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eIF4G2 (DAP5 or Nat1) is a homologue of the canonical translation initiation factor eIF4G1 in higher eukaryotes but its function remains poorly understood. Unlike eIF4G1, eIF4G2 does not interact with the cap-binding protein eIF4E and is believed to drive translation under stress when eIF4E activity is impaired. Here, we show that eIF4G2 operates under normal conditions as well and promotes scanning downstream of the eIF4G1-mediated 40S recruitment and cap-proximal scanning. Specifically, eIF4G2 facilitates leaky scanning for a subset of mRNAs. Apparently, eIF4G2 replaces eIF4G1 during scanning of 5′ UTR and the necessity for eIF4G2 only arises when eIF4G1 dissociates from the scanning complex. In particular, this event can occur when the leaky scanning complexes interfere with initiating or elongating 80S ribosomes within a translated uORF. This mechanism is therefore crucial for higher eukaryotes which are known to have long 5′ UTRs with highly frequent uORFs. We suggest that uORFs are not the only obstacle on the way of scanning complexes towards the main start codon, because certain eIF4G2 mRNA targets lack uORF(s). Thus, higher eukaryotes possess two distinct scanning complexes: the principal one that binds mRNA and initiates scanning, and the accessory one that rescues scanning when the former fails.

Birth trauma of the liver with the development of subcapsular hematoma and hemoperitoneum is reported extremely rarely. The slow enlargement of the hematoma also results in delayed development of bleeding symptoms. Noticeable clinical manifestations appear simultaneously when the hematoma ruptures into the abdominal cavity. Later, the symptoms develop very quickly that doctors failed to understand the root cause of the bleeding. The diagnosis is established only during autopsy. When conservative therapy is ineffective, open surgery is conducted; however, the surgery is associated with a high risk of unfavorable outcomes. Herein, we present a clinical case demonstrating successful treatment with endovascular embolization of a vessel due to bleeding from a giant subcapsular hematoma of the liver in a newborn. The child was born in a settlement of the Arkhangelsk Region and weighed 3480 grams. A vacuum extractor was used to assist the weak mother during delivery. The child was in a critical condition and suffered from asphyxia. Mechanical ventilation was used. At 10 h after birth, the child was taken to a specialized neonatal center of Arkhangelsk (the helicopter flight took 2.5 h). The intensive therapy continued. Negative dynamics followed. At 25 h after birth, hemodynamic indexes decreased. X-ray and ultrasound investigations of the abdominal cavity revealed a large hematoma in the liver. It occupied the entire area of the right liver lobe. Abdominal bleeding was diagnosed. The child was taken to the X-ray department. The newborn underwent urgent endovascular embolization of the right hepatic artery. The bleeding was stopped, and the childs condition was stable. On follow-up at age 1 year and 5 months, the childs development was in accordance with age, and blood biochemical parameters were within normal limits. Ultrasound data revealed well recovery of the liver structure. With extensive birth trauma of the liver, minimally invasive surgery, i.e., endovascular embolization of vessels, can be considered an alternative option to surgical treatment.

The eukaryotic initiation factor 4G2 (eIF4G2, DAP5, Nat1, p97) was discovered in 1997. Over the past two decades, dozens of papers have presented contradictory data on eIF4G2 function. Since its identification, eIF4G2 has been assumed to participate in noncanonical translation initiation mechanisms, but recent results indicate that it can be involved in scanning as well. In particular, eIF4G2 provides leaky scanning through some upstream open reading frames (uORFs), which are typical for long 5′ UTRs of mRNAs from higher eukaryotes. It is likely the protein can also help the ribosome overcome other impediments during scanning of the 5′ UTRs of animal mRNAs. This may explain the need for eIF4G2 in higher eukaryotes, as many mRNAs that encode regulatory proteins have rather long and highly structured 5′ UTRs. Additionally, they often bind to various proteins, which also hamper the movement of scanning ribosomes. This review discusses the suggested mechanisms of eIF4G2 action, denotes obscure or inconsistent results, and proposes ways to uncover other fundamental mechanisms in which this important protein factor may be involved in higher eukaryotes.

Clinical guidelines have long been one of the working tools of the modern doctor, helping him quickly navigate the most effective proven methods of treatment and prevention of various diseases, and also to adapt these methods to the specific tasks of their patients and to achieve maximum personalization of treatment. Clinical practice guidelines are drawn up by professional non-profit associations and are approved by the Scientific Council of the Ministry of Health of the Russian Federation, while often one recommendation is prepared by two or even three associations. The peculiarity of the recommendations offered to your attention is that not only endocrinologists, but also therapists, cardiologists, gynecologists, gastroenterologists, and experts of many other specialties are involved in the prevention and treatment of obesity. The Multidisciplinary Working Group presents this a project in a multidisciplinary journal to bring together the efforts of several professional associations that associated with the need to pay attention not only to obesity itself but also to comorbid conditions. We are looking forward to constructive criticism and a comprehensive discussion of the problem on the pages of our journal.

Background: Obesity is one of the most significant risk factors for type 2 diabetes (T2D), but a large number of patients with morbid obesity maintain normal glycemia for a long time. There are no definite easy-to-measure clinical features that distinguish severely obese people who will or will not develop T2D. These features may be useful in clinical practice to predict T2D development in obese patients.Aims: We aimed to identify clinical features (lifestyle factors, obesity history, concomitant diseases) that may be associated with T2D in obese patients.Materials and methods: The study was conducted at single center during 2002 and 2017 and recruited patients with BMI≥30 kg/m2 who attended bariatric surgeon. Patients weight and height were assessed by the doctor, other features were obtained from the questionnaire: overweight and obesity history (age of onset, duration, family history of obesity), lifestyle factors, T2D and concomitant diseases medical history. Patients were divided into 2 groups with regard to the presence of T2D. Data analysis was performed with Statistica 13.3.Results: The study included 170 patients with known T2D and 528 patients without history of T2D and prediabetes. Both groups had similar gender structure, as well as current and peak BMI. There were no significant differences in overweight/obesity duration, obesity family history, lifestyle factors and smoking status of patients. Obese patients without T2D were younger than T2D patients at the time of T2D onset (median age 40 and 45 years respectively). Patients without T2D started to gain weight earlier than those with T2D (median age 17 and 25 years respectively) and reached their peak BMI during 1 year before study entry, while patients with T2D went through maximum weight previously. The frequencies of concomitant diseases didn’t differ between the groups with the exception of hypertension that started later in patients with T2D (median age 51 and 47 years in patients with and without T2D respectively); also patients with T2D had gastroesophageal reflux disease (GERD) and chronic back pain less often than patients without T2D with regard to age.Conclusions: Clinical features that distinguished obese patients with and without T2D were age at the start of overweight/ obesity and concomitant disease profile (hypertension, GERD, chronic back pain) at corresponding age.

