org/10.1007/s00431-006-0106-3Feigerlová E, Pruhová S, Dittertová L, et al. Aetiological heterogeneity of asymptomatic hyperglycaemia in children and adolescents. Eur J Pediatr. 2006;165(7):446-452. doi: https://doi.org/10.1007/s00431-006-0106-3Pihoker C, Gilliam LK, Ellard S, et al. Prevalence, characteristics and clinical diagnosis of maturity onset diabetes of the young due to mutations in HNF1A, HNF4A, and glucokinase: results from the SEARCH for Diabetes in Youth. J Clin Endocrinol Metab. 2013;98(10):4055-4062. doi: https://doi.org/10.1210/jc.2013-1279Pihoker C, Gilliam LK, Ellard S, et al. Prevalence, characteristics and clinical diagnosis of maturity onset diabetes of the young due to mutations in HNF1A, HNF4A, and glucokinase: results from the SEARCH for Diabetes in Youth. J Clin Endocrinol Metab. 2013;98(10):4055-4062. doi: https://doi.org/10.1210/jc.2013-1279Гиоева О.А., Колодкина А.А., Васильев Е.В., и др. Наследственный вариант сахарного диабета, обусловленного дефектом гена NEUROD1 (MODY6): первое описание в России // Проблемы Эндокринологии. — 2016. — Т. 62. — №3. — C. 16-20. doi: https://doi.org/10.14341/probl201662316-20Gioeva OA, Kolodkina AA, Vasilyev EV, et al. Hereditary variant of diabetes mellitus caused by a defect of the NEUROD1 gene (MODY6): the fi rst description in Russia. Problems of Endocrinology. 2016;62(3):16-20. (In Russ.). doi: https://doi.org/10.14341/probl201662316-20Osbak KK, Colclough K, Saint-Martin C, et al. Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia. Hum Mutat. 2009;30(11):1512-1526. doi: https://doi.org/10.1002/humu.21110Osbak KK, Colclough K, Saint-Martin C, et al. Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia. Hum Mutat. 2009;30(11):1512-1526. doi: https://doi.org/10.1002/humu.21110Hager J, Blanché H, Sun F, et al. Six mutations in the glucokinase gene identified in MODY by using a nonradioactive sensitive screening technique. Diabetes. 1994;43(5):730-733. doi: https://doi.org/10.2337/diab.43.5.730Hager J, Blanché H, Sun F, et al. Six mutations in the glucokinase gene identified in MODY by using a nonradioactive sensitive screening technique. Diabetes. 1994;43(5):730-733. doi: https://doi.org/10.2337/diab.43.5.730Gragnoli C, Cockburn BN, Chiaramonte F, et al. Early-onset Type II diabetes mellitus in Italian families due to mutations in the genes encoding hepatic nuclear factor 1 alpha and glucokinase. Diabetologia. 2001;44(10):1326-1329. doi: https://doi.org/10.1007/s001250100644Gragnoli C, Cockburn BN, Chiaramonte F, et al. Early-onset Type II diabetes mellitus in Italian families due to mutations in the genes encoding hepatic nuclear factor 1 alpha and glucokinase. Diabetologia. 2001;44(10):1326-1329. doi: https://doi.org/10.1007/s001250100644Lehto M, Wipemo C, Ivarsson SA, et al. High frequency of mutations in MODY and mitochondrial genes in Scandinavian patients with familial early-onset diabetes. Diabetologia. 1999;42(9):1131-1137. doi: https://doi.org/10.1007/s001250051281Lehto M, Wipemo C, Ivarsson SA, et al. High frequency of mutations in MODY and mitochondrial genes in Scandinavian patients with familial early-onset diabetes. Diabetologia. 