Vol 17, No 1 (2020)

Original paper
Prediction of early response to liraglutide therapy in patients with obesity
Logvinova O.V., Troshina E.A.

BACKGROUND: The main goal of treating obesity is to reduce the risk of developing its complications and comorbid diseases, which requires a steady decrease in body weight by at least 5–10%. In Russia in 2016, the list of drugs for the treatment of obesity was supplemented by a glucagon-like peptide 1 receptor agonist (GLP-1) – liraglutide . There is evidence that about one third of patients do not achieve a clinically significant decrease in body weight during treatment with liraglutide, while the factors that predict the so-called early response to treatment are currently unknown.

AIM: To identify prognostic factors of an early response to complex therapy of exogenously constitutional obesity, including agonist of GLP-1 receptors liraglutide, and to evaluate the effect of this therapy on the dynamics of levels of endogenous peptide bioregulators of eating behavior (IB).

MATERIALS AND METHODS: The study included 42 patients with exogenously constitutional obesity, which were divided into 2 groups, comparable by sex, age and body mass index (BMI). The first group (n=22) received treatment recommendations for the correction of nutrition and physical activity, as well as liraglutide 3.0 mg for 3 months. The second group (n=20) received only recommendations for the correction of nutrition and physical activity. At the start and after 3 months, anthropometric characteristics and laboratory parameters were evaluated in all patients, including the levels of endogenous peptide bioregulators of IB (leptin, ghrelin, obestatin and GLP-1), their dynamics was compared between groups. Depending on the therapeutic effect, the 1st group was divided into two subgroups: those who achieved (n = 14) and did not achieve (n = 8) a clinically significant decrease in body weight. In both subgroups, baseline characteristics were analyzed as possible prognostic factors for the effectiveness of complex therapy.

RESULTS: To predict an early response to complex therapy, including liraglutide, a mathematical model has been developed that is implemented as a calculator in MS Excel and contains a combination of initial body weight and fasting plasma ghrelin. The dynamics of body weight and BMI in the group of complex therapy was statistically significantly higher than that in the group of isolated lifestyle modifications (ILM).

CONCLUSIONS: The proportion of individuals with an early response to 3.0 mg liraglutide therapy is comparable to that of data from randomized clinical trials. The mathematical model, which includes a combination of initial body weight and plasma ghrelin, allows predicting the likelihood of a clinically significant decrease in body weight after 3 months of using liraglutide 3.0 mg in combination with ILM with a sensitivity of 86% [65%; 97%] and prognostic value of a positive result of 80% [60%; 95%].

Obesity and metabolism. 2020;17(1):3-12
Diagnostic value of salivary cortisol in 1-mg dexamethasone suppression test
Belaya Z.E., Malygina A.A., Grebennikova T.A., Il'yin A.V., Rozhinskaya L.Y., Fadeev V.V., Melnichenko G.A., Dedov I.I.

BACKGROUND: Late-night salivary cortisol and serum cortisol measurements after 1-mg Dexamethasone Suppression Test (1-mg DST) are routinely used to diagnose Cushing’s syndrome (CS). Measuring morning salivary instead of serum cortisol after 1-mg DST would make the diagnostics of CS fully non-invasive.

AIM: To evaluate the diagnostic accuracy of salivary cortisol in 1-mg DST as measured by electrochemiluminescence assay (ECLIA).

MATERIALS AND METHODS: We combined a cohort diagnostic study, including 164 participants (132 females, 32 males) aged from 18 to 77 years: 110 were overweight or obese as increased BMI is the most common sign of Cushing’s Syndrome (CS), and 54 healthy volunteers. In each cohort late-night salivary cortisol was measured (at 23:00) followed by 1-mg DST and blood and salivary sampling for cortisol measurement the next morning at 08:00-09:00. Cortisol in saliva and serum were measured on automatic analyzer Cobas е 601 by F. Hoffmann-La Roche Ltd, using ECLIA. The final diagnosis was confirmed by the histological evaluation after surgery or using a follow-up observation in patients with obesity to exclude Cushing’s syndrome manifestation.