Obese patients without diabetes present an interesting phenotype to explore protective mechanisms against type 2 diabetes (T2D) development. In our study we looked for specific hormonal features of obese patients without T2D.We included 6 groups of patients with different metabolic profiles (n=212): controls with BMI25 kg/m2, HbA1c6%, age 30 years; patients with 25BMI30 kg/m2and HbA1c6%; patients with 25BMI30 kg/m2and HbA1c6%; patients with BMI30 kg/m2and HbA1c6% (+ Obesity - T2D) obese patients without T2D or prediabetes; patients with BMI30 kg/m2and newly-diagnosed T2D/prediabetes, HbA1c6%; patients with known history of T2D on glucose-lowering drugs with BMI30 kg/m2. Insulin, GLP-1, GIP were measured during glucose-tolerance test at 0, 30 and 120 minutes; insulin resistance (IR) was assessed by HOMA-IR.Waist circumference was bigger in patients with obesity despite their metabolic profile comparing to patients without obesity (p0.001). Waist-to-hip ratio was similar in patients with different metabolic status. According to IR + Obesity - T2D group had intermediate position: IR was higher in that group comparing to people without obesity, but was less that in patients with obesity and HbA1c6% (p0.001). + Obesity - T2D group had the most potent baseline insulin secretion, assessed by НОМА-%band the highest postprandial secretion, measured by insulinogenic index among all patient groups with obesity (p0.001). There was no significant difference in GLP-1 secretion; GIP secretion was higher in patients with BMI30 kg/m2comparing to people with BMI30 kg/m2(p0.01).Пациенты с ожирением без нарушений углеводного обмена представляет большой интерес для изучения механизмов, защищающих от развития сахарного диабета 2-го типа (СД 2). Цель.Проанализировать особенности гормональной секреции у лиц с ожирением без СД 2. Материалы и методы.В исследование включены 6 групп пациентов с различным метаболическим статусом (n=212): контрольная группа с индексом массы тела (ИМТ)25 кг/м2, гликированным гемоглобином (HbA1c)6%, возраст 30 лет; пациенты с ИМТ 25ИМТ30 кг/м2и HbA1c6%; пациенты с ИМТ 25ИМТ30 кг/м2и HbA1c6%; пациенты с ИМТ30 кг/м2и HbA1c6% (+ ожирение - СД) группа с ожирением без СД 2 и предиабета; пациенты с ИМТ30 кг/м2и впервые выявленным HbA1c6%; пациенты с известным СД 2 на сахароснижающих препаратах с ИМТ30 кг/м2. В ходе глюкозотолерантного теста (0, 30, 120 мин) определены инсулин, глюкозозависимый инсулинотропный полипептид 1-го типа, глюкозозависимый инсулинотропный полипептид, рассчитан показатель HOMA-IR. Результаты.Окружность талии отмечена больше у пациентов с ожирением вне зависимости от метаболических нарушений по сравнению с лицами без ожирения (p0,001). Соотношение окружностей талии и бедер не позволяло дифференцировать пациентов с разными метаболическими рисками. В группе + ожирение - СД инсулинорезистентность выше, чем у пациентов без ожирения, но ниже, чем у пациентов с ожирением и HbA1c6% (p0,001). Эта группа также имела наиболее высокие показатели базальной (НОМА-%) и стимулированной секреции инсулина (индекс инсулиногенности) среди всех пациентов с ИМТ30 кг/м2(p0,001). Секреция ГПП-1 не отличалась, секреция ГИП отмечена выше в группах с ИМТ30 кг/м2по сравнению с лицами с ИМТ30 кг/м2(p0,01). Заключение.Отличие фенотипа пациентов с ожирением без СД 2 от лиц с СД 2 заключалось в менее выраженной инсулинорезистентности и более сохранной базальной и стимулированной секреции инсулина, достаточной для поддержания нормогликемии.

Public organization “Russian Association of Endocrinologists”. Clinical guidelines.&nbsp

BACKGROUND: Type 2 diabetes (T2D) is multifactorial disease. NATION epidemiological study may provide the information about the prevalence of T2D and prediabetic state in patients with different risk factor combinations in Russian population. AIMS: To evaluate the prevalence of T2D and prediabetic state in NATION cohort depending on the amount of diabetes risk factors. MATERIALS AND METHODS: NATION is an epidemiological, cross-sectional study, designed to assess the prevalence of T2D in Russian adult population, where HbA1c was used to establish T2D (HbAc≥6,5%) and prediabetes (5,7%≤HbA1c

In recent years the theme of the relationship of Alzheimers disease (AD) and metabolic disorders has been widely discussed. Nevertheless, it remains unclear whether AD is a direct cause of carbohydrate metabolism disorders or it is the presence of classical risk factors for type 2 diabetes mellitus (DM 2), primarily obesity, that significantly increases the risk of AD.To evaluate the separate contribution of two factors to the development of disorders of carbohydrate metabolism: (1) weight gain due to a high-calorie diet and (2) experimental-induced AD.Male Wistar rats were injected with streptozocin (STZ) in the lateral ventricles of the brain to induce AD or saline (sham operated animals - SO) during stereotactic operations. After 2 weeks, the animals were divided into four groups: 1) the SO group, which was assigned to the normal calorie (NCD) diet (SO NCD); 2) the SO group, which was assigned to the high-calorie diet (SO HCD); 3) the group to which the norm-calorie diet was prescribed after the administration of STZ into the lateral ventricles of the brain (STZ NCD); 4) the group to which the HCD was assigned after the administration of STZ (STZ HCD). The animals were on a diet for 3 months. Intraperitoneal glucose tolerance tests were carried out before the diet and after 3 months. At the end of the study, a morphological assessment of brain tissue, pancreas, and liver was performed.3 months after surgical interventions and the appointment of diets, the glycemic curves significantly differed in the 4 studied groups: normoglycemia persisted only in the SO + NCD group, while HCD and the STZ administration were accompanied by the development of hyperglycemia (p = 0.0001). The STZ + NСD group, which represented the isolated effect of AD, was also characterized by impaired carbohydrate metabolism. A morphological study showed that HCD leads to a more pronounced ectopic accumulation of fat in the liver and pancreas tissue than NCD. The administration of STZ, regardless of the diet, led to changes typical for the AD model an increase in the size of the ventricles of the brain, degeneration of white matter, and the accumulation of -amyloid in the hypothalamus.The STZ-induced brain damage typical for AD led to impaired carbohydrate metabolism regardless of diet and was an independent risk factor for hyperglycemia.Обоснование. В последние годы широко обсуждается тема взаимной связи болезни Альцгеймера (БА) и метаболических расстройств. Тем не менее остается неясным, является ли БА непосредственной причиной нарушений углеводного обмена или наличие классических факторов риска сахарного диабета 2-го типа (СД 2), в первую очередь ожирения, значимо повышает риск возникновения БА. Цель: оценить раздельный вклад двух факторов в развитие нарушений углеводного обмена 1) увеличения массы тела на фоне высококалорийного питания и 2) экспериментально вызванной БА. Методы. Крысам-самцам линии Вистар были проведены стереотаксические операции по введению в латеральные желудочки мозга стрептозоцина (СТЗ) для моделирования БА либо физиологического раствора (ложнооперированные животные ЛО). Спустя 2 нед животные были разделены на четыре группы: 1) группа ЛО, которой была назначена нормокалорийная (НКД) диета (ЛО+НКД); 2) группа ЛО, которой была назначена высококалорийная диета (ЛО+ВКД); 3) группа, которой была назначена НКД после введения СТЗ в латеральные желудочки мозга (СТЗ+НКД); 4) группа, которой была назначена ВКД после введения СТЗ (СТЗ+ВКД). Длительность нахождения животных на диете составила 3 мес. Перед началом диеты, а также спустя 3 мес животным были проведены интраперитонеальные глюкозотолерантные тесты. По окончании исследования была проведена морфологическая оценка тканей головного мозга, поджелудочной железы, печени. Результаты. Через 3 мес после проведения оперативных вмешательств и введения диет характер гликемических кривых значимо различался в четырех исследуемых группах: нормогликемия сохранялась лишь в группе ЛО+НКД, тогда как ВКД и введение СТЗ сопровождались развитием гипергликемии (р=0,0001). Группа СТЗ+НКД, отражавшая изолированное воздействие БА, также характеризовалась нарушениями углеводного обмена. Морфологическое исследование показало, что ВКД приводит к более выраженному эктопическому накоплению жира в ткани печени и поджелудочной железы, чем НКД. Введение СТЗ вне зависимости от диеты приводило к типичным для модели БА изменениям увеличению размеров желудочков мозга, дегенерации белого вещества и накоплению -амилоида в гипоталамусе. Заключение: СТЗ-индуцированные повреждения структур головного мозга, характерные для БА, приводили к нарушениям углеводного обмена вне зависимости от получаемой диеты и являлись самостоятельным фактором риска развития гипергликемии.

