Vol 64, No 4 (2018)

Original Studies
Statin administration is associated with higher IGF-1 levels in patients without diabetes mellitus
Shpagina O.V., Bondarenko I.Z., Kolesnikova G.S.
Abstract

Background: Research makes it clear that the IGF-1 level correlates with cardiovascular disease, chronic heart failure, and mortality. Yet, little is known about the effect of statins on IGF-1.

Aims: to evaluate the effect of statin treatment on IGF-1 and its association with a cardiovascular risk.

Material and methods: The study included 115 patients (mean age, 55.8±6.1 years) who either were overweight or had mild obesity (body mass index 28.6±3.8 kg/m2) without diabetes. Group 1 consisted of 70 patients with verified coronary artery disease receiving statin therapy; group 2 included 45 healthy subjects. Coronary angiography and treadmill test were used to diagnose coronary artery disease. Impaired glucose tolerance and total cholesterol, triglycerides, LPHD, LPLD, fibrinogen, and IGF-1 levels were evaluated in all the subjects. Heart chamber geometry was assessed by echocardiography.

Results: The IGF-1 level was significantly higher in group 1 compared to the control group (196 and 167 ng/ml, respectively; р=0.014). Serum levels of IGF-1 were associated with duration of statin therapy (R=0.311; p=0.000), stage of hypertension (R=0.187; p=0.04), fibrinogen (R=0.274; p=0.033), TG (R=0.316; p=0.006), total cholesterol (R=–0.213; p=0.016), LPLD (R=–0.184; p=0.038), smoking (R=0.3; p=0.009), ejection fraction (R=0.298; p=0.041), end-diastolic volume (R=0.422; p=0.036), end-systolic volume (R=0.407; p=0.042), end-diastolic dimension (R=0.27; p=0.014), interventricular septal thickness (R=0.247; p=0.02), and left ventricular posterior wall thickness (R=0.258; p=0.019). Rosuvastatin dose positively correlated with the IGF-1 level (R=0.521; p=0.028).

Conclusions: Statin administration is associated with higher IGF-1 levels in patients without diabetes. High IGF-1 level correlates with the risk factors of coronary artery disease: hypertension, lipid profile, and fibrinogen level and has an adverse effect on chronic heart failure by altering the cardiac remodeling.

Problems of Endocrinology. 2018;64(4):200-207
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Expression of transcription and growth factors and the AKT/m-TOR signaling pathway components in papillary thyroid cancer
Spirina L.V., Chizhevskaya S.Y., Kondakova I.V.
Abstract

Background: The molecular mechanism of thyroid cancer development is associated with changes in expression of transcription factors and growth factors accompanied by modified level of the AKT/m-TOR components.

Aims. The aim of study was to determine NF-κB p65, NF-κB p50, HIF-1α, HIF-2α, VEGF, CAIX, VEGFR2 expression and mRNA level of the AKT/m-TOR signaling pathway components in papillary thyroid cancer compared to those in benign lesions.

Material and methods: Forty patients aged 33—66 years with T1-4N0-2M0 papillary thyroid cancer (7 males and 33 females) were enrolled in the study. The mean age was 52.0±2.6 years. The comparison group included patients with benign lesions of thyroid tissue (4 males and 18 females) aged 38—66 years (mean age, 53.0±4.4 years). Expression levels of NF-κB p65, NF-κB p50, HIF-1α, HIF-2α, VEGF, CAIX, VEGFR2, and the AKT/m-TOR signaling pathway components were determined by RT-PCR using specific primers.

Results: Increased expression of transcription factors NF-κB and HIF-2α was found in papillary thyroid cancer. The levels of AKT and PTEN mRNA were elevated in transformed tissues. c-Raf expression was reduced 2.1-fold in cancer compared to that in thyroid tissues with benign lesions. Multiple positive correlations were revealed between transcription and growth factors and the AKT/m-TOR signaling pathway components in cancer. An association between PTEN expression and the NF-κB mRNA level was revealed, being a sign of deregulation in the signaling cascade in cancer tissues.

Conclusions: Overexpression of NF-κB, HIF-2α, AKT, PTEN and reduction of c-Raf expression is typical of thyroid papillary cancer.

