problendoПроблемы ЭндокринологииProblems of Endocrinology0375-96602308-1430Endocrinology Research Centre10.14341/probl20115723-8problendo-4775Research ArticleСтатьиArticlesМолекулярно-генетическая верификация и лечение неонатального сахарного диабета, обусловленного дефектами АТФ-зависимых калиевых каналов: данные наблюдения 9 больных и первое описание мутаций гена ABCC8 в РоссииMolecular-genetic verification and treatment of neonatal diabetes mellitus related to the defects in ATP-dependent potassium channels: Results of the observation of 9 patients and the first description of ABCC8 gene mutations in RussiaDedovI Idedov@endocrincentr.ruTikhonovichIu Vyuliatihonovich@mail.ruPetriaikinaElena Eorg@endocrincentr.ruRybkinaI Gorg@endocrincentr.ruVolkovI Éorg@endocrincentr.ruStotikovaO Vorg@endocrincentr.ruChernykhL Gorg@endocrincentr.ruTiulpakovA Norg@endocrincentr.ruФГУ Эндокринологический научный центр Минздравсоцразвития РоссииRussian FederationМосковская городская детская клиническая больница им. МорозоваRussian FederationРоссийская детская клиническая больницаRussian Federation201115042011572ТОМ 57, №2 (2011)38Copyright © Dedov I.I., Tikhonovich I.V., Petriaikina E.E., Rybkina I.G., Volkov I.É., Stotikova O.V., Chernykh L.G., Tiulpakov A.N., 20112011Dedov I.I., Tikhonovich I.V., Petriaikina E.E., Rybkina I.G., Volkov I.É., Stotikova O.V., Chernykh L.G., Tiulpakov A.N.Dedov I.I., Tikhonovich I.V., Petriaikina E.E., Rybkina I.G., Volkov I.É., Stotikova O.V., Chernykh L.G., Tiulpakov A.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.probl-endojournals.ru/jour/article/view/4775

Методы молекулярно-генетического анализа в клинической практике открыли новые перспективы как для диагностики, так и для проведения патогенетического лечения неонатального сахарного диабета. В настоящее время показано, что в подавляющем большинстве случаев развитие сахарного диабета у детей первых 6 мес жизни связано с дефектом генов, контролирующих закладку, развитие и функциональную активность β-клеток поджелудочной железы, в то время как на долю аутоиммунного сахарного диабета 1-го типа в данной группе приходится менее 1%. Приводятся результаты молекулярно-генетического обследования 14 пациентов с неонатальным сахарным диабетом. В 9 случаях показана связь развития заболевания с наличием мутаций в генах KCNJ11 и АВСС8, при этом мутации в гене АВСС8 описаны впервые в России. Проведен анализ клинических форм неонатального сахарного диабета, показана корреляция между типом мутации, течением заболевания и чувствительностью пациентов к препаратам сульфонилмочевины.

Introduction of the methods for molecular-genetic analysis into clinical practice has opened up new prospects for both diagnosis and pathogenetically sound therapy of neonatal diabetes mellitus. It is currently known that the overwhelming majority of the cases of diabetes mellitus developing in children during the first six month of life are associated with defects of the genes controlling formation, development, and functional activity of pancreatic beta-cells whereas type 1 diabetes mellitus of autoimmune origin accounts for less than 1% of this pathology. This paper reports the results of a molecular-genetic study of 14 patients presenting with neonatal diabetes mellitus. Nine cases are shown to have developed as a result of mutations in KCNJ11 and ABCC8 genes. ABCC8 mutations are described for the first time in Russia. Analysis of clinical forms of neonatal diabetes mellitus revealed correlation between the type of mutations, clinical features of the disease, and susceptibility of the patients to sulfonylurea drugs.

