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Aim: To describe the design of the SOUL trial (Semaglutide cardiOvascular oUtcomes triaL) and the baseline clinical data of its participants. Materials and methods: In SOUL, the effects of oral semaglutide, the first oral glucagon-like peptide-1 receptor agonist, on the risk of cardiovascular (CV) events in individuals with type 2 diabetes and established atherosclerotic CV disease (ASCVD) and/or chronic kidney disease (CKD) will be assessed. SOUL is a randomized, double-blind, parallel-group, placebo-controlled CV outcomes trial comparing oral semaglutide (14 mg once daily) with placebo, both in addition to standard of care, in individuals aged ≥50 years with type 2 diabetes and evidence of ASCVD (coronary artery disease [CAD], cerebrovascular disease, symptomatic peripheral arterial disease [PAD]) and/or CKD (estimated glomerular filtration rate

Background: Beta blockers, mainly propranalol, are usually administered to control heart rate in patients with thyrotoxicosis, especially when congestive heart failure presents. However, when thyrotoxicosis is not controlled, heart rate may be difficult to control even with maximal doses of propranolol. This presentation alerts physicians to the possibility of using ivabradine, a selective inhibitor of the sinoatrial pacemaker, for the control of heart rate. Case presentation: We present a 37-year-old woman with thyrotoxicosis and congestive heart failure whose heart rate was not controlled with a maximal dose of beta blockers during a thyroid storm. The addition of ivabradine, a selective inhibitor of the sinoatrial pacemaker, controlled her heart rate within 48 hours. Conclusion: Ivabradine should be considered in patients with thyrotoxicosis, including those with heart failure, in whom beta blockers are insufficient to control heart rate

The current definition of prediabetes is controversial and subject to continuous debate. Nonetheless, prediabetes is a risk factor for type 2 diabetes, is highly prevalent and is associated with diabetic complications and mortality. Thereby, it has the potential to become a huge strain on healthcare systems in the future, necessitating action from legislators and healthcare providers. But how do we best reduce its associated burden on health? As a compromise between differing opinions in the literature and among the authors of this article, we suggest stratifying individuals with prediabetes according to estimated risk and only offering individual-level preventive interventions to those at high risk. At the same time, we argue to identify those with prediabetes and already established diabetes-related complications and treat them as we would treat individuals with established type 2 diabetes. Graphical abstract

Findley first proposed the presence of age-related dysfunction of the hypothalamic-neurohypophyseal-renal axis more than 60 years ago. More sophisticated studies have since corroborated his findings. As a result, it is now clear that multiple abnormalities in water homeostasis occur commonly with aging, and that the elderly are uniquely susceptible to disorders of body volume and osmolality. This article summarizes the distinct points along the hypothalamic-neurohypophyseal-renal axis where these changes have been characterized, as well as the clinical significance of these changes, with special attention to effects on cognition, gait instability, osteoporosis, fractures, and morbidity and mortality.

Aims: To describe the one-week and 12-month prevalence of musculoskeletal pain in the upper and lower extremities and consequences in relation to care seeking, leisure time activity, and work life in patients with type 1 and 2 diabetes. Methods: A cross-sectional survey including adults diagnosed with type 1 and 2 diabetes from two Danish secondary care databases. Questions covered pain prevalence (shoulder, elbow, hand, hip, knee, ankle) and its consequences based on the Standardised Nordic Questionnaire. Data was presented using proportions (95 % confidence intervals). Results: The analysis included 3767 patients. The one-week prevalence was 9.3–30.8 % and 12-month prevalence 13.9–41.8 %, highest for shoulder pain (30.8–41.8 %). The prevalence was similar between type 1 and 2 diabetes for the upper extremity, but higher in type 2 for the lower extremity. Women had a higher pain prevalence for any joint for both diabetes types, while estimates did not vary between age groups (

Aims/Introduction Imeglimin is a new antidiabetic drug structurally related to metformin. Despite this structural similarity, only imeglimin augments glucose-stimulated insulin secretion (GSIS), with the mechanism underlying this effect remaining unclear. Given that glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) also enhance GSIS, we examined whether these incretin hormones might contribute to the pharmacological actions of imeglimin. Materials and Methods Blood glucose and plasma insulin, GIP, and GLP-1 concentrations were measured during an oral glucose tolerance test (OGTT) performed in C57BL/6JJcl (C57BL/6) or KK-Ay/TaJcl (KK-Ay) mice after administration of a single dose of imeglimin with or without the dipeptidyl peptidase-4 inhibitor sitagliptin or the GLP-1 receptor antagonist exendin-9. The effects of imeglimin, with or without GIP or GLP-1, on GSIS were examined in C57BL/6 mouse islets. Results Imeglimin lowered blood glucose and increased plasma insulin levels during an OGTT in both C57BL/6 and KK-Ay mice, whereas it also increased the plasma levels of GIP and GLP-1 in KK-Ay mice and the GLP-1 levels in C57BL/6 mice. The combination of imeglimin and sitagliptin increased plasma insulin and GLP-1 levels during the OGTT in KK-Ay mice to a markedly greater extent than did either drug alone. Imeglimin enhanced GSIS in an additive manner with GLP-1, but not with GIP, in mouse islets. Exendin-9 had only a minor inhibitory effect on the glucose-lowering action of imeglimin during the OGTT in KK-Ay mice. Conclusions Our data suggest that the imeglimin-induced increase in plasma GLP-1 levels likely contributes at least in part to its stimulatory effect on insulin secretion.