Objective: We have performed the comparative study of basal state of SGK-dependent signaling among obese patients with/without type 2 diabetes mellitus (T2DM). We have accomplished correlation analysis of glucose metabolism and incretin profile parameters against phosphorylation and expression parameters for SGK1 and its substrate NDRG1. Methods: 36 patients with long (>10 years) and morbid (BMI>35 kg/m2) obesity, 18 of which had normal glucose tolerance (NGT) and 18 had T2DM were enrolled in this study. Hyperinsulinemic-euglycemic clamp test and HOMA-IR were used to evaluate the insulin resistance. Blood samples taken at 0, 30 and 120 min of food load test were used to assess incretin profile, insulin and glucose levels. Biopsies from subcutaneous and omental fat depots were obtained during bariatric surgery for all patients and signaling states were analyzed by western blot. Results: Analysis of SGK signaling for subcutaneous fat has shown single significant intergroup difference: enhancing of pSGK-S422 phosphorylation in T2DM group, but also pNDRG-T346 level has tendency to accumulation in subcutaneous fat of NGT patients. Analysis of SGK signaling for omental fat has shown similar results: in this case accumulation of pNDRG-T346 in NGT patients was statistically significant. Correlation analysis has shown strong direct correlation of pNDRG-T346 level with BMI and AUC for GLP-1 and reverse correlation of pNDRG-T346 with Hb1Ac and AUC for glucagon. For pSGK-S422 we have observed opposite characters of correlations with the similar parameters of carbohydrate metabolism and incretin profile. Conclusions: In present work we have taken more patients and have shown critical relevance and general character of stress-dependent SGK1-NDRG1 signal axis as a marker of insulin resistance for different fat depots. Disclosure I. Stafeev: None. A. V. Vorotnikov: None. Y. V. Parfyonova: None. M. V. Shestakova: None. I. Sklyanik: None. E. Mamontova: None. S. Michurina: None. E. Shestakova: None. K. Yahyaev: None. A. Yurasov: None. E. Ratner: None. M. Menshikov: None. Funding Russian Science Foundation (17-15-01435)

To compare glucose - lowering and weight reduction capacity of bypass operations (gastric bypass (GB), biliopancreatic diversion (BPD) vs GLP-1 agonist liraglutide 3.0 mg (models of maximum incretin effect) for 6 months.46 patients with type 2 diabetes and long history (≥10 years) of obesity were divided into 2 groups: surgery - group (n=23) and liraglutide - group (n=23), where liraglutide 3.0 mg in dose - escalation manner was added to baseline glucose - lowering therapy. Anthropometric parameters, HbA1c and insulin resistance (IR) by hyperinsulinemic euglycemic clamp (M-value) were measured before and 16 weeks after the intervention. With the stabilization of glycemia (≤6.5 mmol/l at fasting state, ≤8 mmol/l postprandial) the initial glucose - lowering therapy was canceled.Both surgery and liraglutide 3.0 mg provided target HbA1c in 16 weeks. Bypass operations led to elimination of glucose - lowering therapy in 82.6% patients due to a more significant weight reduction and decrease in IR. In liraglutide - group previous glucose - lowering therapy was cancelled in 78.3% patients, mainly receiving baseline mono - and two - component therapy. The most significant difference between interventions was achieved in BMI (-8.9 kg in surgery group vs -3.8 kg in liraglutide group, p.Цель исследования. Сравнить эффективность хирургического (бариатрические шунтирующие операции) и медикаментозного (лираглутид 3,0 мг/сут) методов коррекции гликемии и ожирения у пациентов с сахарным диабетом 2-го типа (СД2) в течение 6 мес. Материалы и методы. Пациенты с СД2 и ожирением разделены на две группы, сопоставимые по полу, возрасту, индексу массы тела (ИМТ), длительности ожирения, длительности СД2 и структуре предшествовавшей сахароснижающей терапии: I группа («Операция») - пациенты, которым проведена комбинированная бариатрическая операция (гастрошунтирование, билиопанкреатическое шунтирование; n=23) и II группа («Лираглутид») - пациенты, которым к предшествующей терапии добавлен агонист рецепторов глюкагоноподобного петпида-1 (ГПП-1) лираглутид в дозе 3,0 мг/сут (n=23). До и через 6 мес после начала лечения у пациентов оценены антропометрические показатели (масса тела, рост, ИМТ), уровень HbA1c, инсулинорезистентность (ИР) методом оценки М-индекса в ходе гиперинсулинемического эугликемического клэмп - теста. Когда пациенты достигали нормализации углеводного обмена (гликемия ≤6,5 ммоль/л натощак, ≤8 ммоль/л постпрандиально), антигипергликемическую терапию постепенно отменяли. Результаты и обсуждение. Как лираглутид 3,0 мг/сут, так и комбинированные бариатрические операции приводили к достижению целевого значения HbA1c через 6 мес наблюдения (HbA1c 6,2 и 6,3%, соответственно). В группе «Операция» сахароснижающая терапия отменена у 82,6% пациентов на фоне более значимого снижения массы тела и ИР, а в группе «Лираглутид» - у 78,3% пациентов, преимущественно получавших моно - и двухкомпонентную сахароснижающую терапию. Наиболее значимые различия между группами получены в ИМТ (-8,9 кг/м2 в группе «Операция» против -3,8 кг/м2 в группе «Лираглутид»; р.