Problems of Endocrinology. 2018;64(4):208-215
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Gene-gene interactions and the contribution of polymorphic loci of the KCNJ11, ADIPOQ, omentin, leptin, TCF7L2 and PPARg genes to the development of type 2 diabetes mellitus in the Kyrgyz population: a case-control genetic association study using MDR analysis
Isakova Z.T., Talaibekova E.T., Zhyrgalbekova B.Z., Mirrakhimov E.M., Aldasheva N.M., Aldashev A.A.
Abstract

There are many genetic loci associated with type 2 diabetes mellitus (T2DM). The genetic factors involved in the development of the T2DM can depend on the nature of genetic variation within and across different ethnic groups.

Aims — the aim of this study was to investigate the gene-gene interactions and to determine the role of the KCNJ11 (Glu23Lys), ADIPOQ (G276T), omentin (Val109Asp), leptin (G2548A), TCF7L2 (IVS3C/T), PPARg (Pro12Ala) genes in the development of type 2 diabetes mellitus (T2DM) in the Kyrgyz population using MDR analysis.

Material and methods. We examined 114 patients (53 females and 61 males; mean age, 54±7.4) with T2DM and 109 apparently healthy controls (48 females and 61 males; mean age, 50±8.4). Polymorphisms of the KCNJ11 (Glu23Lys), ADIPOQ (G276T), omentin (Val109Asp), leptin (G2548A), TCF7L2 (IVS3C/T), PPARg (Pro12Ala) genes were defined by PCR-RFLP assay.

Results. Among the six genes (KCNJ11, ADIPOQ, omentin, leptin, TCF7L2, PPARg) included in this study, the most significant contribution to the development of T2DM in the Kyrgyz population was detected for the ADIPOQ (2.17%) and KCNJ11 genes (2.01%).

The heterozygous genotype G276T (OR=1.79 CI 95% 1.05—3.05; p=0.036) and the 276T allele (OR=1.68 CI 95% 1.09—2.60; p=0.025) of the ADIPOQ gene were associated with a high risk of developing T2DM in the Kyrgyz population. The 23Lys allele of the KCNJ11 gene was significantly associated with T2DM in the Kyrgyz population (OR=1.62 CI 95% 1.10—2.38; p=0.019). The allele and genotype frequencies of the omentin (Val109Asp), leptin (G2548A), TCF7L2 (IVS3C/T), PPARg (Pro12Ala) genes did not differ between the studied groups (p>0.05).

Conclusions. In Kyrgyz population, the polymorphic loci Glu23Lys of the KCNJ11 gene, the 276T allele and genotype G276T of ADIPOQ are associated with T2DM. The omentin (Val109Asp), leptin (G2548A), TCF7L2 (IVS3C/T), and PPARg (Pro12Ala) genes alone do not have such a significant impact on the development of type 2 diabetes; they contribute to the phenotypic development of T2DM mainly due to gene-gene interactions.

Problems of Endocrinology. 2018;64(4):216-225
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Case Reports
The features of cataract surgery in a patient with Graves’ disease and endocrine ophthalmopathy
Lipatov D.V., Sviridenko N.Y., Bessmertnaya E.G., Tolkacheva A.A.
Abstract

After the phacoemulsification technique was implemented in ophthalmic practice surgeries to replace the clouded lens have become routine for ophthalmologists. Today, over half a million phacoemulsification surgeries are annually conducted in Russia. Cataract combined with endocrine ophthalmopathy poses a significant challenge for an operating surgeon because of the unusual anatomical presentation of the orbit and the eyeball, as well as the elevated intraocular pressure caused by edema of the orbital tissues (i.e., retrobulbar tissue and extraocular muscles) rather than by primary glaucoma.

We analyze the features of surgical treatment of the cataract involving intraocular lens implantation in a patient with Graves’ disease and endocrine ophthalmopathy complicated by secondary ocular hypertension, optical neuropathy, and lagophthalmos.

After restoring the euthyroid state and reducing the severity of endocrine ophthalmopathy, phacoemulsification was performed in both eyes, with an interval of 2 months. Neither intra- nor postoperative complications of the patients’ organ of vision were observed. The maximum corrected visual acuity achieved on both eyes was 0.4–0.5 in the Snellen eye chart.