RESULTS: Among 110 patients, 54 subjects were finally confirmed as having Cushing's syndrome. Reference interval for salivary cortisol after 1-mg DST was estimated to be 0,5–12,7 nmol/l (5–95 procentile). Maximal salivary cortisol level in 1-mg DST registered in healthy person was 29,6 mmol/l. Areas under the curve (AUC) were as following: for salivary cortisol in 1-mg DST – 0,838 (95% СI 0,772–0,905), for blood cortisol in 1-mg DST – 0,965 (95% CI 0,939–0,992) and for late-night salivary cortisol – 0,925 (95% CI 0,882–0,969). The optimal cut-off point for salivary cortisol after 1-mg DST was estimated as 12.1 nmol/l (sensitivity 60%, specificity 92,9%) among CS versus healthy subjects; 12,6 (sensitivity 58,2%, specificity 96,2%) among patients with obesity and CS; and – 12,2 nmol/l (sensitivity 60,7%, specificity 93,4%) among CS and both obese and healthy control subjects. Considering small difference between cut-off points, the recommended cut-off value for salivary cortisol after 1-mg DST is recommended to be 12,0 nmol/l if measured by ECLIA.

CONCLUSION: Although salivary cortisol after 1-mg DST is inferior to serum cortisol after 1-mg DST in the diagnostic performance and diagnostic accuracy, it can be used as a low-invasive screening test with superior specificity.

Obesity and metabolism. 2020;17(1):13-21
Antioxidant vitamin status of obese patients in terms of the risk of comorbidities
Kodentsova V.M., Vrzhesinskaya O.A., Kosheleva O.V., Beketova N.А., Sharafetdinov K.K.

BACKGROUND: Synchronously optimized concentrations of vitamins C, E, A, carotenoids and their ratios in blood plasma help to prevent or slow down the development of many alimentary-dependent diseases and their complications.

AIMS: to characterize the vitamin status of obese patients from the standpoint of the risk of progression of existing and development of associated diseases.

MATERIALS AND METHODS: An observational single-site cross-sectional study of the sufficiency with antioxidant vitamins in 81 patients (21 men, 60 women) aged 20–75 years with body mass index 40,7±1,2 kg/m2, enrolled for treatment from April to June in Federal Research Centre of Nutrition, Biotechnology had been conducted. The concentration of α- and γ-tocopherols, retinol, ascorbic acid, β-carotene was determined in blood serum and their ratios with lipid profile were calculated.

RESULTS: Indicators of vitamin status were determined in 35 patients with obesity, 27 patients with obesity and cardiovascular diseases (CVD), 19 patients with obesity and type 2 diabetes mellitus (T2DM). The concentration of ascorbic acid in more than 50% of patients did not reach the optimal level (50 µmol/l). Compared to patients of other groups, patients with T2DM were better supplied with vitamin E, but worse with other vitamins. They have a non-optimal ratio of concentrations of vitamin C and E more often compared with patients of other groups (p≤0.050). Among them, the combined suboptimal level of vitamin C and β-carotene (<0.4 µmol/l) was detected 1.6–1.8 fold more often. The lack of antioxidants in patients with T2DM according to simultaneously reduced vitamin C/vitamin E ratio (<1.5) and β-carotene level was detected 3.3-fold more often, synchronously lowered vitamin C/vitamin E ratio and vitamin C level – 2.4-fold. γ-tocopherol level in serum of patients with T2DM tended to increase compared with that in patients with obesity (p=0.063) and CVD (p=0.081), γ-tocopherol/triacylglycerides ratio was 1.5-fold higher (respectively р=0.009 и р=0.076). Only in 2 patients with obesity and 2 patients with CVD all serum indicators corresponded to the optimal level of all vitamins. In terms of α-tocopherol/cholesterol (<5 µmol/mol), an increased risk of myocardial infarction was detected in 10.5–42.9% of the examined patients. Glucose level was positively associated with serum levels of α- and γ-tocopherols, as well as cholesterol-adjusted individual tocopherols; while glycemia was inversely associated with triacylglycerides-standardized individual tocopherols, as well as β-carotene and vitamin C/vitamin E ratio.

CONCLUSIONS: In most patients, a non-optimal serum vitamin content was found according to one or several parameters. In order to vitamin C/vitamin E ratio, patients with T2DM need to increase vitamin C intake. Increasing serum β-carotene and achieving an optimal C/E ratio will help to prevent an increase in glycemia.

Obesity and metabolism. 2020;17(1):22-32
Pathogenetic aspects of cachexia
Klochkova I.S., Astafyeva L.I., Kadashev B.A., Sidneva Y.G., Kalinin P.L.

The relevance of cachexia syndrome is determined by its high prevalence in clinical practice. It accompanies the course of not only oncological diseases, but also the majority of chronic somatic pathologies, such as chronic heart failure, renal failure, diabetes mellitus, chronic obstructive pulmonary disease, acquired immunodeficiency syndrome, rheumatoid arthritis, Alzheimer’s disease and others. It is known that even a slight weight loss in patients can determine an unfavorable prognosis of the underlying disease and reduce the effectiveness of therapy, and sometimes it becomes the direct cause of death of the patient.