Background. The COVID-19 pandemic has an impact on the incidence of type 1 diabetes and frequency of diabetic ketoacidosis. However, the exact relationships are unclear. It is also not known whether this is a short-term phenomenon or whether the effects have long-term relevance. Furthermore, it is not known whether these changes during the pandemic are due to direct effects of SARS-CoV-2 or to changes in the patient’s environment during the pandemic. Methods. We conducted an extensive literature search on PubMed. For the estimation of relative risks of new-onset type 1 diabetes, we applied a Poisson regression model and for the comparison of incidences and we included the logarithm of person-years. Furthermore, we performed a meta-analysis using the logarithm of the relative risk for new-onset type 1 diabetes as effect size. Results. Pooling the relative risk estimates in a random-effects meta-analysis revealed that the type 1 diabetes incidence rate increased by 20% (relative risk 1.200 (95% CI 1.125, 1.281)), and that the risk of new-onset type 1 diabetes after a SARS-CoV-2 infection increased by 62% (relative risk 1.622 (95% CI 1.347, 1.953)) compared with the prepandemic period. Conclusion. There is considerable evidence that there is an increase in type 1 diabetes in children during the COVID-19 pandemic. Many studies suggesting a direct effect of SARS-CoV-2 have methodological weaknesses. As no evidence of an increase in presymptomatic cases with isolated islet autoimmunity was found, this could also suggest an accelerated transition from presymptomatic patients to clinically overt type 1 diabetes. Furthermore, there was a marked exacerbation of the preexisting increase in the prevalence of diabetic ketoacidosis at diagnosis of type 1 diabetes during the pandemic. Both the increased incidence of paediatric type 1 diabetes and the higher prevalence of diabetic ketoacidosis at diagnosis led to a massive rise in the number of children with diabetic ketoacidosis during the pandemic.

Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is an X-linked disease caused by activating mutations in the arginine vasopressin (AVP) receptor-2 (AVPR2) gene. Affected patients excrete concentrated urine despite very low levels of AVP, and consequently develop euvolemic hyponatremia. Due to its low frequency, patients may be misdiagnosed and treated incorrectly. We report two related male infants with NSIAD that was initially confused with hyporeninemic hypoaldosteronism (HH). First, a 2-month-old male presented with hyponatremia, low plasma osmolality, relatively high urine osmolality, and low plasma renin-aldosterone levels. These clinical and laboratory findings were compatible with syndrome of inappropriate antidiuretic hormone secretion without apparent cause. Consequently,fludrocortisone was initiated with a presumptive diagnosis of HH While correction of hyponatremia, fludrocortisone treatment led to hypertension and discontinued in a short time. The second patient at age of 1 year was admitted with a history of oligohydramnios, four times hospitalizations due to hyponatremia since birth, and a diagnosis of epilepsy. Similarly, the second infant had clinical and laboratory findings compatible with syndrome of inappropriate antidiuretic hormone secretion with no apparent cause. Fluid restriction normalized his serum sodium despite plasma AVP level was undetectable. In both infants, AVPR2 gene analysis revealed a known mutation (c.409C>T; p.R137C) and confirmed the diagnosis of NSIAD. In conclusion, NSIAD should be considered in all patients with unexplained euvolemic hyponatremia despite high urine osmolality. In case of unawareness from NSIAD, plasma renin-aldosterone profile can be confused with HH, especially in the infants. 34645113

Variants of the melanocortin-4 receptor (MC4R) gene are the most common cause of monogenic obesity. In this situation; while obesity cannot be controlled with diet and exercise, it was shown that Glucagon-like-peptide-1 receptor agonists (GLP-1 RA) provide weight loss in short term. In this paper, we present our experience with Liraglutide treatment in an adolescent patient carrying MC4R gene variant. A female patient had admitted first at the age of 12.5 years with a complaint of progressive weight gain. She had a marked excess of appetite since infancy. In the physical examination of the pubertal female patient with a body mass index (BMI) of 36.1kg/m2 (3.48 SDS), there was no pathological finding except diffuse acanthosis nigricans. Laboratory examinations revealed only insulin resistance. Weight loss couldn't be achieved with lifestyle changes, metformin and orlistat treatments In genetic examination, a sporadic heterozygous c.206T>G(p.I69R) variant (reported previously) was found in the MC4R gene. GLP-1 RA Liraglutide treatment was initiated and a loss of 19.2% reduction was achieved in the patient's body weight and BMI at the end of 32 weeks. However, the patient, whose treatment compliance was disrupted due to significant gastrointestinal complaints, returned to her former weight within a few months after treatment was stopped. In our case carrying a pathogenic variant in the MC4R gene, decrease of appetite and weight loss were achieved with Liraglutide treatment, but this situation could not be maintained. In such cases, there is a need for effective and tolerable treatment options.

