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The aim: To study the association of demographic, clinical, and laboratory factors and the use of glucose-lowering drugs and anti-coronavirus disease (COVID-19) vaccination with the COVID-19-related case fatality rate (CFR) in diabetes mellitus (DM) patients. Methods: This study is a nationwide observational cohort study based on the data from the National Diabetes Register (NDR) that is the database containing online clinical information about the population with DM. The outcomes (death or recovery) for COVID-19 were registered in 235,248 patients with DM [type 1 diabetes mellitus (T1DM), n = 11,058; type 2 diabetes mellitus (T2DM), n = 224,190] from March 20, 2020, until November 25, 2021. The unadjusted odds ratio (OR) and 95% confidence interval (CI) were used to estimate the risk factors for CFR. Then the ranging of significant factors was performed and the most vulnerable groups of factors for the lethal outcome were chosen. Results: The CFR due to COVID-19 was 8.1% in T1DM and 15.3% in T2DM. Increased CFR was associated with the male population [OR = 1.25 (95% CI: 1.09-1.44) in T1DM and 1.18 (95% CI: 1.15-1.21) in T2DM], age =65 years [OR = 4.44 (95% CI: 3.75-5.24) in T1DM and 3.18 (95% CI: 3.09-3.26) in T2DM], DM duration =10 years [OR = 2.46 (95% CI: 2.06-2.95) in T1DM and 2.11 (95% CI: 2.06-2.16) in T2DM], body mass index (BMI) =30 kg/m2 [OR = 1.95 (95% CI: 1.52-2.50)] in T1DM, HbA1c =7% [OR = 1.35 (95% CI: 1.29-1.43)] in T2DM. The atherosclerotic cardiovascular disease (ASCVD) and chronic kidney disease (CKD) were associated with higher CFR in T1DM but not in T2DM. The pre-COVID-19 glucose-lowering therapy in T2DM was differently associated with CFR (OR): 0.61 (95% CI: 0.59-0.62) for metformin, 0.59 (95% CI: 0.57-0.61) for dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors), 0.46 (95% CI: 0.44-0.49) for sodium-glucose co-transporter-2 (SGLT2) inhibitors, 0.38 (95% CI: 0.29-0.51) for glucagon-like peptide-1 receptor agonists (arGLP-1), 1.34 (95% CI: 1.31-1.37) for sulfonylurea (SU), and 1.47 (95% CI: 1.43-1.51) for insulin. Anti-COVID-19 vaccination was associated with a lower fatality risk in both DM types: OR = 0.07 (95% CI: 0.03-0.20) in T1DM and OR = 0.19 (95% CI: 0.17-0.22) in T2DM. Conclusions: The results of our study suggest that increased COVID-19-related fatality risk in both T1DM and T2DM patients associated with the male population, older age, longer DM duration, and absence of anti-COVID-19 vaccination. In T2DM, pre-COVID-19 glucose-lowering therapy with metformin, DPP-4 inhibitors, SGLT2 inhibitors, and arGLP-1 had a positive effect on the risk of death. The most vulnerable combination of risk factors for lethal outcome in both DM types was vaccine absence + age =65 years + DM duration =10 years. [ABSTRACT FROM AUTHOR]