Poly(rC)-binding protein 2 (PCBP2, hnRNP E2) is one of the most abundant RNA-binding proteins in mammalian cells. In humans, it exists in seven isoforms, which are assumed to play similar roles in cells. The protein is shown to bind 3′-untranslated regions (3′-UTRs) of many mRNAs and regulate their translation and/or stability, but nothing is known about the functional consequences of PCBP2 binding to 5′-UTRs. Here we show that the PCBP2 isoform f interacts with the 5′-UTRs of mRNAs encoding eIF4G2 (a translation initiation factor with a yet unknown mechanism of action, also known as DAP5) and Cyclin I, and inhibits their translation in vitro and in cultured cells, while the PCBP2 isoform e only affects Cyclin I translation. Furthermore, eIF4G2 participates in a cap-dependent translation of the PCBP2 mRNA. Thus, PCBP2 and eIF4G2 seem to regulate one another's expression via a novel type of feedback loop formed by the translation initiation factor and the RNA-binding protein.

The article analyzes the research results of using ultrasound oscillations and pulsing magnetic field in order to increase the quality and fasten processing the fish products (sausages, wieners and salami made from minced fish meat). Influence of ultrasound and pulsating magnetic field on resistibility of protein-in-oil emulsion to mechanical and temperature effects, as well as its resistibility to oxidation extend storage terms for minced fish products enriched with protein in-oil emulsions and help to develop the technology for making salami and sausages. Viscosity of protein in-oil emulsion made using magnetic ultrasound and oscillating magnetic field condenses to cream consistency, dispersion of fat balls reaches 4-30 mkm. Such thick emulsions that don’t dilute during thermal processing of minced fish products help to raise the quality of fish sausages, to prolong storage terms of ready-made product by 32-38% due to high resistivity to oxidation. The modern piezoelectric ultrasound installations as well as neodymium magnets have small sizes and low power consumption, can be easily integrated in the permanent production lines of minced fish products. Addition of protein-in-oil emulsions prepared using ultrasound and magnetic field of constant neodymium magnets allows to increase liquid trapping of minced fish, which results in greater product yield and low costs.

Background Obesity and type 2 diabetes mellitus (T2DM) are among the most important morbidity factors. In this study we tested the hypothesis that low proliferative potential of adipose derived stromal cells (ADSC) associates with reduced formation of new fat depots, excess accumulation of fat in the functional adipocytes and their hypertrophy, resulting in fat inflammation and insulin resistance. Methods We screened two groups of obese patients with or without T2DM, matched for BMI, age, and duration of obesity to test the hypothesis that hypertrophy and decreased renewal of adipocytes may underlie transition from obesity to T2DM. All patients were matched for carbohydrate metabolism (fasting blood glucose level, glycated hemoglobin, HOMA-IR index and M-index). The subcutaneous and omental fat tissue biopsies were obtained during bariatric surgery from obese individuals with or without T2DM. The morphology and immunophenotype of subcutaneous and omental fat was assessed in frozen tissue sections. ADSC were isolated from both types of fat tissue biopsies and screened for morphology, proliferative potential and inflammatory status. Results The non-diabetic patients had normal carbohydrate metabolism and moderate insulin resistance measured by HOMA-IR and hyperinsulinemic clamp (M-index), while T2DM patients were extremely insulin resistant by both indexes. The average size of diabetic adipocytes was higher than that of non-diabetic in both subcutaneous and omental fat tissues, indicating adipocyte hypertrophy in T2DM. Both these tissues contained higher level of macrophage infiltration and increased M1-like to M2-like ratio of macrophage subpopulations, suggesting increased fat inflammation in T2DM. This was confirmed by increased activatory phosphorylation of stress-induced JNK1/2 in diabetic ADSC. Conclusion These results suggest that blunted proliferation and increased hypertrophy of diabetic ADSC may lead to reduced insulin sensitivity via increased inflammation mediated by M1 macrophages and JNK1/2 pathway.

Background: Obesity is a risk factor for cognitive disorders. However, it is still unknown whether low-calorie diet will improve cognitive function in obese patients. Aim: To evaluate cognitive function and metabolic features in male Sprague-Dawley rats receiving high-fat and low-calorie diets. Materials and methods: The work was carried out on Sprague Dawley male rats (n = 32), which were divided into 2 groups with 16 animals in each group: Control (normal / low-calorie diet) and Obesity (high-fat diet). In 90 days the rats of the Control group were transferred to a low-calorie diet, the rats of the Obesity group continued to receive high-fat diet. To assess motor activity and cognitive functions at the end of the study (180 days), following behavioral tests were conducted: "open field", "tapering beam", "elevated plus-maze" (EPM) and "passive avoidance reaction". During the study glucose tolerance test were performed: at baseline (GTT 1) and in 30 days (GTT 2). Results: Obesity group rats gained weight significantly faster than the control animals (547.69 ± 11.32 g against 442.8 ± 19.8 g at study end, p = 0.0001). GTT 2 showed normal carbohydrate metabolism in control group, postprandial hyperglycemia in obesity group. Testing in the open field showed that the rats of the obesity group moved more actively across the installation area than the control ones: the total distance covered was 9.352 ± 0.932 m against 6.781 ± 0.951 m, p = 0.046. The results of a tapering beam test showed that the number of hind limb extrusions in obese rats significantly exceeded this parameter in control group (33.7 ± 3 vs. 15.7 ± 2.7, p = 0.0001), test time in both groups did not differ. When testing in EPM, there was no significant difference in any of the key test parameters between the groups. However, the number of looking out from the closed arms in animals of the obesity group was significantly higher than in the control group (4.19 ± 0.6 vs. 2.30 ± 0.58, p = 0.044). When testing the reproduction of conditional reactions of passive avoidance it was shown that after day 1 of the pain stimulation application the latent period of transition to the dark compartment in the obesity group was significantly higher than that of the control group (180.0 ± 0.0 vs. 128 86 ± 21.45, p = 0.008). This indicates a better preservation of the memorial trail compared to the "control" rats. By the end of the study 30% of animals in the control group died. Conclusions: Rats on high-fat diet were more active, less anxious and showed better results in training tests comparing to animals on low-calorie diet. Adherence to low-calorie diet may be harmful for cognitive functions.