Prolyl endopeptidase-like (PREPL) deficiency (MIM#616224) is a rare congenital disorder characterised by neonatal hypotonia and feeding difficulties, growth hormone (GH) deficiency and hypergonadotropic hypogonadism. This syndrome is an autosomal recessive disease resulting from mutations in the PREPL gene (MIM#609557). Herein we report a 7-year-old female patient with biallelic mutations in PREPL (c.1528C>T in one allele and a whole gene deletion in the other) with early growth impairment in infancy. Growth hormone deficiency was confirmed at 20 months of life. Recombinant growth hormone treatment was introduced with a good response. Her clinical features were similar to those of previously reported cases. The description of new patients with PREPL deficiency syndrome is essential to better delineate the phenotypic and genotypic spectrum of the disease.

17β-Hydroxysteroid dehydrogenase 3 deficiency (17HSD3) is a rare autosomal recessive cause of 46, XY disorders of sex development resulting from HSD17B3 gene mutations, in which conversion of androstenedione to testosterone is impared. The clinical signs of 17HSD3 deficiency depend on the residual activity of the enzyme. The diagnosis of 17HSD3 deficiency is based on reduced testosterone/androstenedione ratio (T/AD < 0.8). Patients are usually assigned at birth and raise as female. If the diagnosis is made before puberty, gonadectomy is recommended, taking into account the risk of masculinization during the puberty and estrogen therapy initiation in this period. If the diagnosis of 17HSD3 deficiency is established during puberty, when virilization manifests, the therapeutic strategy is based on the results of comprehensive psychological testing and gender identity of a patient. In patients with more pronounced masculinization or diagnosis established shortly after birth, who are assigned at birth and raise as male, testosterone therapy is used to achieve a male phenotype. The 17HSD3 deficiency and virilization often result in a change of gender identity during puberty. The article presents a clinical case of 17-βhydroxysteroid dehydrogenase type 3 deficiency with late diagnosis due to parental will. The diagnostic approaches and management of the disease are also described.

Hypogonadism in men can cause the development of obesity, primarily abdominal, associated with high cardio-metabolic risks. Chronic obesity, in turn, almost inevitably leads to the manifestation of hypogonadism, which requires treatment and aggravates cardiovascular risks. Testosterone therapy, prescribed according to indications, has a significant positive effect not only on a man’s sexual function, but also on body weight, carbohydrate and lipid metabolism, bone metabolism and the emotional component of men’s health. The improvement of many metabolic parameters in men with verified hypogonadism occurs against the background of fairly long-term testosterone therapy. Hypogonadism and visceral obesity are now considered as components of the metabolic syndrome, mutually burden each other and require a comprehensive therapeutic approach.

In pregnancies of women with obesity or diabetes, neonates are often overgrown. Thus, the pregnancy period in these women offers a window of opportunity to reduce childhood obesity by preventing neonatal overgrowth. However, the focus has been almost exclusively on growth in late pregnancy. This perspective article addresses possible growth deviations earlier in pregnancy and their potential contribution to neonatal overgrowth. This narrative review focuses on six large-scale, longitudinal studies that included ∼14,400 pregnant women with at least three measurements of fetal growth. A biphasic pattern in growth deviation, including growth reduction in early pregnancy followed by overgrowth in late pregnancy, was found in fetuses of women with obesity, gestational diabetes mellitus (GDM), or type 1 diabetes compared with lean women and those with normal glucose tolerance. Fetuses of women with these conditions have reduced abdominal circumference (AC) and head circumference (HC) in early pregnancy (observed between 14 and 16 gestational weeks), while later in pregnancy they present the overgrown phenotype with larger AC and HC (from approximately 30 gestational weeks onwards). Fetuses with early-pregnancy growth reduction who end up overgrown presumably have undergone in utero catch-up growth. Similar to postnatal catch-up growth, this may confer a higher risk of obesity in later life. Potential long-term health consequences of early fetal growth reduction followed by in utero catch-up growth need to be explored.

BACKGROUND Checkpoint inhibitor–associated autoimmune diabetes mellitus (CIADM) is a distinct form of autoimmune diabetes that is a rare complication of immune checkpoint inhibitor therapy. Data regarding CIADM are limited. PURPOSE To systematically review available evidence to identify presentation characteristics and risk factors for early or severe presentations of adult patients with CIADM. DATA SOURCES MEDLINE and PubMed databases were reviewed. STUDY SELECTION English full text articles from 2014 to April 2022 were identified with a predefined search strategy. Patients meeting diagnostic criteria for CIADM with evidence of hyperglycemia (blood glucose level >11 mmol/L or HbA1c ≥6.5%) and insulin deficiency (C-peptide DATA EXTRACTION With the search strategy we identified 1,206 articles. From 146 articles, 278 patients were labeled with “CIADM,” with 192 patients meeting our diagnostic criteria and included in analysis. DATA SYNTHESIS Mean ± SD age was 63.4 ± 12.4 years. All but one patient (99.5%) had prior exposure to either anti-PD1 or anti–PD-L1 therapy. Of the 91 patients tested (47.3%), 59.3% had susceptibility haplotypes for type 1 diabetes (T1D). Median time to CIADM onset was 12 weeks (interquartile range 6–24). DKA occurred in 69.7%, and initial C-peptide was low in 91.6%. T1D autoantibodies were present in 40.4% (73 of 179) and were significantly associated with DKA (P = 0.0009) and earlier time to CIADM onset (P = 0.02). LIMITATIONS Reporting of follow-up data, lipase, and HLA haplotyping was limited. CONCLUSIONS CIADM commonly presents in DKA. While T1D autoantibodies are only positive in 40.4%, they associate with earlier, more severe presentations.