Problems of Endocrinology. 2018;64(4):226-230
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A case of combination of two autoimmune diseases: type 1 diabetes mellitus and systemic scleroderma in a 13-year-old girl
Titovich E.V., Andrianova E.A.
Abstract

Systemic scleroderma is an autoimmune disease of the connective tissue of unknown etiology. It is characterized by skin induration, lesions in the musculoskeletal system and the internal organs, and the Raynaud syndrome. An important component in pathogenesis of systemic scleroderma is disturbance of microcirculation involving endothelial proliferation and destruction, wall thickening and narrowing of the microvessel lumen, vasospasm, hemocyte aggregation, stasis, deformation and reduction of the capillary network (obliterating microangiopathy). Two main forms of the disease are distinguished: the diffuse and localized ones. The systemic nature of the diffuse form of systemic scleroderma is most obvious in the skin, but the digestive tract, respiratory organs, kidneys and the cardiovascular, endocrine, musculoskeletal and genitourinary systems are also affected. The incidence rate of systemic scleroderma is 6.3—12 cases per million population. Single case reports on scleroderma combined with other autoimmune diseases, including type 1 diabetes mellitus, in children and adolescents are available in literature. A rare case of a combination of two autoimmune diseases, type 1 diabetes mellitus and systemic scleroderma, in a 13-year-old girl is reported in this paper.

Problems of Endocrinology. 2018;64(4):231-234
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Reviews
Health status of children conceived by assisted reproductive technologies: endocrinologist’s position
Zyuzikova Z.S., Volevodz N.N., Grigoryan O.R., Degtyareva E.I., Dedov I.I.
Abstract

Assisted reproductive technologies (ART) are currently widely used around the world because of the increased prevalence of infertility (presently, about 15% of married couples suffer from infertility), as well as the increased access to treatment and public funding for this method. Hence, the number of children conceived by ART is steadily increasing every year.

This review focuses on the pressing problem of the health status of children conceived by assisted reproductive technologies (ART) by analyzing modern publications on the state of physical, gonadal and psychosomatic development, features of the endocrine system and cardiometabolic diseases, the risk of imprinting changes, congenital malformations and oncological disorders.

The data presented that there is no increased risk of childhood cancer or deterioration in quality of life. However, it is expected that the cardiovascular and metabolic risk factors found in childhood can worsen in later life and may ultimately be responsible for chronic cardiometabolic disease. Furthermore, the issue of fertility, especially in the male population conceived by ART, remains open, thus requiring additional longer-term research.

Problems of Endocrinology. 2018;64(4):235-243
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Methylation of estrogens, obesity and breast cancer
Chagay N.B., Mkrtumyan A.M.
Abstract

Methylation of catechol estrogens is catalyzed by catechol-O-methyltransferase. Synthesis and activity of this enzyme is encoded by the COMT gene. Downregulation of COMT expression is responsible for the risk of developing estrogen-dependent tumors. Obesity is a factor determining the overall methylation status in the body.

There are two main types of adipose tissue differing in their functional and metabolic characteristics, as well as the microscopic structure: white adipose tissue (WAT) and brown adipose tissue (BAT). Lipolysis of WAT is controlled by hormone-sensitive lipase, which depends is catecholamine dependent. BAT is a special type of adipose tissue whose main function is to produce heat. Activation of β3-adrenergic receptors by catecholamines, both at the central and peripheral levels, is the primary mechanism regulating thermogenesis in mature BAT.

Obese patients develop adipose tissue hypoxia, as well as WAT and BAT dysfunction. Adrenergic stimulation of thermogenesis is unclaimed because of «whitening» of brown adipocytes, which manifests itself as degradation of mitochondria. Redirection of stimulation of hormone-sensitive lipase by catecholamines to WAT and the increased need to enhance COMT expression are the potential consequences of modifying the BAT metabolism.

Estrogens are natural modulators of lipolysis (as they selectively affect activity of hormone-sensitive lipase) and regulators of BAT thermogenesis. Obesity is accompanied by elevated synthesis of estrone. However, in postmenopausal women it is characterized by a decrease in the total mass and activity of BAT. The role of BAT in the progression or inhibition of growth of the estrogen-dependent tumor tissue at premenopausal and postmenopausal age has not been studied yet and is of interest to researchers. The possible correlation between the activity of brown adipocytes and the COMT expression level is discussed in the context of the risk of developing benign breast dysplasia and cancer.