неонатальный сахарный диабетАТФ-зависимые K-каналыАВСС8глибенкламидneonatal diabetes mellitusATP-dependent potassium channelsKCNJ11 and ABCC8 genesglibenclamidKCNJ11ReferencesGloyn A.L., Pearson E.R., Antcliff J.F. et al. Activating mutations in the ATP-sensitive potassium channel subunit Kir6.2 gene are associated with permanent neonatal diabetes. N Engl J Med 2004;350:1838-1849.Gloyn A.L., Pearson E.R., Antcliff J.F. et al. Activating mutations in the ATP-sensitive potassium channel subunit Kir6.2 gene are associated with permanent neonatal diabetes. N Engl J Med 2004;350:1838-1849.Babenko A.P., Polak M., Cavé H. et al. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med 2006;355:456-466.Babenko A.P., Polak M., Cavé H. et al. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med 2006;355:456-466.Njolstad P.R., Sovik O., Cuesta-Munoz A. et al. Neonatal diabetes mellitus due to complete glucokinase deficiency. N Engl J Med 2001;344:1588-1592.Njolstad P.R., Sovik O., Cuesta-Munoz A. et al. Neonatal diabetes mellitus due to complete glucokinase deficiency. N Engl J Med 2001;344:1588-1592.Stoffers D.A., Zinkin N.T., Stanojevic V. et al. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet 1997;15:106-110.Stoffers D.A., Zinkin N.T., Stanojevic V. et al. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet 1997;15:106-110.Taha D., Barbar M., Kanaan H., Williamson Balfe J. Neonatal diabetes mellitus, congenital hypothyroidism, hepatic fibrosis, polycystic kidneys, and congenital glaucoma: a new autosomal recessive syndrome? Am J Med Genet 2003;122A:269-273.Taha D., Barbar M., Kanaan H., Williamson Balfe J. Neonatal diabetes mellitus, congenital hypothyroidism, hepatic fibrosis, polycystic kidneys, and congenital glaucoma: a new autosomal recessive syndrome? Am J Med Genet 2003;122A:269-273.Senee V., Chelala C., Duchatelet S. et al. Mutations in GLIS3 are responsible for a rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism. Nat Genet 2006;38:6:682-687.Senee V., Chelala C., Duchatelet S. et al. Mutations in GLIS3 are responsible for a rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism. Nat Genet 2006;38:6:682-687.Edghill E.L., Bingham C., Slingerland A.S. et al. Hepatocyte nuclear factor-1 beta mutations cause neonatal diabetes and intrauterine growth retardation: support for a critical role of HNF-1β in human pancreatic development. Diabet Med 2006;23:1301-1306.Edghill E.L., Bingham C., Slingerland A.S. et al. Hepatocyte nuclear factor-1 beta mutations cause neonatal diabetes and intrauterine growth retardation: support for a critical role of HNF-1β in human pancreatic development. Diabet Med 2006;23:1301-1306.Hoveyda N., Shield J.P., Garrett C. et al. Neonatal diabetes mellitus and cerebellar hypoplasia/agenesis: report of a new recessive syndrome. J Med Genet 1999;36:700-704.Hoveyda N., Shield J.P., Garrett C. et al. Neonatal diabetes mellitus and cerebellar hypoplasia/agenesis: report of a new recessive syndrome. J Med Genet 1999;36:700-704.Sellick G.S., Barker K.T., Stolte-Dijkstra I. et al. Mutations in PTF1A cause pancreatic and cerebellar agenesis. Nat Genet 2006;36:12:1301-1305.Sellick G.S., Barker K.T., Stolte-Dijkstra I. et al. Mutations in PTF1A cause pancreatic and cerebellar agenesis. Nat Genet 2006;36:12:1301-1305.Stoy J., Edghill E.L., Flanagan S.E. et al. Insulin gene mutations as a cause of permanent neonatal diabetes. Proc Natl Acad Sci USA 2007;104:15040-15044.Stoy J., Edghill E.L., Flanagan S.E. et al. Insulin gene mutations as a cause of permanent neonatal diabetes. Proc Natl Acad Sci USA 2007;104:15040-15044.Delepine M., Nicolino M., Barret T. et al. EIF2AK3, encoding translation initiation factor-2 alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nat Genet 2000;25:406-409.Delepine M., Nicolino M., Barret T. et al. EIF2AK3, encoding translation initiation factor-2 alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nat Genet 2000;25:406-409.Bennett C.L., Yoshioka R., Kiyosawa H. et al. X-Linked