Summary: Hypercortisolism in humans suppresses osteoblastogenesis and osteoblast function through the upregulation of Wnt-signaling antagonists (sclerostin, Dkk1) and changes in microRNAs levels (miR-125b-5p, miR-218-5p, miR-34a-5p, miR-188-3p, miR-199a-5p) which are associated with mesenchymal stem-cell commitment to adipocytes or cartilage cells over the osteoblasts. Introduction: The purpose of this study was to evaluate the responses of bone to chronic glucocorticoid (GC) excess by measuring the levels of selected mRNA and microRNA (miR) in bone samples of patients with Cushing's disease (CD). Methods: Bone samples were obtained during transsphenoidal adenomectomy from the sphenoid bone (sella turcica) from 16 patients with clinically and biochemically evident CD and 10 patients with clinically non-functioning pituitary adenomas (NFPA) matched by sex, age, and body mass index. Quantitative polymerase chain reactions (qPCR) were used to examine the expression of genes (mRNA and miRs) known to be involved in bone remodeling regulation based on studies in animals and cell culture. Results: Hypercortisolism was associated with the downregulation of genes involved in osteoblast function and maturation (ACP5, ALPL, BGLAP, COL1A1, COL1A2, BMP2, RUNX2, TWIST1). An excess of GC caused increased expression of Wnt-signaling antagonists (Dkk1, SOST) and changes in the levels of miRs that are known to suppress osteoblastogenesis (miR-125b-5p, miR-218-5p, miR-34a-5p, miR-188-3p, miR-199a-5p) p < 0.05, q < 0.1. Interestingly, compensatory mechanisms were found in long-term hypercortisolism: upregulation of Wnt10b, LRP5, and LRP6; downregulation of SFRP4; changes in miRs involved in osteoblastogenesis (miR-210-5p, miR-135a-5p, miR-211, miR-23a-3p, miR-204-5p); and downregulation of genes associated with osteoclastogenesis. None of these changes prevented the suppression of bone formation. Conclusions: An excess of endogenous GC in humans suppresses bone formation through the upregulation of Wnt-signaling antagonists and dysregulation of miRs involved in mesenchymal stem-cell commitment. Both Wnt-signaling antagonists and miRs seem to be promising targets for further research in therapeutic intervention in glucocorticoid-induced osteoporosis. [ABSTRACT FROM AUTHOR]

This paper highlights the problem of neuroendocrine tumours (NETs) with clinical symptoms of hypercorticism caused by hypersecretion of adrenocorticotropic hormone (ACTH) by tumour cells. In most cases (85%), the tumours were localized in the pituitary gland (Cushing's disease); 15% of the patients had an extrapituitary tumour that manifest as an ectopic ACTH secretion (EAS). Comparative analysis of clinical, hormonal, histological, and immunohistochemical characteristics of pituitary and extrapituitary ACTH-secreting NET was performed. It included 46 patients with CD and 38 ones exhibiting ectopic ACTH secretion (EAS). Results of the study suggest differences between CD and EAS in terms of the severity of clinical manifestations and duration of the disease. Hormonal studies showed that EAS unlike CD was associated with high plasma ACTH and cortisol levels, late-evening salivary cortisol and daily urinary free cortisol, the absence of a 60% or greater reduction of cortisol in the HDDST test, and the presence of a low (less than 2) ACTH gradient in response to desmopressin administration with catheterization of cavernous sinuses. The study of morphofunctional characteristics of the removed NET demonstrated the ability of both pituitary and extrapituitary NETs to express ACTH as well as GH, PRL, LH, and FSH. The angiogenic markers (CD31 and VEGF) were detected with equal frequency regardless of the NET localization. The histological structure of all corticotropinomas suggested their benign origin, but extrapituitary NETs were represented by different morphological types with varying malignancy, invasiveness, and metastatic properties. A higher cell proliferation potential (Ki-67) was documented for NET in patients presenting with an ectopic ACTH secretion compared to those having corticotropinomas. [ABSTRACT FROM AUTHOR]

Alleles and genotypes of polymorphic markers of paraoxonase 1 and paraoxonase 2 genes ( PON1 and PON2) encoding enzymes of the organism antioxidant defense were compared in type 1 diabetes mellitus patients with or without diabetic nephropathy. The patients with nonoverlapping (“polar”) phenotypes constituted different groups. The first group contained patients with diabetic nephropathy (DN+, n = 62), clinical proteinuria (albuminuria above 300 mg per day), and at least 15-year disease duration. In control group, the patients had no diabetic nephropathy (DN−, n = 68), their albuminuria was below 200 mg per day, and disease duration was at least 20 years. Comparative analysis with exact Fisher’s test revealed no significant differences in frequencies of alleles and genotypes of the PON1 gene polymorphic marker Gln192Arg and of PON2 gene polymorphic markers Ala148Gly and Cys311Ser. Our results suggest that the polymorphic markers studied are not associated with diabetic nephropathy among Russian patients in Moscow. [ABSTRACT FROM AUTHOR]