Cachexia is a complex metabolic syndrome, which is based on a violation of the central regulation of metabolism. The dangerous combination of decreased appetite (anorexia) and increased metabolism is the result of an imbalance in energy exchange. Treatment of cachexia syndrome is ineffective and limited in means. Given the progressive and irreversible nature of this syndrome, early diagnosis and prevention of its development are the primary task of the doctor.

The article describes the main pathogenetic aspects of the development of cachexia syndrome. They can be common in different diseases. The article discusses the difficulties of diagnosing cachexia syndrome, the possibilities and prospects of treatment.

Obesity and metabolism. 2020;17(1):33-40
Subclinical hypothyroidism and metabolic syndrome: reasons for drug intervention
Ruyatkina L.A., Ruyatkin D.S.

The high prevalence of metabolic syndrome (MS) and subclinical hypothyroidism (SHypo) creates danger of integral cardio-metabolic risk (CMR). A concept is being developed to increase thyroid-stimulating hormone (TSH) levels as a component of MS with the key role of insulin resistance (IR). To identify groups of active intervention, the definitions of SHypo with age and gender characteristics are analyzed. The results of randomized clinical trials showed a higher incidence of prediabetes and type 2 diabetes mellitus (T2DM) in SHypo, as well as positive associations of autoimmune thyroiditis (AIT) with components of MS, especially in postmenopausal women. The association of SHypo with a systemic inflammatory response is analyzed, which can determine an increase in cardio-metabolic risk. At the same time, most of the thyroid dysfunction and the components of MS are associated with insulin resistance.

The feasibility of SHypo treating with levothyroxine is discussed: the threshold parameters of thyroid-stimulating hormone (TSH) are not determined for initiating treatment; in old age, due to a decrease in the need for thyroid hormones, an increase in the upper reference range of TSH is discussed; there is no evidence of a decrease in cardiovascular risk and mortality. In parallel, data have been accumulated on a decrease in TSH levels in overt and subclinical hypothyroidism in patients with MS and T2DM with metformin therapy. The gender effect of metformin on the activity of the hypothalamus-pituitary-thyroid axis was suggested, its new antihyperglycemic mechanism of action, including the activation of the AMP protein kinase (adenosine monophosphate (AMP) -activated protein kinase) in the pituitary gland, was revealed.

It is possible that metformin is a promising therapeutic agent not only for patients with type 2 diabetes and thyroid disease, but also for MS and obesity. The multifaceted capabilities of metformin, including the correction of peripheral and central insulin resistance and a decrease in TSH levels in patients with SHypo, emphasizes an integrated approach to the prevention of CMR. The prolonged release form of metformin has several advantages: better tolerance, greater efficiency in the correction of IR, lipid and carbohydrate metabolism, additional indication - treatment of prediabetes, the possibility of prescribing for creatinine clearance up to 30 ml/min.

Obesity and metabolism. 2020;17(1):41-47
Insulin resistance in obesity: pathogenesis and effects
Lavrenova E.A., Drapkina O.M.

The prevalence of obesity in the world is described as the global epidepic. Being not only a chronic recurrent disease but also a serious risk factor, obesity leads to the development and aggravation of many non-communicable diseases. Excessive amount and adipose tissue dysfunction in obesity determines the risk of the development of type 2 diabetes, arterial hypertension, atherosclerosis, non-alcoholic fatty liver disease etc. Secondary insulin resistance often underlies the development of the above mentioned conditions. The mechanisms contributing to the development of insulin resistance in case of excessive adipose tissue accumulation are being intensively investigated over the last decades, however many questions yet remain unsolved. In this article we present the key mechanisms underlying insulin resistance in obesity and diagnostic approaches for insulin resistance as well as the current data in this topic. The authors review the close links between insulin resistance and obesity related diseases, namely disorders of carbohydrate metabolism, dyslipidemia, arterial hypertension, coronary artery disease and reproductive disorders.

Obesity and metabolism. 2020;17(1):48-55
Toll-like receptors in the pathophysiology of obesity
Kytikova O.Y., Novgorodtseva T.Р., Denisenko Y.К., Antonyuk M.V., Gvozdenko T.A.