syndrome of polyendocrinopathy, immune dysfunction, and diarrhea maps to Xp11.23-Xq13.3. Am J Hum Genet 2000;66:461-468.Bennett C.L., Yoshioka R., Kiyosawa H. et al. X-Linked syndrome of polyendocrinopathy, immune dysfunction, and diarrhea maps to Xp11.23-Xq13.3. Am J Hum Genet 2000;66:461-468.Aguilar-Bryan L., Bryan J. Neonatal diabetes mellitus. Endocr Rev 2008;29:3:265-291.Aguilar-Bryan L., Bryan J. Neonatal diabetes mellitus. Endocr Rev 2008;29:3:265-291.Flanagan S.E., Edghill E.L., Gloun A.L. et al. Mutations in KCNJ11, which encodes Kir 6.2, are a common case of diabetes diagnosed in the first 6 months of life, with the genotype determited by genotype. Diabetologia 2006;49:1190-1197.Flanagan S.E., Edghill E.L., Gloun A.L. et al. Mutations in KCNJ11, which encodes Kir 6.2, are a common case of diabetes diagnosed in the first 6 months of life, with the genotype determited by genotype. Diabetologia 2006;49:1190-1197.Балаболкин М.И., Клебанова Е.М. Применение глибенкламида и метформина в виде препарата комбинированного действия для лечения сахарного диабета 2-го типа. Рус мед журн 2006;4:13:977-981.Балаболкин М.И., Клебанова Е.М. Применение глибенкламида и метформина в виде препарата комбинированного действия для лечения сахарного диабета 2-го типа. Рус мед журн 2006;4:13:977-981.Pearson E.R., Flechtner I., Njolstad P.R. et al. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir 6.2 mutations. N Engl J Med 2006;355:467-477.Pearson E.R., Flechtner I., Njolstad P.R. et al. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir 6.2 mutations. N Engl J Med 2006;355:467-477.Rafiq M., Flanagan S.E., Patch A.M. et al. Effective treatment with oral sulfonylureas in patients with diabetes mellitus to sulfonyrea receptor 1(SUR1) mutations. Diabet Care 2007;31:204-209.Rafiq M., Flanagan S.E., Patch A.M. et al. Effective treatment with oral sulfonylureas in patients with diabetes mellitus to sulfonyrea receptor 1(SUR1) mutations. Diabet Care 2007;31:204-209.Малиевский О.А., Нурмухамедова Д.С., Башарова Р.В. Опыт лечения неонатального сахарного диабета, обусловленного мутацией гена KCNJ11, кодирующего субъединицу Кир 6.2, препаратами сульфонилмочевины. Всероссийская научно-практическая конференция "Задачи детской эндокринологии в реализации Национального проекта "Здоровье": Материалы. М 2008;73.Малиевский О.А., Нурмухамедова Д.С., Башарова Р.В. Опыт лечения неонатального сахарного диабета, обусловленного мутацией гена KCNJ11, кодирующего субъединицу Кир 6.2, препаратами сульфонилмочевины. Всероссийская научно-практическая конференция "Задачи детской эндокринологии в реализации Национального проекта "Здоровье": Материалы. М 2008;73.Емельянов А.О., Петряйкина Е.Е., Кураева Т.Л. и др. Возможности эффективной терапии неонатального сахарного диабета препаратами сульфонилмочевины при наличии мутаций в гене KCNJ11: собственные наблюдения. Сахарный диабет 2009;3:86-89.Емельянов А.О., Петряйкина Е.Е., Кураева Т.Л. и др. Возможности эффективной терапии неонатального сахарного диабета препаратами сульфонилмочевины при наличии мутаций в гене KCNJ11: собственные наблюдения. Сахарный диабет 2009;3:86-89.Кураева Т.Л., Емельянов А.О. Клиническая и генетическая гетерогенность неонатального сахарного диабета. Сахарный диабет 2009;3:10-15.Кураева Т.Л., Емельянов А.О. Клиническая и генетическая гетерогенность неонатального сахарного диабета. Сахарный диабет 2009;3:10-15.Den Dunnen J.T., Antonarakis S.E. Nomenclature for the description of human sequence variations. Hum Genet 2001;109:1:121-124.Den Dunnen J.T., Antonarakis S.E. Nomenclature for the description of human sequence variations. Hum Genet 2001;109:1:121-124.Shyng S.L., Nichols C.G. Octameric stoichiometry of the KATP channel complex. J Gen Physiol 1997;110:655-664.Shyng S.L., Nichols C.G. Octameric stoichiometry of the KATP channel complex. J Gen Physiol 1997;110:655-664.Higgins C.F., Linton K.J. The ATP switch model for ABC transporters. Nat Struct Mol Biol 2004;11:918-926.Higgins C.F., Linton K.J. The ATP