1999;42(9):1131-1137. doi: https://doi.org/10.1007/s001250051281Lorini R, Klersy C, d’Annunzio G, et al. Maturity-onset diabetes of the young in children with incidental hyperglycemia: a multicenter Italian study of 172 families. Diabetes Care. 2009;32(10):1864-1866. doi: https://doi.org/10.2337/dc08-2018Lorini R, Klersy C, d’Annunzio G, et al. Maturity-onset diabetes of the young in children with incidental hyperglycemia: a multicenter Italian study of 172 families. Diabetes Care. 2009;32(10):1864-1866. doi: https://doi.org/10.2337/dc08-2018Takeda J, Gidh-Jain M, Xu LZ, et al. Structure/function studies of human beta-cell glucokinase. Enzymatic properties of a sequence polymorphism, mutations associated with diabetes, and other site-directed mutants. J Biol Chem. 1993;268(20):15200-15204.Takeda J, Gidh-Jain M, Xu LZ, et al. Structure/function studies of human beta-cell glucokinase. Enzymatic properties of a sequence polymorphism, mutations associated with diabetes, and other site-directed mutants. J Biol Chem. 1993;268(20):15200-15204.Ellard S, Beards F, Allen LI, et al. A high prevalence of glucokinase mutations in gestational diabetic subjects selected by clinical criteria. Diabetologia. 2000;43(2):250-253. doi: https://doi.org/10.1007/s001250050038Ellard S, Beards F, Allen LI, et al. A high prevalence of glucokinase mutations in gestational diabetic subjects selected by clinical criteria. Diabetologia. 2000;43(2):250-253. doi: https://doi.org/10.1007/s001250050038Bertini C, Maioli M, Fresu P, et al. A new missense mutation in the glucokinase gene in an Italian Mody family. Diabetologia. 1996;39(11):1413-1414.Bertini C, Maioli M, Fresu P, et al. A new missense mutation in the glucokinase gene in an Italian Mody family. Diabetologia. 1996;39(11):1413-1414.Gidh-Jain M, Takeda J, Xu LZ, et al. Glucokinase mutations associated with non-insulin-dependent (type 2) diabetes mellitus have decreased enzymatic activity: implications for structure/function relationships. Proc Natl Acad Sci U S A. 1993;90(5):1932-1936. doi: https://doi.org/10.1073/pnas.90.5.1932Gidh-Jain M, Takeda J, Xu LZ, et al. Glucokinase mutations associated with non-insulin-dependent (type 2) diabetes mellitus have decreased enzymatic activity: implications for structure/function relationships. Proc Natl Acad Sci U S A. 1993;90(5):1932-1936. doi: https://doi.org/10.1073/pnas.90.5.1932Mantovani V, Salardi S, Cerreta V, et al. Identification of eight novel glucokinase mutations in Italian children with maturity-onset diabetes of the young. Hum Mutat. 2003;22(4):338. doi: https://doi.org/10.1002/humu.9179Mantovani V, Salardi S, Cerreta V, et al. Identification of eight novel glucokinase mutations in Italian children with maturity-onset diabetes of the young. Hum Mutat. 2003;22(4):338. doi: https://doi.org/10.1002/humu.9179Velho G, Blanché H, Vaxillaire M, et al. Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY-2 families. Diabetologia. 1997;40(2):217-224. doi: https://doi.org/10.1007/s001250050666Velho G, Blanché H, Vaxillaire M, et al. Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY-2 families. Diabetologia. 1997;40(2):217-224. doi: https://doi.org/10.1007/s001250050666Galán M, Vincent O, Roncero I, et al. Effects of novel maturity-onset diabetes of the young (MODY)-associated mutations on glucokinase activity and protein stability. Biochem J. 2006;393(Pt1):389-396. doi: https://doi.org/10.1042/BJ20051137Galán M, Vincent O, Roncero I, et al. Effects of novel maturity-onset diabetes of the young (MODY)-associated mutations on glucokinase activity and protein stability. Biochem J. 2006;393(Pt1):389-396. doi: https://doi.org/10.1042/BJ20051137McKinney JL, Cao H, Robinson JF, et al. Spectrum of HNF1A and GCK mutations in Canadian families with maturity-onset diabetes of the young (MODY). Clin Invest Med. 2004;27(3):135-141.McKinney JL, Cao H, Robinson JF, et al. Spectrum of HNF1A and GCK mutations in Canadian families with maturity-onset diabetes of the young (MODY). Clin Invest Med. 2004;27(3):135-141.Barrio R, Bellanné-Chantelot C, Moreno JC, et al. Nine novel mutations in maturity-onset diabetes of the young (MODY) candidate genes in 22 Spanish families. J Clin Endocrinol Metab. 