BACKGROUND: Insulinoma is a pancreatic neuroendocrine tumor that manifests by impaired carbohydrate metabolism with the development of hypoglycemic syndrome. The instrumental methods used at the present stage do not always make it possible to identify a tumor; moreover, the data obtained often contradict each other. Thus, the search for new possibilities of visualization of insulinoma is relevant.AIM: Evaluation of diagnostic effectiveness of scintigraphy with single-photon emission computed tomography combined with X-ray computed tomography (SPECT/CT) with 99mTc-Tectrotide for insulinoma in a Russian cohort of patients.MATERIALS AND METHODS: A single-centre (Endocrinology Research Centre of the Ministry of Health of the Russia), experimental, single-stage, controlled study. In the years 2017–2021 patients with pancreatic insulinoma (group 1) and hyperinsulinemic hypoglycemia of a different genesis (group 2) with negative or contradictory results of the 1st line imaging methods (ultrasound, magnetic resonance imaging (MRI), computed tomography (CT)) were included. All participants underwent the whole-body scintigraphy and low-dose SPECT/CT with 99mTc-Tectrotide (500–900 MBq). The studies were performed on a tomograph of the SPECT/GE Discovery NM/CT 670 using low-energy high-resolution collimators (LEHR) in the «whole body» mode.RESULTS: In the group 1 (n=21), according to the results of a pathomorphological study, the presence of 26 insulin-producing tumors was confirmed. Group 2 included 9 patients. According to the SPECT/CT with 99mTc-Tectrotide, 14 tumors were diagnosed in group 1 out of 26 insulin-producing tumors of the pancreas, and negative results were obtained in group 2 in 100% of cases. Thus, the sensitivity and specificity of the method were: 54%, 95% CI [33%; 73%] and 100%, 95% CI [68%; 100%], respectively.CONCLUSION: SPECT/CT with 99mTc-Tectrotide can detect insulinoma in 54% of cases with negative or contradictory results of 1st-line imaging methods (ultrasound, MRI, CT). This study can be effectively used as an alternative to SPECT/CT with 111In-octreotide, as a 2nd-line method for topical search for an insulin-producing pancreatic tumor.

BACKGROUND: The information available to date on the effect of metformin on the transcriptome and secretory capacity of adipocytes in human adipose tissue (AT) is scarce and contradictory. The study analyzed whether metformin in vitro modulates gene expression and secretion of adiponectin and leptin in the AT of subcutaneous (SAT), epicardial (EAT) and perivascular (PVAT) localization of patients with ischemic artery disease (IHD).AIM: To assess the effect of metformin at various concentrations (1 and 10 mmol / L) on the level of expression of adiponectin and leptin genes and their content in adipocytes of subcutaneous, epicardial and perivascular AT of patients with IHD.MATERIALS AND METHODS: The study included 134 patients with IHD and indications for direct myocardial revascularization by coronary artery bypass grafting (CABG). During the operation, biopsies of SAT, EAT and PVAT were obtained for 3–5 gram, which served as a source of adipocytes. Isolated adipocytes were cultured for 24 hours with and without metformin (1 and 10 mmol / L). After a day of incubation, the expression of the ADIPOQ and LEP genes and the level of secretion of adiponectin and leptin in the culture medium of adipocytes were determined. Statistical processing was performed using the GraphPad Prism 6 software package (GraphPad Software, La Jolla, CA, USA) and Statistica software, 6.1 (Dell Software, Inc., Round Rock, TX, USA).RESULTS: The adipocytes of the EAT and PVAT of patients with IHD were characterized by an imbalance in the adipokine system, manifested by a low level of ADIPOQ expression and a high LEP expression in comparison with adipocytes of the SAT. Metformin increased the level of ADIPOQ expression and its secretion by adipocytes regardless of their location, while a low concentration (1 mmol / L) in adipocytes of EAT had a stronger effect compared to 10 mmol / L. Metformin had a multidirectional effect on the level of leptin in adipocytes, which depended on their localization: both in low (1 mmol / L) and high concentrations (10 mmol / L), the drug reduced the level of LEP expression and protein secretion in the culture medium of adipocytes of the SAT. EAT had no significant effect on adipocytes. In PVAT, metformin increased the expression and secretion of leptin regardless of concentration.CONCLUSION: Metformin has a direct effect on adipocytes in SAT, EAT, and PVAT and is able to modulate their activity, which is a promising strategy for maintaining the balance of adipokines in AT, especially epicardial and perivascular localization.

