ometendoОжирение и метаболизмObesity and metabolism2071-87132306-5524Endocrinology Research Centre10.14341/omet13052ometendo-13052Research ArticleОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯORIGINAL STUDIESВрожденные нарушения метаболизма глюкозы у взрослых с недиабетической гипогликемиейCongenital disorders of glucose metabolism in adults with nondiabetic hypoglycemiahttps://orcid.org/0000-0002-8771-8300ЮкинаМ. Ю.YukinaM. Yu.

Юкина Марина Юрьевна, к.м.н. 

Researcher ID: P-5181-2015; Scopus Author ID: 57109367700 

117036, Москва, ул. Дм. Ульянова, 11

Marina Yu. Yukina, MD, PhD 

Researcher ID: P-5181-2015; Scopus Author ID: 57109367700 

11 Dm. Ulyanova street, 117036 Moscow

yukina.marina@endocrincentr.ruhttps://orcid.org/0000-0002-8520-8702ТрошинаЕ. А.TroshinaE. A.

Трошина Екатерина Анатольевна, д.м.н., профессор 

Москва

Ekaterina A. Troshina, MD, PhD, Professor

Moscow

troshina@inbox.ruhttps://orcid.org/0000-0001-6876-3336НуралиеваН. Ф.NuralievaN. F.

Нуралиева Нурана Фейзуллаевна, к.м.н.

Москва

Nurana F. Nuralieva, MD, PhD 

Moscow

NNurana@yandex.ruhttps://orcid.org/0000-0003-1172-3557ПоповС. В.PopovS. V.

Попов Сергей Владимирович, к.б.н. 

Москва

Sergey V. Popov, PhD in biology

Moscow

swpopov73@gmail.comhttps://orcid.org/0000-0002-9717-9742МокрышеваН. Г.MokryshevaN. G.

Мокрышева Наталья Георгиевна, д.м.н., профессор

Москва

Natalia G. Mokrysheva, MD, PhD, Professor

Moscow

mokrisheva.natalia@endocrincentr.ruНациональный медицинский исследовательский центр эндокринологииРоссияEndocrinology Research CentreRussian Federation202417062024212136150Copyright © Юкина М.Ю., Трошина Е.А., Нуралиева Н.Ф., Попов С.В., Мокрышева Н.Г., 20242024Юкина М.Ю., Трошина Е.А., Нуралиева Н.Ф., Попов С.В., Мокрышева Н.Г.Yukina M.Y., Troshina E.A., Nuralieva N.F., Popov S.V., Mokrysheva N.G.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.omet-endojournals.ru/jour/article/view/13052Обоснование

Обоснование. Недавние клинические описания показали, что у взрослых пациентов причиной недиабетических гипогликемий (НДГ) могут быть различные генетически-детерминированные нарушения метаболизма глюкозы или синтеза/биодоступности инсулина. В связи с чем у взрослых пациентов с НДГ неясного генеза актуально проведение генетического исследования с целью поиска мутаций в генах, ассоциированных с врожденным нарушением метаболизма глюкозы (ВНМГ).

Цель

Цель. Оценить эффективность проведения генетического тестирования для исключения ВНМГ взрослым пациентам с идиопатической НДГ.

Материалы и методы

Материалы и методы. На основании проведенного анализа литературы разработана таргетная панель, включающая 30 генов, мутации в которых ассоциированы со следующими группами заболеваний: 1) врожденный гиперинсулинизм (KCNJ11, ABCC8, GLUD1, HADH, UCP2, HNF4A, HNF1A, GCK, INSR, SLC16A1); 2) болезни накопления гликогена (AGL); 3) другие нарушения обмена углеводов (ALDOB, FBP1); 4) дефекты гликозилирования (PMM2, ALG3, PGM1, MPI); 4) дефекты окисления жирных кислот (ACADM, ETFA, ETFB, ETFDH, FLAD1, SLC25A32, SLC52A1, SLC52A2, SLC52A3); 5) нарушения метаболизма кетоновых тел (CPT1A, CPT2, HMGCL); 6) митохондриальные нарушения (DLD). В исследование включено 29 пациентов (из них с идиопатической НДГ 17 и, в качестве группы контроля, с инсулиномой 12) в возрасте от 19 до 66 лет, которым проведено генетическое исследование с применением данной кастомной панели.