Obesity is a complex and relevant global medical and social problem. The adipose tissue is not only a place of deposition of energy substrates but also a source of secretion of pro-inflammatory and anti-inflammatory mediators involved in the development of the chronic latent systemic inflammatory process in the organism with obesity. The metabolic signal in obesity contributes to the polarization of macrophages in the M1 direction and triggers the Th1 immune response, causing the development of adipose tissue inflammation. A chronic inflammatory condition plays a key role in the pathophysiology of obesity-induced insulin resistance. Toll-like receptors (TLRs) may be a possible pathophysiological link in the development of insulin resistance in inflammation. At the same time, inflammation-induced lipolysis is necessary for the release of energy resources during the development of the infectious process. Thus, low-grade inflammation is important to protect against adipocyte dysfunction. These results suggest that pro-inflammatory signaling is not exclusively pathogenic in obesity. In this regard, the study of inflammatory signaling pathways involved in the modulation of chronic inflammation of adipose tissue is particularly relevant. This review summarizes current views on the structure, function of TLRs and their involvement in the pathogenesis of chronic inflammation in obesity. The possibility of using TLRs as a therapeutic target in this pathology is discussed. Obviously, further study of inflammatory signaling pathways involving TLRs initiating the development of chronic inflammation of adipose tissue will allow the development of new and effective therapeutic strategies for obesity and its metabolic complications.

Obesity and metabolism. 2020;17(1):56-63
Quality of life, sexual function, and bariatric surgery: a systematic review
Ahmadi S., Teixeira L., Domingues J., Chacon-Mikahil M., Cavaglieri C., Gutierrez G.

BACKGROUND: Obesity is associated with numerous comorbidities and affects various aspects of life, including quality of life (QOL) and sexual function (SF). Bariatric surgery (BS) is an effective treatment for obese people. Also QOL and SF after BS in the people are not well known.

AIMS: To provide insight in the available prospective evidence regarding the short and long-term effects of BS on QOL and SF.

MATERIALS AND METHODS: A systematic multi-database search was conducted for ‘quality of life’, ‘Sexual function’ and ‘Bariatric surgery’. Only prospective studies with QOL or SF before and after BS were included. The ‘quality assessment tool for before–after studies with no control group’ was used to assess the methodological quality.

RESULTS: Twenty-four studies met the inclusion criteria. Most studies were assessed to be of ‘fair’ to ‘good’ methodological quality. Seven different questionnaires were used to measure both QOL and SF. A significant increase in QOL after BS and light increase in SF were found in all studies (P≤0.05).

CONCLUSIONS: Both QOL and SF are increased after BS on both the short and long term. However, due to the heterogeneity of the studies and the generality of the questionnaires are them hard to make a distinction among different BS and difficult to see a relation with medical profit. Therefore, designing QOL and SF measurements to the post BS population are recommended as the focus of future studies.

Obesity and metabolism. 2020;17(1):64-72
Characteristics of calcium and phosphorous metabolism in patients after bariatric surgery and the role of vitamin d supplementation in the prevention and treatment of postoperative bone and mineral disorders
Berkovskaya M.A., Kushkhanashkhova D.A., Sych Y.P., Fadeev V.V.

This article provides a review of current literature on the effect of various doses of vitamin D on the parameters of calcium and phosphorus metabolism in patients after bariatric surgery.

The decrease of bone mineral density is one of the most frequent complications of the bariatric surgery, which increases the risk of fractures. There are many different mechanisms for impaired mineral metabolism after bariatric surgery, but a decrease in the absorption of calcium and vitamin D plays a key role in this process. Vitamin D is the most important endocrine regulator of calcium homeostasis in the body, which provides the absorption of 90% of calcium in the gut. Patients with morbid obesity have a high risk of vitamin D deficiency even before surgery, which may worsen after operation and in the absence of timely treatment lead to severe disturbances of calcium and phosphorus metabolism.

It was found that high doses of vitamin D after bariatric surgery can improve parameters of bone metabolism, and, as a result, prevent fractures after surgery, which generally has a beneficial effect on the quality of life and labor prognosis. The results of the studies available to date open up new opportunities for the prevention and treatment of postoperative complications associated with impaired bone metabolism.

Obesity and metabolism. 2020;17(1):73-81
The relationship of vitamin D status with the development and course of diabetes mellitus type 1
Povaliaeva A.A., Pigarova E.A., Dzeranova L.K., Rozhinskaya L.Y.

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease that develops as a result of a genetic predisposition and environmental factors. Literature data indicate that the suboptimal status of vitamin D can be considered as a risk factor for the development of T1DM, especially at some stages of life. Adequate vitamin D supplementation in childhood may provide a protective effect and reduce the risk of developing T1DM at a later age. Pathogenesis of T1DM predisposes to abnormalities in the metabolism of vitamin D, including the development of vitamin D deficiency. Moreover, the immunomodulating effect of calcitriol (induction of immune tolerance and T-cell anergy, impaired B-cell activity and antibodies production) suggests the therapeutic potential of vitamin D in autoimmune diseases, including T1DM. A number of studies have demonstrated the positive clinical effects of various vitamin D preparations with respect to maintaining residual β-cell function, improving glycemia control in patients with T1DM. Determining the optimal doses of vitamin D for patients with T1DM may contribute to disease control and prevention of complications.