Acromegaly is a severe neuroendocrine disease characterized by hypersecretion of growth hormone (GH) caused in 95% of cases by pituitary adenoma, which leads to the development of pathology of various organs and systems. The severity of the condition is due not only to the direct effect of somatotropic hormone on the body and the effect of the adenoma on the surrounding structures, but also to the age of the patient and complications associated with the disease. Improvement in treatment methods allows for a personalized approach to patient management, taking into account various aspects of the clinical case. It is important for a specialist to take into account comorbidity in acromegaly, both in terms of pathological disorders and the impact on the patient’s psycho-emotional state. We present a clinical case of successful treatment with somatostatin analogues (ASS) in a patient who is afraid of surgery and has cardiovascular complications of acromegaly. Since the onset of acromegaly, confirmed by an elevated level of insulin-like growth factor-1 (IGF-1) and an endosellar pituitary macroadenoma measuring 11x9.5x8 mm, ASS therapy was initiated in the patient. The choice in favor of conservative treatment was due to a burdened cardiovascular history and the patient’s fear of surgery. Within three years from the start of drug therapy, there was a significant improvement in overall well-being, a tendency to reduce the size of the pituitary adenoma, and biochemical remission was achieved. The clinical case described by us confirms the possibility of successful primary treatment of ASS in a patient with acromegaly, taking into account all individual characteristics.

In the fall of 2019, global health was confronted with a new RNA virus — severe acute respiratory syndrome coronavirus 2 SARS-CoV-2. Against the background of the rapid spread of infection, research centers around the world began to develop specific vaccines against COVID-19, using the accumulated experience and empirical data on the stereotypes of the structure and physiology of other viral agents of this family (severe acute respiratory syndrome virus (SARS) and Middle East respiratory syndrome (MERS). However, even before the development of anti-COVID vaccines, it was suggested that they are probably less effective in a number of individuals, in particular, in people who are overweight or obese. This hypothesis arose on the basis of past studies using vaccines for other purposes in this categories of people, as well as in numerous experiments on mice, thanks to which scientists came to the conclusion that, due to an excess amount of adipose tissue in the body, there is a state of a permanent inflammatory process, some immune dysfunction, and, as a result, a reduced local and systemic response. resistance against bacterial and viral agents.In this literature review, using current publications obtained by searching for “covid-19 vaccination and obesity” and “vaccination and obesity” in the PubMed databases and “covid-19 vaccination and obesity” and “vaccination and obesity” in the e- Library discusses changes in the immune response both to infection itself and to immunization in the presence of overweight or obesity.

BACKGROUND: Influence of obesity on the body at whole and with regard to metabolic changes is still unclear. In Russia there are a few data about prevalence of metabolic phenotypes among population based on epidemiological data.AIM: to assess the prevalence of metabolic phenotypes among citizens of Arctic area of the Russian Federation (in the Arkhangelsk city setting).MATERIALS AND METHODS: a cross-sectional study was conducted using a random sample of Arkhangelsk citizens (n=2380) 35–69 years old, which was obtained within a population study of cardiovascular diseases («Know your heart» (KYH)). The participants were divided into metabolic phenotypes according to the presence of obesity (BMI≥30 kg/m2) and metabolic syndrome (AHA/NHBLI): phenotype 1 — metabolically healthy normal weight, phenotype 2 — metabolically unhealthy normal weight, phenotype 3 — metabolically healthy obesity, phenotype 4 — metabolically unhealthy obesity.RESULTS: 2352 participants of KYH were included in the study, 982 (41,8%) men and 1370 (58,3%) women. Mean age was 53,9 (SD 9,7) years. The distribution of participants by metabolic phenotypes was as follows: 1167 (49,6%) persons had phenotype 1, 489 (20,8%) — phenotype 2, 248 (10,5%) — phenotype 3, 448 (19,1%) — phenotype 4. In men, the second common after the first phenotype was phenotype 2, while in women, the second position was shared by the 2nd and 4th phenotypes, which had approximately the same frequency. «Arterial hypertension» was the most prevalent component of metabolic syndrome and seen in 68–96% men and 38–94% women in the study with different phenotypes. The proportions of phenotypes with metabolic disorders increased with age.CONCLUSION: in a study of a random population sample within the framework of the concept of metabolic phenotypes, a half of the participants had no obesity and metabolic syndrome. Proportions of participants with metabolic disorders with and without obesity was 20% each. Only 10% of participants had «metabolically healthy» obesity. If excluding individuals without obesity and metabolic syndrome, the phenotype characterized by metabolic disorders in the absence of obesity was the most common among men. Phenotypes with metabolic disorders on the background of obesity or without obesity were equally common among women. The most common component of metabolic syndrome was «arterial hypertension». There was a tendency of accumulation of metabolic disturbances with age.