Результаты

Результаты. В результате проведенного обследования у 8 пациентов с идиопатической НДГ (47%, 95% ДИ (23%; 72%)) выявлено 12 генетических вариантов (все гетерозиготные), причем у двух пациентов выявлено по одному варианту в разных генах (AGL и HMGCL; ACADM и FLAD1) и у одного пациента — три варианта (один в гене ETFA и два в гене ABCC8). Частоты генетических вариантов: AGL — 18%, 95% ДИ (4%; 43%), ETFA — 12% (1%; 36%), HMGCL — 6% (0%; 29%), ALDOB — 6% (0%; 29%), CPT1A — 6% (0%; 29%), ABCC8 — 6% (0%; 29%), ACADM — 6% (0%; 29%), FLAD1 — 6% (0%; 29%). У 5 пациентов с инсулиномой (42%, 95% ДИ (15%; 72%)) выявлено 5 генетических вариантов (все гетерозиготные). Частоты генетических вариантов: ABCC8 — 17%, 95% ДИ (2%; 48%), HNF1A – 8% (0%; 38%), ETFDH – 8% (0%; 38%), MPI – 8% (0%; 38%). При этом клинически значимые варианты выявлены только у одного пациента из группы с идиопатической НДГ (6%, 95% ДИ (0%; 29%)) в гене ABCC8 и у одного пациента из группы с инсулиномой (8%, 95% ДИ (0%; 38%)) в этом же гене врожденного гиперинсулинизма (ВГИ). Доброкачественные варианты не включались в данный анализ.

Заключение

Заключение. Разработана панель из 30 генов, варианты которых ассоциированы с ВНМГ. Результаты нашего исследования подтверждают возможность выявления ВНМГ во взрослом возрасте, в частности ВГИ, и свидетельствуют в пользу необходимости проведения генетического тестирования, в первую очередь пациентам с идиопатической НДГ.

BACKGROUND

BACKGROUND: Recent clinical descriptions have shown that in adult patients, the cause of nondiabetic hypoglycemia (NDH) may be various genetically determined disorders of glucose metabolism or insulin synthesis/bioavailability. In this connection, in adult patients with NDH of unclear genesis, it is important to conduct a genetic study in order to search for mutations in genes associated with congenital disorders of glucose metabolism (CDGM).

AIM

AIM: To evaluate the effectiveness of genetic testing to exclude CDGM in adult patients with idiopathic NDH.

MATERIALS AND METHODS

MATERIALS AND METHODS: Based on the analysis of the literature, a targeted panel has been developed, including 30 genes, mutations in which are associated with the following groups of diseases: 1) congenital hyperinsulinism (KCNJ11, ABCC8, GLUD1, HADH, UCP2, HNF4A, HNF1A, GCK, INSR, SLC16A1); 2) glycogen storage diseases (AGL); 3) other carbohydrate metabolism disorders (ALDOB, FBP1); 4) glycosylation defects (PMM2, ALG3, PGM1, MPI); 4) defects in fatty acid oxidation (ACADM, ETFA, ETFB, ETFDH, FLAD1, SLC25A32, SLC52A1, SLC52A2, SLC52A3); 5) disorders of ketone body metabolism (CPT1A, CPT2, HMGCL); 6) mitochondrial disorders (DLD). Twenty nine patients (n=29: with idiopathic NDH n=17 and with insulinoma n=12) aged 19 to 66 years underwent a genetic study using this custom panel.

RESULTS

RESULTS: As a result of the examination 12 genetic variants (all heterozygous) were identified in 8 patients with idiopathic NDH (47%, 95% CI (23%; 72%)), at that two mutations were detected in three patients: in the genes AGL and HMGCL; ACADM and FLAD1, respectively; and one patient had three mutations: one mutation in the ETFA gene and two mutations in the ABCC8 gene. Frequencies of genetic variants: AGL — 18%, 95% CI (4%; 43%), ETFA — 12% (1%; 36%), HMGCL — 6% (0%; 29%), ALDOB — 6% (0%; 29%), CPT1A — 6% (0%; 29%), ABCC8 — 6% (0%; 29%), ACADM — 6% (0%; 29%), FLAD1 — 6% (0%; 29%). 5 genetic variants (all heterozygous) were identified in 5 patients with insulinoma (42%, 95% ДИ (15%; 72%)). Frequencies of genetic variants: ABCC8 — 17%, 95% CI (2%; 48%), HNF1A — 8% (0%; 38%), ETFDH — 8% (0%; 38%), MPI — 8% (0%; 38%). We did not include benign variants in this analysis. At the same time, clinically significant variants were identified only in one patient from the group with idiopathic NDH (6%, 95% CI (0%; 29%)) in the ABCC8 gene and in one patient from the group with insulinoma (8%, 95% CI (0%; 38%)) in the same gene congenital hyperinsulinism (CHI).

CONCLUSION

CONCLUSION: A panel of 30 genes has been developed, variants of which are associated with a CDGM. The results of our study confirm the possibility of detecting CDGM in adulthood, in particular CHI, and indicate the need for genetic testing, primarily in patients with idiopathic NDH.

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