Objective: In our study we have compared basal insulin and mTOR signaling in subcutaneous fat of obese T2DM vs. obese subjects with normal glucose tolerance (NGT). We have performed correlation analysis of phosphorylation’s parameters against clinical parameters of carbohydrate metabolism and incretin secretion profiles. Methods: 22 patients with long (>10 years) and morbid (BMI > 35 kg/m2) obesity, 12 of which had NGT and 10 had T2DM were enrolled in this study. Hyperinsulinemic-euglycemic clamp test and HOMA-IR were used to measure insulin resistance. Blood samples taken at 0, 30 and 120 min of food load test were used to assess incretin profile, insulin and glucose levels. Amount of total and visceral fat was determined by bioelectrical impedance analysis. Subcutaneous fat biopsies were obtained during bariatric surgery for all patients and signaling state was analyzed by western blots. Results: As assessed by western blots of insulin receptor substrate (IRS), Akt, Raptor, Rictor, mTOR and S6K1, the basal insulin signaling and mTORC activities were comparable in NGT and T2DM groups, whereas phosphorylation of AS160 (pAS160-S318) was significantly lower and serum and glucocorticoid-induced kinase (SGK; pSGK-S422) was significantly higher in T2DM group. Various correlations were found between the degree of insulin resistance and amount of visceral fat, changes in incretin profile, glucose metabolic parameters and phosphorylation level of AS160, incretin secretion profile and phosphorylated levels of AS160 or SGK1. Conclusions: Altered phosphorylation of AS160 and SGK1 is associated with obese T2DM phenotype and impaired incretin profile. We think that AS160 and SGK1 phosphorylations can be important markers of the prediabetes-to-diabetes transition. Disclosure I. Stafeev: None. I. Sklyanik: None. S. Michurina: None. E. Shestakova: Employee; Spouse/Partner; AstraZeneca. Speaker’s Bureau; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novartis Pharma K.K., Novo Nordisk A/S, Sanofi-Aventis, Takeda Pharmaceutical Company Limited. A. Yurasov: None. K. Yahyaev: None. A. Karmadonov: None. E. Ratner: None. M. Menshikov: None. A.V. Vorotnikov: None. Y.V. Parfyonova: None. M.V. Shestakova: None. Funding Russian Science Foundation (17-15-01435)

There are several models of T2DM remission after bariatric surgery (ABCD, DiaRem, DRS), but none of them includes insulin resistance. Moreover these models are not suitable for early prediction of T2DM remission (within several months after surgery). Methods: We included 42 patients with T2DM and morbid obesity (BMI 42.3 [38.9; 48.1] kg/m2) after bariatric surgery (16 pts after restrictive procedures and 26 pts after bypass surgery). Insulin resistance was measured by hyperinsulienic euglycaemic test with M-index estimation (mg/kg/min) and HOMA-IR before the surgery. Glycaemia normalization was assessed by self-monitoring of blood glucose (FPG < 110 mg/dl (6.1 mmol/l) and postprandial PG < 140 mg/dl (7.8 mmol/l) in 1 month after surgery) as well as HbA1c < 6.0% (42 mmol/mol) in 3 months after surgery. ROC-curve identified insulin resistance predictive value of blood glucose normalization after bariatric surgery. Statistical analysis was performed using SPSS v.23.0. Results: All patients had severe insulin resistance at baseline (median M-index before surgery 1.535 mg/kg/min, HOMA-IR 10.0). Within 1 month after surgery 7 patients (16,7%) reached blood glucose normalization, within 3 months - 22 patients (52,4%), within 6 months - 31 patient (73,8%), in 12 months - 35 patients (83,3%). ROC-analysis showed that M-index within 1st month after surgery was predictive of blood glucose normalization; insulin resistance cut-off value was 1.876 mg/kg/min (Youden’s index). HOMA-IR and M-index in 3, 6 and 12 months after surgery didn’t predict glycaemia normalization. Conclusion: Baseline insulin resistance value defined as M-index > 1.876 mg/kg/min can be used to predict early blood glucose normalization within 1 month after bariatric surgery. Disclosure I. Sklyanik: None. E. Shestakova: Employee; Spouse/Partner; AstraZeneca. Speaker’s Bureau; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novartis Pharma K.K., Novo Nordisk A/S, Sanofi-Aventis, Takeda Pharmaceutical Company Limited. I. Stafeev: None. S. Michurina: None. A. Karmadonov: None. A.V. Vorotnikov: None. K. Yahyaev: None. A. Yurasov: None. M. Menshikov: None. A. Mayorov: Speaker’s Bureau; Self; Abbott, LifeScan, Inc., Novo Nordisk A/S, Roche Diabetes Care, Sanofi-Aventis. Y.V. Parfyonova: None. M.V. Shestakova: None. Funding Russian Science Foundation (17-15-01435)

Background: Under normal physiological conditions, adipose derived stem cells (ADSC) maintain adipose tissue homeostasis by responding to metabolic loading through proliferation and differentiation. Nevertheless, in T2DM their properties might be compromised. ADSC give rise to thermogenic beige adipocytes that make a significant contribution into excess energy utilization in obesity. We compared ADSC response to beiging inductors in obese patients with type 2 diabetes mellitus (T2DM) and with normal glucose tolerance (NGT). Methods: We collected subcutaneous fat biopsies from 5 obese NGT (BMI>35kg/m2) and 5 obese T2DM patients during bariatric surgery. ADSC were enzymatically isolated and underwent white and beige adipogenic differentiation. UCP-1 level was evaluated by RT-PCR and Western blot. Expression of lipid metabolism and electron transport chain (ETC) genes were analyzed by RT-PCR. ROS production was evaluated by fluorescent microscopy. Results: UCP-1 expression was decreased in beige adipocytes from T2DM patients in mRNA and protein levels. Nevertheless, expression and phosphorylation of lipolytic proteins were equal in beige adipocytes of NGT and T2DM groups. Expression analysis of ETC genes also has not shown any statistically significant differences. All the while, we revealed increased mitochondrial ROS production in T2DM beige adipocytes during beige differentiation. Conclusions: These results indicate association of ADSC thermogenic potential and T2DM development. Decreased UCP1 level in complex with normal lipolysis and ETC activity in beige adipocytes from T2DM patients may be liable to elevated ROS level, known to initiate mitochondria damage and insulin resistance. Disclosure S. Michurina: None. I. Stafeev: None. I. Sklyanik: None. E. Shestakova: Employee; Spouse/Partner; AstraZeneca. Speaker’s Bureau; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novartis Pharma K.K., Novo Nordisk A/S, Sanofi-Aventis, Takeda Pharmaceutical Company Limited. A. Yurasov: None. K. Yahyaev: None. E. Ratner: None. M. Menshikov: None. M.V. Shestakova: None. Y.V. Parfyonova: None. Funding Russian Science Foundation (17-15-01435)