Background Oxidative stress is involved in the origin of type 1 diabetes. Low efficiency of the scavenging antioxidant system has been shown to be related to the pathogenesis of the disease. This, therefore suggests that genes encoding catalase and other antioxidant enzymes may implicate in the development of type 1 diabetes. Methods Nine microsatellite markers that cover about 10 megabases around the catalase ( CAT) gene on chromosome 11p13 were analyzed using polymerase chain reaction (PCR) and fluorescence-based genotyping on an automatic DNA sequencer. We also evaluated three single-nucleotide polymorphisms (SNP) within genes encoding catalase (T1667T and C(−262)T dimorphism) and ETS homologous factor ( EHF) (C255T SNP) using a PCR-restriction fragment-length polymorphism approach. Multipont linkage analysis in 37 affected sibling pairs was performed using GENEHUNTER 2.1. We examined the markers for association with the disease by transmission disequilibrium tests in 57 discordant sibling pairs and by a case-control study in 258 unrelated healthy donors and 247 affected patients. Results We obtained close-to-suggestive evidence of linkage to type I diabetes, with the maximum linkage peak between markers D11S907 and D11S2008. Analysis of three SNPs at the CAT and EHF gene located within the region of maximum linkage showed that T1667T and C(−262)T markers of the CAT gene are strongly associated with the disease. Conclusion Our findings support evidence of a new putative type 1 diabetes susceptibility locus on chromosome 11p13 and suggest that the CAT gene may play a role in conferring susceptibility to the disorder in Russian patients. Copyright © 2004 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Using analytical technologies it is possible now to measure the entire diversity of molecules even in a small amount of biological samples. Metabolomic technologies simultaneously analyze thousands of low-molecular substances in a single drop of blood. Such analytical performance opens new possibilities for clinical laboratory diagnostics, still relying on the measurement of only a limited number of clinically significant substances. However, there are objective difficulties hampering introduction of metabolomics into clinical practice. The Institute of Biomedical Chemistry (IBMC), consolidating the efforts of leading scientific and medical organizations, has achieved success in this area by developing a clinical blood metabogram (CBM). CBM opens opportunities to obtain overview on the state of the body with the detailed individual metabolic characteristics of the patient. A number of scientific studies have shown that the CBM is an effective tool for monitoring the state of the body, and based on the CBM patterns (signatures), it is possible to diagnose and monitor the treatment of many diseases. Today, the CBM creation determines the current state and prospects of clinical metabolomics in Russia. This article, dedicated to the 80th anniversary of IBMC, is a review of these achievements focused on a discussion of their implementation in clinical practice.

Aim: To evaluate the ovarian reserve function in female patients with obesity in comparison with women without obesity., Materials and Methods: This study evaluated 500 caucasian women, age 20-30 years, 250 with obesity (body mass index, BMI ≥30 kg/m2) and 250 without obesity (BMI &lt;30 kg/m2). Anthropometrics, serum concentrations of anti-Mullerian hormone (AMH), inhibin B, follicle stimulating hormone, luteinizing hormone, estradiol, progesterone, and testosterone were compared as ovarian volume (cm3) and antral follicle count (AFC), determined by ovarian transvaginal ultrasonography., Results: We reveal statistically significant difference in following parameters: AMH (2.7±0.47 ng/ml vs. 3.8±0.63 ng/ml; p&lt;0.05), testosterone (1.4±0.3 nmol/l vs. 0.7±0.2 nmol/l; p&lt;0.01), ovarian volume (7.2±1.9 cm3 vs 9.5±1.7 cm3; p&lt;0.05), and AFC (13.3±4.5 vs 20.7±7.2; p&lt;0.01) in obesity group vs. control group respectively., Conclusion: Ovarian reserve function is significantly lower in obese patients than in healthy control subjects of young reproductive age, but ovarian reserve parameters are in normal reference range even in obese patients.