BACKGROUND: The model of obesity under experimental conditions is reproduced by using high-calorie diets in animals. It has been established that metabolic disorders cause meta-inflammation not only in peripheral organs and tissues, but also in brain structures. The search for effective neuroprotective antioxidants to suppress inflammatory processes in the cerebral cortex in obesity is an urgent task due to the widespread prevalence of this disease.AIM: to evaluate the effect of minor biologically active substances — carnosine (CAR) and α-lipoic acid (ALA) on the cytokine profile of the frontal cortex of the left hemisphere of the brain in Wistar male rats with obesity induced by a high-calorie choline-deficient diet.MATERIALS AND METHODS: The studies were carried out on male Wistar rats with an initial body weight of 150±10 g. The animals were randomized by body weight into 5 groups. For 8 weeks, rats of the 1st (control) group received a complete modified diet of AIN93M; rats of the 2nd group consumed a high-calorie choline-deficient diet (HCHDR), the fat content of which was 45%, fructose — 20% of the energy value of the diet; rats of the 3rd group received HCHDR with the addition of CAR at a dose of 75 mg per 1 kg of body weight; rats of the 4th group received HCHDR with the addition of ALA at a dose of 75 mg per 1 kg of body weight; rats of the 5th group received HCHDR with the addition of the CAR + ALA complex in a total dose of 150 mg per 1 kg of body weight. Animals were removed from the experiment by decapitation under ether anesthesia. The levels of triglycerides (Tg) and free fatty acids (FFA) in blood plasma (mmol) were determined on a biochemical analyzer (Konelab 20i, Thermo Clinical Labsystems Oy, Finland). Content of cytokines and chemokines (pg/ml): GM-CSF, IL-10, IL-17A, IL-12p40, IL-12p70, IL-1α, IL-2, IL-4, IL-5, IFN-γ, MCP-1, M-CSF, MIP-1α, MIP-2, MIP-3α, RANTES, and TNF-α in cerebral cortex lysates were determined by multiplex immunoassay using a Luminex 200 analyzer (Luminex Corporation, USA). To assess the relationship between the level of cytokines in blood plasma and changes in their concentrations under the influence of HCCDR in lysates of the cortex of the frontal lobe of the left hemisphere of the brain, the ratio was calculated: the level of cytokines pg/ml in blood plasma [1]/the content of cytokines pg/ml in lysates (pl/ lys) for each sample.RESULTS: On the model of obesity in rats, the presence of an inflammatory process in the cerebral cortex was established, as evidenced by an increase in the content of pro-inflammatory factors: IL-2, M-CSF, MIP-1α and RANTES and a decrease in the content of immunoregulatory cytokines of varying severity: IL-10, IL17A, IL-12p40, IL-12p70, TNF-a, MIP-2 and MIP-3α in group 2 rats. (HCHDR) compared with the control group. Enrichment of HCHDR with biologically active substances: CAR, ALA or their complex, ensured the normalization of lipid metabolism, as evidenced by the decrease in the ratio of circulating Tg to FFA in the blood serum of rats to control values: 1st gr. (control) — 1,04±0.23; 2nd gr. (HCHDR) — 1,64±0.63; 3rd gr. (CAR) — 0,98±0.31; 4th gr. (ALA) — 0,86±0.31; 5th gr. (CAR+ALA) — 1,02±0.38. Enrichment of HCHDR with CAR, ALA or their complex led to a decrease in the content of pro-inflammatory and apoptosis-regulating cytokines and chemokines in the cortex of the frontal lobe of the rat brain: IL-1α, IL-2, IL-17A, M-CSF, MCP-1, MIP3α and RANTES, along with an increase in the level of the anti-inflammatory cytokine IL-10, which indicates the suppression of the inflammatory process induced by the consumption of HCHDR in rats.CONCLUSION: The data obtained indicate the prospect of using CAR and ALA or their complex as neuroprotective antioxidants to reduce the inflammatory process in brain structures in obesity.

BACKGROUND: The global prevalence of vitamin D deficiency is currently a real threat due to association with major chronic non-communicable diseases. Abdominal obesity, hypertension, dyslipidemia, and hyperglycemia contribute significantly to cardiometabolic risk in late postmenopausal women.AIM: to assess the frequency of deficiency and insufficiency of 25(OH)D in late postmenopausal residents of Yekaterinburg; to establish associations of 25(OH)D serum concentration with components of metabolic syndrome and severity of menopausal symptoms.MATERIALS AND METHODS: During the period from October 2018 to March 2020 145 independently living late postmenopausal residents of Yekaterinburg were enrolled in a cross-sectional study. The following scope of data regarding each of the subjects was collected: complaints and anamnesis, anthropometry, diagnosis of metabolic syndrome, arterial hypertension and diabetes mellitus, assessment of 25 (OH)D level by the ECLIA method, LDL-C, HDL-C levels, serum TG by the enzymatic colorimetric method, as well as the evaluation of the modified menopausal index.RESULTS: Adequate serum level of 25(OH)D was detected in 20.6% patients, insufficiency and deficiency were found in 33.1 and 46.2% cases, respectively. In patients with vitamin D deficiency and insufficiency, the most frequent metabolic syndrome components were arterial hypertension (p=0.02; OR 3.5; CI 1.2–10.6) and abdominal obesity (p=0.03; OR 2.8; CI 1.1–7.2). Vitamin D deficient subjects had significantly lower serum HDL and increased TG levels (p=0.04), compared to the adequately provided 25(OH)D patients. Vitamin D levels were not associated with the severity of menopausal symptoms in late postmenopausal women. Regular daily intake of 400–2000 IU of colecalciferol contributed to higher serum 25(OH)D level.CONCLUSION: a high prevalence of vitamin D deficiency among postmenopausal women of Yekaterinburg was detected. Diagnosis and correction of vitamin D levels are necessary for timely reduction of cardiometabolic risk, primarily due to the potential pleiotropic effects of D-hormone on the renin-angiotensin-aldosterone system, carbohydrate and lipid metabolism.