2002;87(6):2532-2539. doi: https://doi.org/10.1210/jcem.87.6.8530Barrio R, Bellanné-Chantelot C, Moreno JC, et al. Nine novel mutations in maturity-onset diabetes of the young (MODY) candidate genes in 22 Spanish families. J Clin Endocrinol Metab. 2002;87(6):2532-2539. doi: https://doi.org/10.1210/jcem.87.6.8530Jetton TL, Liang Y, Pettepher CC, et al. Analysis of upstream glucokinase promoter activity in transgenic mice and identification of glucokinase in rare neuroendocrine cells in the brain and gut. J Biol Chem. 1994;269(5):3641-3654. doi: https://doi.org/10.1016/S0021-9258(17)41910-7Jetton TL, Liang Y, Pettepher CC, et al. Analysis of upstream glucokinase promoter activity in transgenic mice and identification of glucokinase in rare neuroendocrine cells in the brain and gut. J Biol Chem. 1994;269(5):3641-3654. doi: https://doi.org/10.1016/S0021-9258(17)41910-7Njølstad PR, Søvik O, Cuesta-Muñoz A, et al. Neonatal diabetes mellitus due to complete glucokinase deficiency. N Engl J Med. 2001;344(21):1588-1592. doi: https://doi.org/10.1056/NEJM200105243442104Njølstad PR, Søvik O, Cuesta-Muñoz A, et al. Neonatal diabetes mellitus due to complete glucokinase deficiency. N Engl J Med. 2001;344(21):1588-1592. doi: https://doi.org/10.1056/NEJM200105243442104Velho G, Petersen KF, Perseghin G, et al. Impaired hepatic glycogen synthesis in glucokinase-deficient (MODY-2) subjects. J Clin Invest. 1996;98(8):1755-1761. doi: https://doi.org/10.1172/JCI118974Velho G, Petersen KF, Perseghin G, et al. Impaired hepatic glycogen synthesis in glucokinase-deficient (MODY-2) subjects. J Clin Invest. 1996;98(8):1755-1761. doi: https://doi.org/10.1172/JCI118974Овсянникова А.К., Шахтшнейдер Е.В., Иванощук Д.Е., и др. Течение сахарного диабета взрослого типа у молодых лиц старше 18 лет, обусловленного мутацией гена глюкокиназы (GCK-MODY): данные проспективного наблюдения // Сахарный диабет. — 2021. — Т. 24. — №2. — С. 133-140. doi: https://doi.org/10.14341/DM12319Ovsyannikova OК, Shakhtshneider EV, Ivanoshchuk DE, et al. GCK-MODY diabetes course in persons over 18 years of age: prospective observation. Diabetes Mellitus. 2021;24(2):133-140. (In Russ.). doi: https://doi.org/10.14341/DM12319Hughes AE, De Franco E, Globa E, et al. Identification of GCK-maturity-onset diabetes of the young in cases of neonatal hyperglycemia: A case series and review of clinical features. Pediatr Diabetes. 2021;22(6):876-881. doi: https://doi.org/10.1111/pedi.13239Hughes AE, De Franco E, Globa E, et al. Identification of GCK-maturity-onset diabetes of the young in cases of neonatal hyperglycemia: A case series and review of clinical features. Pediatr Diabetes. 2021;22(6):876-881. doi: https://doi.org/10.1111/pedi.13239Дедов И.И., Зубкова Н.А., Арбатская Н.Ю., и др. MODY2: клинические и молекулярно-генетические характеристики 13 случаев заболевания. Первое описание МОDY в России // Проблемы Эндокринологии. — 2009. — Т. 55. — №3. — C. 3-7. doi: https://doi.org/10.14341/probl20095533-7Dedov II, Zubkova NA, Arbatskaya NY, et al. MODY2: clinical and molecular genetic characteristics of 13 cases of the disease. The first description of MODY in Russia. Problems of Endocrinology. 2009;55(3):3-7. (In Russ.). doi: https://doi.org/10.14341/probl20095533-7Steele AM, Wensley KJ, Ellard S, et al. Use of HbA1c in the identification of patients with hyperglycaemia caused by a glucokinase mutation: observational case control studies. PLoS One. 2013;8(6):e65326. doi: https://doi.org/10.1371/journal.pone.0065326Steele AM, Wensley KJ, Ellard S, et al. Use of HbA1c in the identification of patients with hyperglycaemia caused by a glucokinase mutation: observational case control studies. PLoS One. 2013;8(6):e65326. doi: https://doi.org/10.1371/journal.pone.0065326Тутельян В.