Aim: The purpose of our study is to assess the effects of glucagon-like peptide-1 receptor agonists (GLP-1R agonists) on early markers of kidney damage in patients with type 1 diabetes mellitus (DM)., Materials and Methods: The study included 27 patients with type 1 diabetes with normo- (n=16) and microalbuminuria (n=11) on intensive insulin injection regimen with insulin analogs. Patients were divided into two groups: 15 patients continued insulin therapy throughout the follow-up period, 12 patients were given 1.2 mg GLP-1R agonist (Liraglutide) once a day in addition to the insulin therapy for 6 months. HbA1c, lipid profile, classic markers of kidney damage (albuminuria, creatinine, glomerular filtration rate); plazma (neutrophilic gelatinase-associated lipoxalin - NGAL, molecule renal damage of type 1 - KIM-1, cystatin C, osteopontin) and urinary kidney biomarkers (nephrin, podocyne, uromodulin, NGAL, KIM-1, collagen type IV, cystatin C) were evaluated prior and in dynamics at 6 months. Kidney biomarkers levels were assessed by the enzyme-linked immunosorbent assay (ELISA)., Results: We observed a significant decrease in the urinary excretion of type IV collagen, cystatin C, increased uromodulin excretion and decrease in the plasma levels of osteopontin, NGAL and cystatin C in the group of combined insulin and GLP-1R agonist therapy., Conclusion: Changes in the level of sensitive kidney biomarkers indicate a possible renoprotective effect of GLP-1R agonist therapy in patients with type 1 diabetes at an early stages of kidney damage.

The article presents data on modern approaches to the diagnosis of various manifestations of hyperparathyroidism according to multispiral computed tomography, which do not require morphological verification and ensure the correctness of the diagnostic process. The radiological picture and differential diagnostics of changes from parathyroid glands and bone structures at hyperparathyroidism are described in detail.

Endocrine Medical Research center (EMRC) of the Ministry of health of Russia is unique clinical center, that have no analogs in the world. All forms of endocrine disorders may be diagnosed and treated here by implication of innovative methods. Institute of reproductive medicine of EMRC was open on 2017, director of this institute - MD, PhD E.N. Andreeva. Staff of this institute include highly experienced investigators and physicians. One of the most ambitious projects of the institute is development of prevention, diagnostic and treatment algorithm for patients with infertility of endocrine origin. For these purposes large prospective clinical trial (5000 patients) will be conducted with implementation of most modern genetic, laboratory and instrumental diagnostic methods. Results of this trial will allow diagnose, treat and prevent reproductive pathology in patients with endocrine diseases.

The oncogenes and/or tumour suppressor genes which may be involved in the transformation process for the vast majority of pituitary tumours remain unknown. There is substantial evidence for derangement of cell cycle control in such tumours, but cell cycle protein mutations identified in other human malignancies are restricted to only a very small subset of sporadic pituitary neoplasms. Krüppel-like factors are DNA-binding transcriptional regulators with diverse effects including the upregulation of the cell cycle protein p21(WAF1/CIP1). It has been reported that the Krüppel-like transcription factor 6 (KLF6) gene is mutated in a proportion (15-55%) of human prostate cancers, and more recent data are emerging regarding mutated KLF6 in nasopharyngeal carcinomas, astrocytoid gliomas and colorectal cancer. We therefore speculated that other tumours such as pituitary adenomas might also harbour such mutations that may be involved in the control of cell proliferation in the pituitary. The aim of the current study was thus to analyse the KLF6 gene for mutations in sporadic pituitary tumours. We analysed 60 pituitary adenomas (15 GH-, four ACTH-, two PRL-secreting and 39 non-functioning) with direct sequence analysis of exons 2 and 3 of the KLF6 gene, the region where most of the previously described mutations are located. Three non-functioning pituitary adenomas of the 60 pituitary tumours (5%) had two identical sequence changes in exon 2 (missense mutation Val165Met, 523G-->A and a silent substitution in Ser77Ser codon 261C-->T). Analysis of genomic DNA extracted from peripheral lymphocytes in one patient confirmed these changes to be present in the germline and they therefore probably represent polymorphisms, although we cannot exclude the possibility that these are predisposing germline mutations. We conclude that mutations of the KLF6 gene are unlikely to play an important role in sporadic pituitary tumorigenesis.