BACKGROUND: The steadily increasing number of people with obesity requires the development of simple and accurate methodological approaches to assess the absolute and relative amount of body fat mass. The body adiposity index (BAI) is one of the indices proposed to assess the body fat percentage. However, the comparison analysis of common methods, i.e., of bio-electrical impedance analysis and ultrasound scanning, and BAI was not performed for the Russian population.AIM: Comparison analysis of the body fat percentage estimates by bio-electrical impedance analysis, ultrasound scanning, and body adiposity index in the group of adult male and females.MATERIALS AND METHODS: An examination of healthy males and females from Moscow was conducted. Height, weight, waist and hip circumferences were measured. The body fat percentage was obtained by bio-electrical impedance analysis — BIA (ABC-02 Medas), ultrasound scanning — US (BodyMetrixTM, IntelaMetrix), and body adiposity index.RESULTS: 263 females and 134 males aged 18 to 73 years participated in the study. Correlation coefficients between BAI values and the body fat percentage obtained by BIA and US were 0.749 and 0.763 (pСССССС=0.84 [0.80–0.86]) and no systematic bias. Lower level of agreement was obtained in the group of males.CONCLUSION: Conducted study allows to conclude that, at the individual level, BAI is not an appropriate method for estimating the body fat percentage relatively to other indirect methods. However, all three methods can be used in the group of pooled males and females when testing at the population level.

Diabetes is characterized by elevation of plasma glucose due to an insufficiency of the hormone insulin and is associated with both inadequate insulin secretion and impaired insulin action. The Banting Medal for Scientific Achievement Commemorates the work of Sir Frederick Banting, a member of the team that first used insulin to treat a patient with diabetes almost exactly one hundred years ago on 11 January 1922. This article is based on my Banting lecture of 2022 and concerns the mechanism of glucose-stimulated insulin secretion from pancreatic β-cells, with an emphasis on the metabolic regulation of the KATP channel. This channel plays a central role in insulin release. Its closure in response to metabolically generated changes in the intracellular concentrations of ATP and MgADP stimulates β-cell electrical activity and insulin granule exocytosis. Activating mutations in KATP channel genes that impair the ability of the channel to respond to ATP give rise to neonatal diabetes. Impaired KATP channel regulation may also play a role in type 2 diabetes. I conjecture that KATP channel closure in response to glucose is reduced because of impaired glucose metabolism, which fails to generate a sufficient increase in ATP. Consequently, glucose-stimulated β-cell electrical activity is less. As ATP is also required for insulin granule exocytosis, both reduced exocytosis and less β-cell electrical activity may contribute to the reduction in insulin secretion. I emphasize that what follows is not a definitive review of the topic but a personal account of the contribution of my team to the field that is based on my Banting lecture.

BACKGROUND: Carotid atherosclerosis (CA) and lower extremity peripheral artery disease (PAD) is a common and potentially life-threatening comorbidity in diabetes.AIM: to determine risk factors and biomarkers of the association of CA and PAD in patients with type 2 diabetes.MATERIALS AND METHODS: A single-center cross-sectional comparative study was carried out. Three hundred ninety one patients with type 2 diabetes were included. Duplex ultrasound of carotid and low limb arteries, screening/monitoring of diabetic complications and associated diseases, and assessment of glycemic control, biochemical and coagulation parameters were performed. Factors involved in vascular wall remodeling, including calponin-1, relaxin, L-citrulline, matrix metalloproteinase-2 and -3, were measured in blood serum by ELISA.RESULTS: The signs of CA and PAD were observed in 330 and 187 patients respectively. In 178 patients, both CA and PAD were revealed. The risk of combined involvement of carotid and lower extremity arteries was higher in patients with diabetic retinopathy (OR=2.57, pCONCLUSION: In subjects with type 2 diabetes, carotid and lower extremity atherosclerotic disease is associated with age, diabetes duration, abdominal obesity, microvascular and macrovascular complications, glucose variability, and high serum levels of L-citrulline.