BACKGROUND: Since the obtaining of data on the effect of Alogliptin towards the lipid profile, body weight and blood pressure (BP) of patients, the additional analysis of the results of the ENTIRE study, completed in the Russian Federation in 2018, was conducted. AIMS: Assess the dynamics of HbA1c, body weight, fats indices, blood pressure (BP), and characterize the profile of the patient who received the maximum clinical benefit on treatment of Alogliptin therapy in the ENTIRE study. MATERIALS AND METHODS: A prospective non-interventional observational study that included patients aged 18 years and older with first-onset type 2 diabetes mellitus (T2DM) or patients with T2DM who did not achieve their glycemic targets during the previous therapy. RESULTS: A decrease in glycated hemoglobin (HbA1c) by more than 0.5% was detected in 73.5% of patients. The most significant absolute decrease of HbA1c was noticed in patients with initially higher values. Younger patients with a shorter duration of T2DM showed the more often compensation of carbohydrate metabolism. The average loss of weight was -2.64.2 kg. 76.6% of patients showed the loss of weight. The most significant decrease in body weight was noticed in patients with a large initial body mass index and a shorter duration of the disease. 74.7% of patients showed a decrease of the level of low-density lipoproteins (LDL). The most significant absolute decrease in LDL was noticed in patients with initially higher values and more often in younger people with a shorter duration of T2DM. The average decrease in systolic blood pressure (BP) was 5.90.3 mm Hg; the average decrease in diastolic blood pressure (BP) was 2.70.2 mm Hg. 59% of patients showed decrease of blood pressure during the group analyzing. The most frequent BP reduction was observed in younger patients with shorter duration of T2DM. At the same time, a more significant absolute decrease in blood pressure was noticed in patients with initially higher indicators, and an increase, on the contrary, was observed in patients with initially lower indicators. CONCLUSIONS: The intensification of Alogliptin therapy allowed to achieve the compensation of carbohydrate metabolism, moderate decrease of body weight, blood pressure and LDL indices within the majority of patients with T2DM. The most frequent achievement of HbA1c targets was noticed in young patients with a shorter duration of T2DM.

Background : At present a lot of attention is paid to the so-called “metabolically healthy obesity”. More than a half of patients with prolonged history of obesity lack any carbohydrate metabolism disorders. Unfortunately, physiological factors forming the foundation of a favorable metabolic profile in such patients are not sufficiently defined. Aims : Evaluation of insulin resistance (IR) degree, the level of insulin secretion by pancreatic β-cells, and the contribution of both these mechanisms to the maintenance of normal carbohydrate metabolism in patients with prolonged history of obesity. Methods : An observational cross-sectional non-blinded selective comparative case-control study was performed. Patients with prolonged history of obesity without carbohydrate metabolism disorders and with type 2 diabetes mellitus (DM2) were included into the study. The following parameters were analyzed: IR parameters (М-index, HOMA-IR); insulin secretion parameters (НОМА-%β and insulinogenic index, glucose disposition index, GDI); body composition indices (total body fat and visceral fat area). Results : 68 patients participated in the study: 34 patients with obesity and normal carbohydrate metabolism («Obesity and NCM» group), and 34 patients with obesity and DM2 («Obesity and DM2» group); both groups were matched by body mass index, known obesity duration, and sex ratio (males/females) in each group. «Obesity and NCM» groups significantly differed from «Obesity and DM2» group by the following parameters: lower IR level (М-index median 4.13 vs 1.52 mg/kg/min, p

Aim. This study aims to analyse the rhythm and levels of incretins and neuropeptides secretion in patients with Cushing disease (CD) and acromegaly, and thus specify the pathogenesis of carbohydrate metabolism disturbances. Matherials and methods. In this study, 42 patients (mean age, 37.5 years) with CD and acromegaly were enrolled. All patients were newly diagnosed with CD and acromegaly, and none had a history of previous drug therapy, radiotherapy or pituitary surgery. All patients underwent OGTT, during which glucose, glucagon, GLP-1, GLP-2, GIP and ghrelin were evaluated at 0, 30 and 120 min, respectively. Results. During OGTT, glucose levels were not significantly different between the groups. The relevance of pre-diabetes was higher in patients with CD. In these patients, while glucagon levels were substantially higher at all cut-off points than those in controls (р = 0.001), GIP secretion was slightly lower. The acromegaly group was characterised by an inverse rhythm of GIP secretion with no peak level at 30 min. In addition, GLP-1 levels were significantly higher in patients with CD (р = 0.047). Similarly, GLP-2 levels were also significantly higher in patients with CD than in those with acromegaly and controls (p = 0.001). Finally, ghrelin levels were significantly higher in patients with CD (р = 0.013) and acromegaly (р = 0.023). Conclusion. More pleiotropic actions of glucocorticoids can explain the higher relevance of carbohydrate metabolism disturbances in patients with CD. This can also be explained by higher levels of glucagon secretion, which do not depend on the type of carbohydrate metabolism disorder and are stimulated by a direct action of glucocorticoids on the glucagon receptor. GIP and GLP-1 secretion in patients with CD and acromegaly are characterised by the inverse rhythm with no peak levels, implying that these hormones do not play a crucial role in the development of carbohydrate disturbances in these patients. In contrast, GLP-2 and ghrelin seem to influence and potentially regulate glucose homeostasis in patients with CD and acromegaly.

Type 2 diabetes and obesity are two enormous epidemic diseases of the 21stcentury. Because obesity is a primary risk factor for type 2 diabetes development, patients with diabetes are frequently obese. This comorbidity makes it challenging for these patients to not only compensate diabetes but also bring their weight back to normal. Several anti-diabetic drugs cause weight gain, which augments insulin resistance, and thus demands anti-diabetic treatment intensification. For the treatment, it is crucial to find an anti-diabetic treatment drug that is efficient but does not cause weight gain. In the last few decades, new anti-diabetic drugs with minimal or decrementing effects on the body weight have been introduced. New molecules appearing in the anti-obesity treatment are capable of not only reducing weight but also compensating diabetes. This study focuses on the current anti-obesity and anti-diabetic treatment and optimal combinations for treating comorbid patients.