switch model for ABC transporters. Nat Struct Mol Biol 2004;11:918-926.Babenko A.P., Gonzalez G., Bryan J. The N-terminus of KIR6.2 limits spontaneous bursting and modulates the ATP-inhibition of KATP channels. Biochem Biophys Res Commun 1999;255:231-238.Babenko A.P., Gonzalez G., Bryan J. The N-terminus of KIR6.2 limits spontaneous bursting and modulates the ATP-inhibition of KATP channels. Biochem Biophys Res Commun 1999;255:231-238.Chan K.W., Zhang H., Logothetis D.E. N-terminal transmembrane domain of the SUR controls trafficking and gating of Kir6 channel subunits. EMBO J 2003;22:3833-3843.Chan K.W., Zhang H., Logothetis D.E. N-terminal transmembrane domain of the SUR controls trafficking and gating of Kir6 channel subunits. EMBO J 2003;22:3833-3843.Bryan J., Vila-Carriles W.H., Zhao G. et al. Toward linking structure with function in ATP-sensitive K+ channels. Diabetes 2004;53:Suppl 3:S104-S112.Bryan J., Vila-Carriles W.H., Zhao G. et al. Toward linking structure with function in ATP-sensitive K+ channels. Diabetes 2004;53:Suppl 3:S104-S112.Gribble F.M., Ashcroft F.M. Differential sensitivity of β-cell and extrapancreatic K(ATP) channels to gliclazide. Diabetologia 1999;42:845-848.Gribble F.M., Ashcroft F.M. Differential sensitivity of β-cell and extrapancreatic K(ATP) channels to gliclazide. Diabetologia 1999;42:845-848.Koster J.C., Cadario F., Peruzzi C. et al. The G53D mutation in Kir6.2 (KCNJ11) is associated with neonatal diabetes and motor dysfunction in adulthood that is improved with sulfonylurea therapy. J Clin Endocrinol Metab 2008;93:1054-1061.Koster J.C., Cadario F., Peruzzi C. et al. The G53D mutation in Kir6.2 (KCNJ11) is associated with neonatal diabetes and motor dysfunction in adulthood that is improved with sulfonylurea therapy. J Clin Endocrinol Metab 2008;93:1054-1061.Aguilar-Bryan L., Nichols C.G., Wechsler S.W. et al. Cloning of the beta cell high affinity sulfonylurea receptor: a regulator of insulin secretion. Science 1995;268:423-426.Aguilar-Bryan L., Nichols C.G., Wechsler S.W. et al. Cloning of the beta cell high affinity sulfonylurea receptor: a regulator of insulin secretion. Science 1995;268:423-426.Flanagan S.E., Clauin S., Bellanné-Chantelot C. et al. Update of mutations in the genes encoding the pancreatic beta-cell K(ATP) channel subunits Kir6.2 (KCNJ11) and sulfonylurea receptor 1 (ABCC8) in diabetes mellitus and hyperinsulinism. Hum Mutat 2009;30:170-180.Flanagan S.E., Clauin S., Bellanné-Chantelot C. et al. Update of mutations in the genes encoding the pancreatic beta-cell K(ATP) channel subunits Kir6.2 (KCNJ11) and sulfonylurea receptor 1 (ABCC8) in diabetes mellitus and hyperinsulinism. Hum Mutat 2009;30:170-180.Ellard S., Flanagan S.E., Girard C.A. et al. Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects. Am J Hum Genet 2007;81:375-382.Ellard S., Flanagan S.E., Girard C.A. et al. Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects. Am J Hum Genet 2007;81:375-382.Stoy J., Greeley S.A., Paz V.P. et al. Diagnosis and treatment of neonatal diabetes: an United States experience. Pediat Diabetes 2008;9:450-459.Stoy J., Greeley S.A., Paz V.P. et al. Diagnosis and treatment of neonatal diabetes: an United States experience. Pediat Diabetes 2008;9:450-459.Masia R., De Leon D.D., MacMullen C. et al. A mutation in the TMD0-L0 region of SUR1 (L225P) causes permanent neonatal diabetes mellitus (PNDM). Diabetes 2007;56:1357-1362.Masia R., De Leon D.D., MacMullen C. et al. A mutation in the TMD0-L0 region of SUR1 (L225P) causes permanent neonatal diabetes mellitus (PNDM). Diabetes 2007;56:1357-1362.Proks P., Arnold A.L., Bruining J. et al. A heterozygous activating mutation in the sulphonylurea receptor SUR1 (ABCC8) causes neonatal diabetes. Hum Mol Genet 2006;15:1793-1800.Proks P., Arnold A.L., Bruining J. et al. A heterozygous activating mutation in the sulphonylurea receptor SUR1 (ABCC8) causes neonatal diabetes. Hum Mol Genet 2006;15:1793-1800.

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