Aim — to research molecular genetic and clinical characteristics of diabetes mellitus MODY2 and MODY3 in children. Material and methods. Genetic testing for GCK and HNF1α was performed in 169 patients with carbohydrate metabolism disorders, with age of diagnosis under 18. Carbohydrate metabolism disorders were interpreted as MODY. Analysis of clinical data at the presentation of carbohydrate metabolism disorder and cases follow-up was provided in 62 patients with genetic confirmed MODY2 and 18 patients with genetic confirmed MODY3. Results. Ratio MODY2 and MODY3 was 3,4:1. Carbohydrate metabolism disorders were diagnosed earlier in MODY2 than in MODY3 — 7,8 years (4,0; 10,5) vs. 11,8 years (9,7; 13,5) (p<0,01). Degree of carbohydrate metabolism disorder was less in MODY2 — in 22,4% of patients all makers of carbohydrate metabolism disorder (HbA1c, fasting glycaemia, 120 min glycaemia) were less than diabetic range, in MODY3 all these makers were diabetics in 100% of cases. Patients with MODY2 significantly less frequently were treated with antihyperglycemic drugs. Carbohydrate metabolism disorders in one of the parents were diagnosed earlier in MODY3 — in 24 years (18,5; 35,3) vs. 32 years (27; 37) in MODY2 (p<0,05), parents were treated with antihyperglycemic drugs — in 94,4% vs. 22,2% respectively (p<0,01). Conclusion. This study is the largest in Russia and estimated that MODY2 is the most prevalence and has had milder presentation and less dysfunction of β-cells to compare to MODY-HNF1α.

We report the case of a 12-year-old boy with a glucokinase (GCK) mutation, and diabetes with hyperinsulinemia and insulin resistance. For 4 years, the patient intermittently received insulin medications Actrapid HM and Protaphane HM (total dose 5 U/day), with glycated hemoglobin (HbA_1c) levels of 6.6%–7.0%. After extensive screening the patient was found to carry a heterozygous mutation (p.E256K) in GCK (MIM #138079, reference sequence NM_000162.3). Insulin therapy was replaced by metformin at 1,700 mg/day. One year later, his HbA_1c level was 6.9%, postprandial glycemia at 120 min of oral glucose tolerance test was 15.4 mmol/L, hyperinsulinemia had increased to 508.9 mU/L, homeostasis model assessment index was 114.2 and the Matsuda index was 0.15. Insulin resistance was confirmed by a hyperinsulinemic euglycemic clamp test – M-index was 2.85 mg/kg/min. This observation is a rare case of one of the clinical variants of diabetes, which should be taken into account by a vigilant endocrinologist due to the need for nonstandard diagnostic and therapeutic approaches.

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: 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: 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 — 5 years) and age of manifestation (A — prepubertal and B — puberty).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: 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.

Неиммунный сахарный диабет у детей, обусловленный гетерозиготными мутациями в гене глюкокиназы (GCK-MODY): анализ данных 144 пациентов

Уровень С-пептида и распространенность панкреатических аутоантител у детей с сахарным диабетом 1 типа при разной длительности заболевания

BACKGROUND: MODY (maturity-onset diabetes of the young) is a rare monogenic form of diabetes mellitus, the gold standard of diagnosis is mutations detection in the genes responsible for the development of this form diabetes. Genetic test is expensive and takes a lot of time. The diagnostic criteria for MODY are well known. The development of clinical decision support system (CDSS) which allows physicians based on clinical data to determine who should have molecular genetic testing is relevant.AIM: Provided a retrospective analysis of clinical data of the patients with T1DM and MODY, from 0 to 18 years old, regardless of the duration of the disease to develop the model. Based on clinical data, a feedforward neural network (NN) was implemented - a multilayer perceptron.MATERIALS AND METHODS: Development of the most effective algorithm for predicting MODY in children based on available clinical indicators of 1710 patients with diabetes under the age of 18 years using a multilayer feedforward neural network.RESULTS: The sample consisted of 1710 children under the age of 18 years with T1DM (78%) and MODY (22%) diabetes. For the final configuration of NS the following predictors were selected: gender, age at passport age, age at the diagnosis with DM, HbA1c, BMI SDS, family history of DM, treatment. The performance (quality) assessment of the NN was carried out on a test sample (the area under the ROC (receiver operating characteristics) curve reached 0.97). The positive predictive value of PCPR was achieved at a cut-off value of 0.40 (predicted probability of MODY diabetes 40%). At which the sensitivity was 98%, specificity 93%, PCR with prevalence correction was 78%, and PCR with prevalence correction was 99%, the overall accuracy of the model was 94%.Based on the NN model, a CDSS was developed to determine whether a patient has MODY diabetes, implemented as an application.CONCLUSION: The clinical prediction model MODY developed in this work based on the NN, uses the clinical characteristic available for each patient to determine the probability of the patient having MODY. The use of the developed model in clinical practice will assist in the selection of patients for diagnostic genetic testing for MODY, which will allow for the efficient allocation of healthcare resources, the selection of personalized treatment and patient monitoring.