Dear Colleagues! We are glad to present the8th Editionof Standards of Diabetes Care. These evidence-based guidelines were designed to standardize and facilitate diabetes care in all regions of the Russian Federation. The Standards are updated on the regular basis to incorporate new data and relevant recommendations from national and international clinical societies, including World Health Organization Guidelines (WHO, 2011, 2013), International Diabetes Federation (IDF, 2011, 2012, 2013), American Diabetes Association (ADA, 2012, 2017), American Association of Clinical Endocrinologists (AACE, 2017), International Society for Pediatric and Adolescent Diabetes (ISPAD, 2014) and Russian Association of Endocrinologists (RAE, 2011, 2012, 2015). Current edition of the “Standards” also integrates results of completed randomized clinical trials (ADVANCE, ACCORD, VADT, UKPDS, SAVOR, TECOS, LEADER, EMPA-REG OUTCOME, etc.), as well as findings from the national studies of diabetes mellitus (DM), conducted in close partnership with a number of Russian hospitals. Latest data indicates that prevalence of DM in the world increased during the last decade more than two-fold, reaching some 415 million patients by the end of 2015. According to the current estimation by the International Diabetes Federation, 642 million patients will be suffering from DM by 2040. These observations resulted in the UN Resolution on Diabetes 61/225 passed on 20.12.2006, and in 2011 - UN Political Declaration, addressed to national health systems, calling for the establishment of multidisciplinary strategy in the prevention and control of non-communicable diseases, where special attention is drawn to the problem of diabetes as one of the leading causes of disability and mortality. Like many other countries, Russian Federation experiences a sharp rise in the prevalence of DM. According to Russian Federal Diabetes Register, there are at least 4.35 million patients with DM in this country by the end of 2016 (3% of population) with 92% (4 million) – Type 2 DM, 6% (255 th) – Type 1 DM and 2% (75 th) – other types of DM. However, these results underestimates real quantity of patients, because they consider only registered cases. Results of Russian epidemiological study (NATION) confirmed that only 50% of Type 2 DM are diagnosed. So real prevalence of patients with DM in Russia is no less than 8-9 million patients (about 6% of population). This is a great long-term problem, because a lot of patients are not diagnosed, so they don’t receive any treatment ant have high risk of vascular complications. Severe consequences of the global pandemics of DM include its vascular complications: nephropathy, retinopathy, coronary, cerebral, coronary and peripheral vascular disease. These conditions are responsible for the majority of cases of diabetes-related disability and death. Current edition of the “Standards” emphasizes the patient-oriented approach in making decisions on therapeutic goals, such as levels of glycaemia and blood pressure. It also features updated guidelines on the management of Type 2 DM and its vascular complications, added information about bariatric surgery as a method of treatment of DM with morbide obesity. This text represents a consensus by the absolute majority of national experts, achieved through a number of fruitful discussions held at national meetings and forums. These guidelines are intended for endocrinologists and diabetologists, primary care physicians, cardiologists and other medical professionals involved in prevention and treatment of DM. On behalf of the Working Group

Background Obesity, remaining a topical issue of modern medicine, leads to development of latent inflammation and insulin resistance in adipose tissue with subsequent development of type 2 diabetes mellitus (T2DM). Among patients with obesity, patients with obesity and normal glucose tolerance (NGT) are often encountered. In our study we have tested the hypothesis that low proliferative potential of adipose derived stromal cells (ADSC) associates with reduced formation of new fat depots, excess accumulation of fat in the functional adipocytes and their hypertrophy, resulting in fat inflammation and insulin resistance. Methods We screened two groups of obese patients with or without T2DM, matched for BMI, age, and duration of obesity to test the hypothesis that hypertrophy and decreased renewal of adipocytes may underlie transition from obesity to T2DM. All patients were matched for carbohydrate metabolism (fasting blood glucose level, glycated hemoglobin, HOMA-IR index and M-index). The subcutaneous and omental fat tissue biopsies were obtained during bariatric surgery from obese individuals with or without T2DM. The morphology and immunophenotype of subcutaneous and omental fat was assessed in frozen tissue sections. ADSC were isolated from both types of fat tissue biopsies and screened for morphology, proliferative potential and inflammatory status. Results The non-diabetic patients had normal carbohydratemetabolism andmoderate insulin resistancemeasured byHOMA-IR and hyperinsulinemic clamp (M-index),while T2DM patientswere extremely insulin resistant by both indexes. The average size of diabetic adipocytes was higher than that of non-diabetic in both subcutaneous and omental fat tissues, indicating adipocyte hypertrophy in T2DM. We have shown that ADSC from T2DM patients had significantly higher level of inflammation. According to measurement of p62 expression and LC3 modification we can say that ADSC from T2DM patients have less autophagy level compare with ADSC from NGT patients. Immunohistochemistry have shown that patients with T2DM have much more infiltration of CD68+-cells in subcutaneous and omental adipose tissue and immunophenotype (balance of M1-M2 macrophages) of adipose tissue at this patients shift toward inflammatory state. Conclusion These results suggest that decreased proliferation and increased hypertrophy of diabetic ADSC may lead to reduced insulin sensitivity via increased inflammation mediated by M1-macrophages and JNK1/2 pathway. Acknowledgement/Funding This work was supported by RSF grant #17-15-01435

Objective To compare basal insulin and mTOR signaling in subcutaneous fat of obese T2DM vs. obese subjects with normal glucose tolerance (NGT), and correlate it with clinical parameters of carbohydrate metabolism and incretin secretion profiles. Methods Recruited were 22 patients with long (>10 years) and morbid (BMI > 35 kg/m2) obesity, 12 of which had NGT and 10 had T2DM. Hyperinsulinemic-euglycemic clamp test and HOMA-IR were used to measure insulin resistance. Blood samples taken at 0, 30 and 120 min of food load test were used to assess incretin profile, insulin and glucose levels. Amount of total and visceral fat was determined by bioelectrical impedance analysis. Subcutaneous fat biopsies were obtained during bariatric surgery for all patients and analyzed by western blots. Results As assessed by western blots of insulin receptor substrate (IRS), Akt, Raptor, Rictor, mTOR and S6K1, the basal insulin signaling and mTORC activities were comparable in NGT and T2DM groups, whereas phosphorylation of AS160 was significantly lower and that of serum and glucocorticoid-induced kinase (SGK) was significantly higher in T2DM group. Various correlations were found between the degree of insulin resistance and amount of visceral fat, changes in incretin profile, glucose metabolic parameters and phosphorylation level of AS160, incretin secretion profile and phosphorylated levels of AS160 or SGK1. Conclusion Altered phosphorylation of AS160 and SGK1 is associated with obese T2DM phenotype.

Objective Adipose derived stem cells (ADSC) are defective in metabolic disorders in various functionalities and properties including differentiation, multipotent state, metabolism and immunomodulation. However, the role of ADSC beiging potential in promoting of type 2 diabetes mellitus (T2DM) development remains unclear. Here we uncover association between potential of subcutaneous ADSC to beige differentiation and T2DM in patients with obesity. Methods ADSC were isolated from subcutaneous adipose tissue of patients with long morbid obesity (BMI > 35 kg/m2) and normal glucose tolerance (NGT) or T2DM. ADSC were differentiated into white or beige adipocytes and levels of thermogenic markers, lipid metabolism and electron transport chain (ETC) genes was analyzed by Western blotting and RT-PCR. ROS production was estimated by fluorescent microscopy. Results We have shown decreased UCP-1 expression in beige adipocytes from T2DM patients. Nevertheless, signal and expression activities of lipolysis were equal in NGT and T2DM beige adipocytes. Expression analysis of ETC genes also has not shown any statistically significant differences. Interestingly, we revealed increased mitochondrial ROS production in T2DM beige adipocytes during beige differentiation. Conclusions In summary, compromised UCP1 expression in beige adipocytes of T2DM patients may cause increase of mitochondrial ROS. Elevated oxidative level is liable to act as damaging mechanism leading to insulin resistance or, alternatively, serve as compensatory mechanism for thermogenesis activation.