А., Батурин А.К., Конь И.Я., и др. Распространенность ожирения и избыточной массы тела среди детского населения РФ: мультицентровое исследование // Педиатрия. Журнал им. Г.Н. Сперанского. — 2014. — Т. 93. — №5. — С. 28-31.Tutel’yan VA, Baturin AK, Kon’ IYa, et al. Rasprostranennost’ ozhireniya i izbytochnoi massy tela sredi detskogo naseleniya RF: mul’titsentrovoe issledovanie. Pediatria. 2014;93(5):28-31 (In Russ.).Kleinberger JW, Copeland KC, Gandica RG, et al. Monogenic diabetes in overweight and obese youth diagnosed with type 2 diabetes: the TODAY clinical trial. Genet Med. 2018;20(6):583-590. doi: https://doi.org/10.1038/gim.2017.150Kleinberger JW, Copeland KC, Gandica RG, et al. Monogenic diabetes in overweight and obese youth diagnosed with type 2 diabetes: the TODAY clinical trial. Genet Med. 2018;20(6):583-590. doi: https://doi.org/10.1038/gim.2017.150Lehto M, Tuomi T, Mahtani MM, et al. Characterization of the MODY3 phenotype. Early-onset diabetes caused by an insulin secretion defect. J Clin Invest. 1997;99(4):582-591. doi: https://doi.org/10.1172/JCI119199Lehto M, Tuomi T, Mahtani MM, et al. Characterization of the MODY3 phenotype. Early-onset diabetes caused by an insulin secretion defect. J Clin Invest. 1997;99(4):582-591. doi: https://doi.org/10.1172/JCI119199Wilkin TJ. The accelerator hypothesis: weight gain as the missing link between Type I and Type II diabetes. Diabetologia. 2001;44(7):914-922. doi: https://doi.org/10.1007/s001250100548Wilkin TJ. The accelerator hypothesis: weight gain as the missing link between Type I and Type II diabetes. Diabetologia. 2001;44(7):914-922. doi: https://doi.org/10.1007/s001250100548Clément K, Pueyo ME, Vaxillaire M, et al. Assessment of insulin sensitivity in glucokinase-deficient subjects. Diabetologia. 1996;39(1):82-90. doi: https://doi.org/10.1007/BF00400417Clément K, Pueyo ME, Vaxillaire M, et al. Assessment of insulin sensitivity in glucokinase-deficient subjects. Diabetologia. 1996;39(1):82-90. doi: https://doi.org/10.1007/BF00400417Gungor N, Saad R, Janosky J, Arslanian S. Validation of surrogate estimates of insulin sensitivity and insulin secretion in children and adolescents. J Pediatr. 2004;144(1):47-55. doi: https://doi.org/10.1016/j.jpeds.2003.09.045Gungor N, Saad R, Janosky J, Arslanian S. Validation of surrogate estimates of insulin sensitivity and insulin secretion in children and adolescents. J Pediatr. 2004;144(1):47-55. doi: https://doi.org/10.1016/j.jpeds.2003.09.045Stanik J, Dusatkova P, Cinek O, et al. De novo mutations of GCK, HNF1A and HNF4A may be more frequent in MODY than previously assumed. Diabetologia. 2014;57(3):480-484. doi: https://doi.org/10.1007/s00125-013-3119-2Stanik J, Dusatkova P, Cinek O, et al. De novo mutations of GCK, HNF1A and HNF4A may be more frequent in MODY than previously assumed. Diabetologia. 2014;57(3):480-484. doi: https://doi.org/10.1007/s00125-013-3119-2Spyer G, Macleod KM, Shepherd M, et al. Pregnancy outcome in patients with raised blood glucose due to a heterozygous glucokinase gene mutation. Diabet Med. 2009;26(1):14-18. doi: https://doi.org/10.1111/j.1464-5491.2008.02622.xSpyer G, Macleod KM, Shepherd M, et al. Pregnancy outcome in patients with raised blood glucose due to a heterozygous glucokinase gene mutation. Diabet Med. 2009;26(1):14-18. doi: https://doi.org/10.1111/j.1464-5491.2008.02622.x

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