Cell cycle dysregulation is one of the defining features of cancer. Cyclin-dependent kinase 4 (CDK4), together with its regulatory subunit cyclin D, governs cell cycle progression through the G1 phase. Cyclin-dependent kinase inhibitors, including p16(INK4A) (encoded by CDKN2A), in turn regulate CDK4. In particular, dysregulation of the p16/CDK4/cyclin D complex has been established in a variety of types of human tumours. Dominant activating mutations affecting codon 24 of the CDK4 gene (replacement of Arg24 by Cys or His) render CDK4 insensitive to p16(INK4) inhibition and are responsible for melanoma susceptibility in some kindreds. However, 'knock-in' mice homozygous for the CDK4(R24C) mutation were noted to develop multiple neoplasia, most commonly including endocrine tumours: pituitary adenomas, insulinomas and Leydig cell testicular tumours. We therefore speculated that sporadic human endocrine tumours might also harbour such mutations. The aim of the current study was to analyze the CDK4 gene for the two characterized activating mutations, R24C and R24H, in sporadic human pituitary adenomas, insulinomas and Leydig cell tumours. We used DNA extracted from 61 pituitary adenomas, and paired tumorous and neighboring normal genomic DNA extracted from 14 insulinoma and 6 Leydig cell tumour samples. Genomic DNA from patients with familial melanoma harbouring the R24C or the R24H mutations served as positive controls. All samples were subjected to PCR, mutation-specific restriction digests and/or sequencing. Both methodologies failed to detect mutations at these two sites in any of the sporadic endocrine tumours including pituitary adenomas, benign or malignant insulinomas or Leydig cell tumours, while the positive controls showed the expected heterozygote patterns. Protein expression of CDK4 was demonstrated by immunohistochemistry and Western blotting in pituitary and pancreatic samples. These data suggest that the changes in the regulatory 'hot-spot' on the CDK4 gene, causing various endocrine tumours in CDK4(R24C/R24C )mice, are not a major factor in sporadic pituitary, insulin beta-cell or Leydig cell tumorigenesis.

Mutations in the prophet of Pit-1 gene (PROP1) have been shown to be responsible for combined pituitary hormone deficiency (CPHD) with deficiencies of growth hormone (GH), Prolactin (Prl), thyroid-stimulating hormone (TSH) and gonadotropins. We previously reported that homozygosity for a 2bp deletion in exon 2 (296delGA) accounted for CPHD in three patients from two Russian families. Here we report a second mutational hot spot in exon 2. This 2bp 149delGA deletion results in a frame shift that leads to the same serine to stop codon change at codon 109 (S109X). The predicted proteins are each truncated at residue 108 but diverge from the wild type sequence at different points in the homeodomain. Compound heterozygosity for the two mutations (149delGA/296delGA) was detected in 5 of 14 CPHD children from 4 families (36%). This provides the first evidence of heterozygosity for two common deletions as a cause of CPHD in Russian children.

To ascertain the molecular background of combined pituitary hormone deficiency, screening for mutations in the pituitary-specific transcription factor (Pit-1/GHF-1) gene (PIT1) was performed on a cohort of 15 children from Russia with combined growth hormone (GH)/prolactin (Prl)/thyroid-stimulating hormone (TSH) deficiency. The group of patients, suspected of PIT1 mutations, consisted of four familial cases (seven patients) and eight sporadic cases. All had complete GH deficiency and complete or partial Prl and TSH deficiency. Direct sequencing of all six exons of PIT1 and its promoter region showed a C to T transition mutation at codon 14 of exon 1 in a 3 8/12-year-old girl. This novel PIT1 mutation results in a proline to leucine substitution (P14L). The patient was heterozygous for mutant and normal alleles. The heterozygous P14L mutation was also present in her mother as well as in her maternal aunt and grandmother, all of whom were phenotypically normal. There was no mutation in the father's DNA, suggesting the need for reevaluation of genomic imprinting. In other children of our series, no mutation in PIT1 or in its promotor region was identified. This is the first report on the analysis of PIT1 and its promoter region in Russian children with GH/Prl/TSH deficiency. However, as the involvement of PIT1 mutation is rare in Russia, the other negative cases need to be analyzed for another candidate gene responsible for combined GH/Pr/TSH deficiency.