Aim . To evaluate the prevalence of undiagnosed type 2 diabetes mellitus (T2DM) among patients with cardiovascular disease. Materials and methods . T2DM screening programs among patients with cardiovascular disease were held from 2013 to 2014 in several Russian cities. In total, 1001 patients aged ≥40 years with hypertension and/or atherosclerotic disease and without prior diagnosis of T2DM were screened in outpatient cardiology clinics. T2DM diagnosis was based on fasting plasma glucose levels, glycated haemoglobin (HbA1c) and/or oral glucose tolerance test (OGTT) results. Blood pressure (BP), family history of T2DM, cardiovascular disease, total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglyceride levels were analysed. Results . Fasting glucose was measured in 1000 (99.8%) patients, HbA1c was measured in in 623 (62.2%) and OGTT was performed in 286 (2.6%). Fasting glucose detected 8% of newly diagnosed T2DM; among patients who underwentHbA1c measurement, the prevalence of T2DM was 10.91%, and among patients who underwent OGTT, the prevalence was 13.99%. Depending on the chosen test, the prevalence of undiagnosed pre-diabetes (impaired fasting glycaemia and impaired glucose tolerance) was in the range of 14.4%–36.4%. The majority of patients with T2DM diagnosed by OGTT did not have target blood pressure and lipid levels; 67.5% had elevated systolic BP, 47.5% had elevated diastolic BP, 90.9% had high LDL (≥1.8 mmol/l) and 52.9% had high triglyceride levels (≥1.7 mmol/l). Conclusion . A high prevalence of undiagnosed T2DM (from 8% to 13.99%, depending on the diagnostic criteria) and pre-diabetic state in patients with cardiovascular disease may require screening for T2DM in this high-risk group.

Some current international and national guidelines for type 2 diabetes recommend intensive start of antidiabetic treatment if HbA1c is more than 7.5% at the moment of diagnosis of type 2 diabetes. The article speculates on the possible benefits of combination therapy at the very early stages of type 2 diabetes progression.

Recent decades have been marked by advances in omics sciences based on high-throughput technologies, which have enabled the measurement of enormous numbers of molecules in biosamples. This study investigated the capacity of blood plasma metabolome to be used for diagnostics. Blood plasma samples ( n = 120) were methanol-treated to remove proteins. The remaining metabolite fractions were directly analyzed by mass spectrometry. Various diagnostic substances with different molecular weights, chemical classes, and plasma abundances were directly estimated from mass spectra or predicted from mass spectra by neural networking. Predicted levels of these substances were correlated ( r = 0.51–0.78) with their actual values. Blood plasma metabolomics may be considered as a diagnostic tool capable of substituting for several clinical laboratory tests.

Objective to consider the protection of both the state and the taxpayer in order to improve the implementation of laws and decisions of tax bodies basing on the fact that the central problem of tax legislation is the problem of nonexecution of the Taxation Code and judicial acts. Methods general and specific scientific methods of research were used including systematic and structured problemtheoretical formallegal logical methods etc. Results the reasons are analyzed of nonexecution or improper execution of legislative acts and court decisions by taxpayers. It is concluded that the taxpayer has fewer possibilities to force the tax body to execute the court decision while these possibilities of the taxpayer are hidden in the Taxation Code. Recommendations are given to increase the opportunities for taxpayers to protect their rights from the arbitrariness of bureaucratic bodies means of taxpayersrsquo rights protection are systematized. Scientific novelty the main problem of nonexecution of the laws and decisions of tax bodies is the presence of persons who do not fulfill their responsibilities as taxpayers. In addition the reasons of nonexecution of laws and decisions of tax authorities are not systematized as well as the issues of combating these trends and the statutory possibilities of the taxpayerrsquos nonexecution of the laws and decisions of tax bodies as a means of protecting their interests. However the development of the law enforcement system can be achieved by improving the taxpayersrsquo rights protection. The author proposes specific measures to improve the taxpayer protection which will increase the citizens awareness and the budget replenishment. Practical significance of the study is to protect the state by improving the protection of every citizen and legal entity. The taxpayer should know that the state is not only a punitive mechanism but a mechanism that can protect a particular taxpayer. nbsp

Objective. Glucose-dependent insulinotropic polypeptide (GIP) as well as glucagon-like peptide-1 (GLP-1) is intestinal incretin hormone that stimulates insulin secretion in response to feeding. Much evidence of GIP contribution to obesity development has been found recently. Aim. The aim of the study was to evaluate glucose-stimulated GIP and GLP-1 secretion in people with type 2 diabetes (T2D) risk factors and different body mass index (BMI). Materials and methods. Total GIP and GLP-1 secretion was estimated in 127 patients with T2D risk factors during OGTT (75 g glucose) on 0, 30 and 120 minutes. Results. Patients with BMI≥ 35 kg/m 2 had significantly higher fasting and stimulated GIP levels than participants with less BMI. GIP secretion was also higher in patients was insulinresistance, estimated by HOMA-IR, comparing to non-insulinresistant patients. Difference in GLP-1 secretion in patients within several BMI groups was nonsignificant. Conclusion. Our results suggest GIP is related to obesity degree, that means it can play a role in lipid metabolism and obesity development.

Type 2 diabetes mellitus (T2 DM) is often seen in patients with obesity. Bariatric surgery, aimed to decrease body weight, can often help those patientsto improve glycemic status. After some of bariatric operations patients reach normoglycemia in few days, the fact that cant be explained onlyby reduction in weight. Recent trials revealed that the reorganization of gastrointestinal tract provides hypoglycemic effect of such operations. Thisarticle explains the role of proximal and distal gut in pathophysiology of T2 DM.

Introduction. The relevance of carbohydrate metabolism studying in patients with Cushing disease can be explained by frequent occurrence of glucose metabolism disturbances on the one hand, and difficulties in glucose-lowering therapy in these patients on the other. The effectiveness of hyperglycaemia treatment may be reduced due to difficulties in remission / cure of the underlying disease, as well as to the use of specific drug-therapy, leading to the hyperglycaemia. There is a growing interest in research aimed at studying the role of incretin system in the pathogenesis of secondary hyperglycemia associated with neuroendocrine diseases recently.Methods. A total of 20 patients with Cushing disease were included, (19 female and 1 male), the mean age was 37.5 years (18-69). All of the patients were diagnosed with Cushing disease for the first time (using urinary free cortisol levels and MRI-data); none of them had a history of previous drug therapy, radiotherapy or pituitary surgery. The mean HbA1c level was 5,8% (5,3-6,2). All patients underwent OGTT, during which glucose, glucagon, GLP1, GLP2, GIP, ghrelin were measured at 0, 30 and 120 min respectively. The control group included 21 patients without previous history of carbohydrate metabolism disturbances. After OGTT 57% were presented without any carbohydrate metabolism disturbances, 28,57% presented with prediabetes and 14,43% were diagnosed with diabetes.Results. After glucose levels analyzing 40% of patients were diagnosed with early carbohydrate metabolism disturbances ,15% were diagnosed with diabetes. After glucose intake a slight inrease in glucagon levels with a peak by 30’ (p=0,001) compared to gradually decreasing levels in controls was observed . The levels of GIP during OGTT were not significantly different compared to control group. GLP-1 and GLP-2 levels were significantly higher compared to controls (p=0,017 and p