AIMS/INTRODUCTION: To evaluate the benefit of sodium–glucose cotransporter 2 inhibitors (SGLT2i) versus dipeptidyl peptidase-4 inhibitors (DPP4i) in reducing cardiovascular disease (CVD) events in patients with type 2 diabetes mellitus with and without a CVD history.MATERIALS AND METHODS: This retrospective cohort study used Japanese hospital administrative data from the Medical Data Vision database (January 2015 to April 2020). Patients with type 2 diabetes mellitus (n=625,739) who were new users of an SGLT2i (n=57,070; 9.1%) or DPP4i (n=568,669; 90.9%) were included. Outcomes included hospitalization for heart failure (hHF), all-cause death (ACD) and the composite of hHF or ACD. Hazard ratios (HR) were calculated using the inverse probability weighting Cox proportional hazards model to compare CVD event risks between treatment groups.RESULTS: Compared with DPP4i, SGLT2i was associated with a significant reduction in hHF risk among patients without a CVD history (HR 0.507, 95% confidence interval 0.283–0.907), but not in the full cohort or those with a CVD history. SGLT2i was associated with a significant risk reduction of ACD (HR 0.592, 95% confidence interval 0.481–0.729) and the composite of hHF or ACD (HR 0.712, 95% confidence interval 0.613–0.826), compared with DPP4i in the full cohort; similar results were observed among patients with and without a CVD history.CONCLUSION: In this real-world study, SGLT2i versus DPP4i was associated with a significant reduction in hHF, ACD and hHF or ACD events in patients with type 2 diabetes mellitus without a CVD history.

BACKGROUND: High prevalence of anemia in diabetes mellitus (DM) determines the relevance of studying its pathogenetic aspects, the role of anemia in DM complications development and the issue of differential diagnosis between iron deficiency anemia (IDA) and anemia of chronic disease (ACD)).AIM: To establish the diagnostic value of classical parameters for diagnosing anemia in DM and propose an optimized algorithm for the differential diagnosis of ACD and IDA in DM type 1 and 2 using new markers.MATERIALS AND METHODS: The observational, single-centre, comparative, controlled, single-stage study. Patients underwent assessment of glycated hemoglobin, creatinine, microalbuminuria; indicators of iron metabolism — hematocrit, the number of erythrocytes, reticulocytes, hemoglobin, serum iron, transferrin, ferritin, the level of soluble transferrin receptors (sTfR), sTfR/logFerpitin index, and inflammation markers — erythrocyte sedimentation rate (ESR), leukocyte count, high sensitive CRP and TNF-α. ROC-analysis was used to assess the differential diagnosis markers informative content.RESULTS: We examined 135 patients: 51 with DM 1 and 84 with DM 2. The patients were stratified into groups based on anemia type: 1) ACD 2) IDA 3) latent iron deficiency 4) without ferrokinetics disorders. According to the ROC-analysis in DM patients, the following parameters had high information content in ACD. ESR — sensitivity 92%, specificity 85%, diagnostic threshold 26.5 mm/h (area under the curve (AUC) 0.943; pCONCLUSION: In differential diagnosis of IDA and ACD in DM, ESR, leukocyte count, microalbuminuria, sTfR and sTfR/logFerritin index have a high diagnostic value. This allows proposing them as additional markers for differential diagnosis of anemia in DM.

The condition known today as diabetes mellitus was described as early as 1550 B.C. in the papyrus of Ebers, when Ayurvedic physicians noted the sweet taste of urine in patients with polyuria. This fact allows diabetes to be considered as one of the most well-known antiquity diseases. During all these thousands of years scientists have been trying to «unravel» this «mysterious» condition, and to find the cause and ways to cure the disease. Therefore, the long history of the diabetes existence is rich in discoveries, which often had a tremendous impact on all medicine. Insulin discover and investigation has become a key moment in diabetes history. A lot of scientists who have worked on the study of the insulin structure and developed new methods have been honored with the Nobel Prize. In our opinion, this review highlights the most important works of the 20th century, which played a key role in the discovery of a drug for the treatment of diabetes mellitus patients.

The interplay between liver and bone metabolism remains largely uncharacterized. Here, we uncover a mechanism of liver-bone crosstalk regulated by hepatocyte SIRT2. We demonstrate that hepatocyte SIRT2 expression is increased in aged mice and elderly humans. Liver-specific SIRT2 deficiency inhibits osteoclastogenesis and alleviates bone loss in mouse models of osteoporosis. We identify leucine-rich α-2-glycoprotein 1 (LRG1) as a functional cargo in hepatocyte-derived small extracellular vesicles (sEVs). In SIRT2-deficient hepatocytes, LRG1 levels in sEVs are upregulated, leading to increased transfer of LRG1 to bone-marrow-derived monocytes (BMDMs), and in turn, to inhibition of osteoclast differentiation via reduced nuclear translocation of NF-κB p65. Treatment with sEVs carrying high levels of LRG1 inhibits osteoclast differentiation in human BMDMs and in mice with osteoporosis, resulting in attenuated bone loss in mice. Furthermore, the plasma level of sEVs carrying LRG1 is positively correlated with bone mineral density in humans. Thus, drugs targeting hepatocyte-osteoclast communication may constitute a promising therapeutic strategy for primary osteoporosis.