Combined pituitary hormone deficiency (CPHD), including growth hormone (GH), prolactin (Prl) and thyroid-stimulating hormone (TSH) in children is now considered a heterogeneous syndrome. Recent findings on expression of mouse pituitary-specific homeodomain factors demonstrate dependence of adenopituitary ontogeny on interactive expression of these factors, suggesting their involvement in etiology of CPHD. Prophet of Pit-1 (Prop-1) gene, a novel pituitary-specific homeodomain factor, was analyzed in 14 Russian children with CPHD, in whom Pit-1 gene was intact. We found a mutational hot spot in three patients from two families in homeodomain part of the second exon of Prop-1 gene. The common 2-base pair deletion (GA296) in the homozygous state resulted in a Serine to Stop codon (S109X) substitution and generated a truncated Prop-1 protein. Parents were phenotypically normal and heterozygous for GA296 deletion, indicating an autosomal recessive inheritance. These results demonstrate a novel type of Prop-1 gene mutation as one of the causes of CPHD in Russian patients.

Fifty-five serum samples from 99 Type 1 and 71 serum samples from 81 Type 2 diabetic patients (56% and 88%, respectively) brought about a 1.5-3.5-fold increase in total cholesterol content of cultured human intimal aortic cells. This atherogenic effect did not correlate with patient's age, diabetes duration or plasma lipid levels, and was mainly due to low density lipoprotein (LDL). Cholesterol accumulation in cells incubated with LDL highly correlated with that in cells exposed to corresponding patient's serum (r = 0.872 and r = 0.811, P < 0.0001, in Type 1 and Type 2 diabetic patients, respectively). In LDL from diabetic patients the sialic acid content was decreased by an average of 30% (P < 0.05), as compared with healthy subjects, and the fructosyl lysine content was increased by an average of 25% (P < 0.05). Atherogenic effect of patients' LDL significantly correlated with their fructosyl lysine content (P < 0.0001) and negatively correlated with sialic acid content (P < 0.0001). Two LDL fractions were further separated from the total LDL preparation by affinity chromatography on Ricinus communis agglutinin-agarose. The bound (desialylated) LDL fraction was characterized by an increased fructosyl lysine content and the altered neutral lipid and phospholipid composition, while non-bound (sialylated) LDL fraction did not differ from normal LDL. Desialylated, but not sialylated, LDL fraction induced massive cholesterol accumulation in cultured cells. In conclusion, the cholesterol accumulating effect of diabetic patients' blood sera is mainly related to atherogenic low density lipoprotein fraction, which is modified in various ways--by increased non-enzymatic glycosylation, desialylation and alterations in lipid composition. This multiple-modified LDL may contribute to the premature atherosclerosis development in diabetes mellitus.

The acute effects of protein loading (1.5 g kg-1) on glomerular filtration rate (GFR) and urinary albumin excretion (UAE) were investigated in 23 type-I diabetic patients with no clinical nephropathy, and in 7 healthy subjects (controls). The results were compared with renal morphology data. In controls and in 14 diabetic patients (group 1) GFR increased by 27 and 37%, respectively, corresponding to normal renal reserve, but in 9 patients (group 2) GFR decreased by 20%, indicating the absence of a renal reserve. Microalbuminuria was found in none of the patients in group 1 and in 50% of patients in group 2. Two hours after the load UAE increased in all groups, but the increase was most marked in group 2, despite the fall in GFR. The two groups of patients did not differ with regard to the duration and control of diabetes, but differed markedly in terms of baseline GFR (131 vs. 195 ml min-1, P less than 0.01, in groups 1 and 2, respectively). Renal morphology showed minimal non-specific glomerular injury in group 1, and signs of glomerulosclerosis in group 2. We conclude that the impaired renal response to protein load precedes other subclinical manifestations of diabetic renal injury, and may be useful in the diagnosis of latent diabetic nephropathy.