Problems of Endocrinology. 2018;64(4):244-251
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The interaction between polyphenols and food proteins: prospects for diet therapy of metabolic syndrome and type 2 diabetes mellitus
Mazo V.K., Petrov N.A., Sarkisyan V.A., Kochetkova A.A.
Abstract

The use of minor biologically active components of food (flavonoids) as functional food ingredients for foods for special dietary uses is a promising trend in prevention and treatment of carbohydrate and lipid metabolism disorders resulting from the metabolic syndrome and type 2 diabetes mellitus. Unlike the in vitro studies that are conducted mainly on cell cultures, the results of clinical studies may be influenced by low bioavailability of polyphenols. This fact makes it impossible to reach the beneficial effects of polyphenols in some cases. Thus, the problem of polyphenol bioavailability enhancement is the main direction in producing highly effective specialized anti-diabetic food products. In this review, the interaction between proteins and polyphenolic compounds is discussed from the viewpoint of the potential to protect polyphenols against degradation in the digestive tract, to increase their stability and pharmacological activity compared to those of the conventional compositions. The problems of interactions between polyphenols and food proteins, digestive enzymes and cell transporters in the gastrointestinal tract have not been sufficiently covered in Russian academic publications. The studies focused on the mechanisms of interactions between polyphenols and proteins, considering the corresponding structural changes are of interest for predicting possible changes in their bioavailability. Polyphenol binding to proteins is influenced by the primary structure of a protein macromolecule, the spatial distribution of amino acid residues responsible for polyphenol binding, and some other parameters characterizing the conditions of interactions.

Problems of Endocrinology. 2018;64(4):252-257
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Neuromediators and neuropeptides: the biomarkers for metabolic disturbances in obesity
Gmoshinski I.V., Apryatin S.A., Shipelin V.A., Nikitjuk D.B.
Abstract

The role of biogenic amines (serotonin, dopamine) and neuropeptides in regulation of energy homeostasis of the organism and their role as markers of metabolic disorders in obesity (Ob) in animal experimental models and in clinical observations is reviewed. The energy homeostasis of the body is controlled via competition of alternative regulatory mechanisms that are mainly localized in the hypothalamus (HT). At the level of aminergic regulation, these are the serotonin and dopamine systems; at the level of the peptidergic system, these are NPY/AgRP and POMC/CART-related peptides. Opioid and cannabinoid receptors and their endogenous ligands closely linked to peptidergic and aminergic regulatory subsystems of the central nervous system ensure the connection between the «metabolic» regulation loop responding to a deficit or excess of energy substrates the «hedonistic» one associated with the body’s perception of pleasure from food consumption. The response of peptidergic and aminergic HT neurons to food and hormonal signals originating from the outside is based on the interaction between the corresponding ligands and G-protein-coupled receptors specific to them. Disruption or breakdown of the central mechanisms is considered to be one of the main pathogenetic factors of obesity and, simultaneously, the reason why reducing diet therapy proves inefficient or unstable. Partial permeability of the blood—brain barrier for neuropeptides makes them an attractive biomarker in the diagnosis of metabolic abnormalities in obese patients.

Problems of Endocrinology. 2018;64(4):258-269
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Pharmacotherapy of obesity: what’s new?
Troshina E.A., Ershova E.V.
Abstract

The lifestyle change that underlies the treatment of such a prevalent chronic disease as obesity is often insufficient to successfully clinically relevant reduce body weight, especially in the presence of comorbid conditions and diseases (type 2 diabetes, atherogenic dyslipidemia, arterial hypertension, ischemic heart disease, hyperuricemia and gout, obstructive sleep apnea syndrome, polycystic ovary syndrome and other menstrual irregularities etc.). The availability in our country until recently, only two drugs for the treatment of obesity is extremely limited choice in the case of existing contraindications to this or another drug or the appearance of any side effects. The registration in Russia in 2016 of a new drug for the treatment of obese patients, including morbid or complicated concomitant diseases and conditions, an analogue of human glucagon-like peptide-1 — liraglutide in a dose of 3.0 mg, has replenished the arsenal of obesity pharmacotherapy and substantially extended capabilities of management of obesity and overweight including patients with severe comorbidities.

Problems of Endocrinology. 2018;64(4):270-276
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