Obesity and metabolism. 2020;17(1):82-87
Case Report
Сase of successful treatment of chronic gastric remnant haemorrhagic ulcer after Roux-en-Y gastric bypass
Ryzhov M.K., Zubeev P.S., Grekova N.S., Vasyankin V.I.

Acute bleeding from a gastric remnant ulcer is an exceptionally rare complication, especially if it occurs several years after bariatric surgery. We present a case of a patient with a bleeding gastric remnant ulcer that occurred 6 years (2013–2019) after the Roux-en-Y Gastric Bypass (RYGB) performed for morbid obesity. The patient was urgently hospitalized in the surgical department with the clinic of gastrointestinal bleeding, according to fibroesophagogastroscopy, no sources of bleeding were found in the examined departments. On the background of conservative treatment, there was an improvement in the condition, but on the fifth day of hospitalization there was a clinic of recurrence of bleeding, while repeated emergency endoscopic examination of the sources also did not reveal. In this regard, it was decided to perform surgery to examine the «residual» stomach. With the help of laparoscopic transgastric gastroduodenoscopy, we were able to detect the source of active bleeding in the stomach excluded from digestion - a bleeding ulcer in the area of small curvature. The removal of this stomach was performed with a good postoperative recovery: the patient was discharged in a satisfactory condition for outpatient treatment, currently feels well, returned to work.

Obesity and metabolism. 2020;17(1):88-92
A case of chronic tophi gout in morbidly obese patient after laparoscopic adjustable gastric banding
Kushnarenko N.N., Mishko M.Y., Medvedeva T.A., Kushnarenko K.E.

Currently, increasing attention is being paid to studying the metabolic activity of adipose tissue, a source of biologically active mediators involved in vascular remodeling, immunological and inflammatory reactions. Today obesity is considered not only as independent risk factor of development of chronic noninfectious diseases (such as arterial hypertension, diabetes mellitus types 2, pathology of a cardiovascular system, malignant neoplasms), but also as a significant predictor of metabolic disorders (dyslipidemia, insulin resistance, hyperuricemia), contributes to the early formation of metabolic syndrome and goat. Despite such an obvious problem, the current state of conservative therapy for overweight and obesity remains unsatisfactory. Most of patients, even after successful treatment, have a recurrence of the disease with the restoration of the initial anthropometric indicators or even an increase in body weight. In this regard, currently more widely used surgical methods of correction of obesity. However along with the expected positive effects of treatment bariatric surgery may be accompanied by the development of a number of specific surgical complications and impaired energy metabolism with aggravation of the existing polymorbid pathology. This clinical case demonstrates the association of obesity with the development of metabolic disorders, illustrates the development of severe tophaceous gout in a patient during 2 years after laparoscopic gastric banding. It shows the possible reasons for its debut and reflects the dynamics of the patient’s condition, as well as the nature and characteristics of the course of the joint syndrome in the postoperative period.

Obesity and metabolism. 2020;17(1):93-99
Navigated repetitive transcranial magnetic stimulation to correct eating behavior in obesity (clinical cases)
Kuznetsova P.I., Logvinova O.V., Poydasheva A.G., Kremneva E.I., Bakulin I.S., Raskurazhev A.A., Lagoda O.V., Suponeva N.A., Troshina E.A., Tanashyan M.M., Piradov M.A.

Obesity is a pathological condition caused by overweight and requiring medical intervention. The clinical and scientific experience gained over the past decades has allowed researchers to consider this problem as an independent disease with its own pathophysiological features, prevalence, incidence, approaches to therapy and prevention. One of the most important factors in the pathogenesis of obesity is disordered eating behavior, the central regulation of which is carried out with the active participation of the prefrontal cortex. Impact on this area (for example, using non-invasive brain stimulation) may be one of the promising ways to modulate eating behavior. The article describes clinical cases of treatment of morbid obesity using navigated rhythmic transcranial magnetic stimulation (rTMS). Different patterns of dorsolateral prefrontal cortex (DLPFC) activation before and after rTMS are demonstrated. Possible mechanisms of the influence of DLPFC on the formation of eating behavior are also considered. These data underline the important role of DLPFC dysregulation in obesity, as well as show potentially effective neuromodulation techniques.

Obesity and metabolism. 2020;17(1):100-109

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