Метформин, препарат первой линии выбора при лечении сахарного диабета 2 типа (СД2), действуя как на периферические ткани, так и на различные области мозга, восстанавливает метаболические и гормональные показатели. Интраназально вводимый инсулин (ИИ), попадая в мозг, нормализует ослабленную при СД2 инсулиновую сигнализацию в ЦНС, в том числе в гипоталамусе, и тем самым улучшает центральную регуляцию метаболизма, пищевого поведения и функций эндокринной системы. Нами высказано предположение, что при совместном использовании метформина и ИИ будет наблюдаться усиление их восстанавливающего эффекта на метаболические и гормональные показатели при СД2. Целью работы было изучить влияние лечения самцов крыс с СД2, вызванным высококалорийной диетой и низкой дозой стрептозотоцина, с помощью метформина (4 недели, 100 мг/кг/сутки) и ИИ (4 недели, 0,5 МЕ/крысу/сутки), по отдельности и совместно, на чувствительность к глюкозе, уровни инсулина, лептина, глюкагоноподобного пептида-1 (ГПП-1), тиреоидных гормонов и тестостерона. Монотерапия метформином улучшала глюкозный гомеостаз, нормализовала базальные и стимулированные глюкозой уровни инсулина, лептина и ГПП-1. Совместное применение метформина с ИИ усиливало восстанавливающие эффекты метформина на чувствительность тканей к инсулину и уровни лептина. Метформин и ИИ нормализовали уровни тиреоидных гормонов и тестостерона, а их совместное применение вызывало активацию тиреоидной системы, о чем свидетельствует повышение уровней тиреоидных гормонов. Полученные нами данные указывают на перспективы комбинированного применения метформина и ИИ для улучшения метаболических и гормональных показателей, а также тиреоидного и андрогенного статуса у пациентов с СД2.

Сахарный диабет 2-го типа (СД2) характеризуется нарушениями в сигнальных системах мозга, в том числе регулируемых инсулином. Для восстановления инсулиновой сигнализации в мозге может быть применен интраназально вводимый инсулин (ИИ). Эффективность ИИ, как показано нами ранее при СД1 и инсулинодефицитном СД2, повышается при совместном применении с интраназально вводимым С-пептидом (ИС). Целью работы было изучить влияние 9-дневного лечения крыс с диет-индуцированным СД2 с ожирением и гиперинсулинемией с помощью ИИ (0,5 МЕ/крысу/сутки) и его комбинации с ИС (36 мкг/крысу/сутки) на метаболические показатели, базальные и стимулированные глюкозой уровни инсулина, адипокинов, глюкагоноподобного пептида-1, грелина, гормональный статус тиреоидной и гонадной систем, уровни инсулина и лептина в гипоталамусе и экспрессию гипоталамических генов, кодирующих рецепторы и пищевые факторы. Монотерапия ИИ нормализовала сниженный при СД2 уровень инсулина в гипоталамусе, улучшала глюкозный гомеостаз, тиреоидный статус, ответы инсулина, лептина и инкретинов на глюкозу, восстанавливала экспрессию гипоталамических генов проопиомеланокортина и M4-меланокортинового рецептора, опосредующих снижение аппетита, и снижала экспрессию гена орексигенного нейропептида Y. Совместное применение ИИ и ИС не усиливало эффекты ИИ. Монотерапия ИС была неэффективной и даже усугубляла метаболические показатели. Таким образом, у крыс с СД2 и гиперинсулинемией ИИ улучшал метаболические и гормональные показатели, что обусловлено нормализацией сниженного в результате ослабления рецептор-опосредуемого транспорта через гематоэнцефалический барьер уровня инсулина в мозге, в то время как ИС, в том числе в комбинации с ИИ, оказался неэффективным.

Type 1 diabetes mellitus (T1DM) is characterized by a deficiency of insulin, as well as C-peptide, which is a modulator of the activity of insulin signaling pathways. The C-peptide replacement therapy for T1DM improves metabolic performance, restores the functions of the nervous and excretory systems. It is believed that through central mechanisms it can restore the functions of the endocrine system that are impaired in T1DM. To compensate the deficiency of the C-peptide in the CNS, an intranasal route of administration can be used. The aim was to study the effect of treatment (9 days) of male Wistar rats with a model of mild T1DM induced by a low-dose streptozotocin (35 mg/kg) using intranasally administered C-peptide (36 μg/rat/day) and insulin (20 μg/rat/day), jointly or separately, on the hormonal parameters of the thyroid and gonadal systems, as well as on the activity of adenylyl cyclase (AC) in the membranes isolated from the thyroid and testes. The enzyme adenylyl cyclase is involved in the regulation of the synthesis of thyroid hormones in the thyrocytes and testosterone in the Leydig cells. The plasma levels of thyroid-stimulating (TSH) and luteinizing hormones (LH), thyroid hormones, testosterone, insulin and leptin were measured. The treatment of rats with a C-peptide in the combination with insulin caused a decrease in hyperglycemia, despite hypoinsulinemia, restored the reduced levels of triiodothyronine, testosterone and leptin, normalized the TSH level increased in T1DM, and did not affect the LH level, which did not change in the conditions of T1DM. One of the mechanisms for normalizing the functions of the thyroid and gonadal systems in the case of treatment with the insulin and C-peptide was the restoration of the stimulating effect of TSH on AC activity in the thyroidal membranes and the corresponding effect of human chorionic gonadotropin in the testicular membranes. The monotherapy with insulin was less effective, while monotherapy with C-peptide partially restored an androgen status only on the third day after the start of treatment. Thus, we have shown the potentiating effect of the C-peptide on insulin-induced restoration of the functions of the thyroid and gonadal systems in rats with mild T1DM, which, in our opinion, is based on the enhancement of insulin signaling in the hypothalamus in the presence of the C-peptide.

The brain serotonin system plays a key role in the regulation of behavior and cognitive functions, but also in the control of food intake and energy metabolism. This involves the serotonergic midbrain neurons expressing the type 2 tryptophan hydroxylase (TPH-2), which catalyzes the synthesis of serotonin, and the hypothalamic neurons expressing the serotonin receptors. Currently, the changes in the expression and distribution of TPH-2 in midbrain neurons in obesity remain poorly understood. Along with this, it is assumed that serotonin can also be synthesized in the hypothalamic neurons, affecting the serotonin system within the hypothalamus, but there are no data on the expression and possible localization of TPH-2 in the hypothalamic neurons. The aim of the work was to study the TPH-2 expression in the midbrain and its distribution in the neurons of the arcuate, paraventricular and supraoptic nuclei of the hypothalamus in mice with diet-induced obesity (DIO) and in agouti mice with genetically-induced obesity of the melanocortin type. The TPH-2 gene expression was detected in the hypothalamus of C57Bl/6J mice, and the double immunolabeling showed the localization of this enzyme in proopiomelanocortin (POMC) -immunopositive neurons and paraventricular of the arcuate nuclei and in vasopressin-immunopositive neurons of the paraventricular and supraoptic nucleus. In both types of obesity, the number of TPH-2-immunopositive granules in the POMC- and vasopressin-immunopositive neurons was increased, although the expression of the Tph2 gene was increased only in agouti mice. In the midbrain of DIO mice, the content of TPH-2 was decreased, while in agouti mice it did not change. These results indicate the important role of serotonin synthesized in the hypothalamus, which, together with serotonin coming from the midbrain, is involved in the compensatory changes of hypothalamic signaling in obesity. The detection of TPH-2-immunopositive hypothalamic neurons of different types, capable of synthesizing serotonin, indicates the existence of new mechanisms of the autocrine and paracrine serotonin regulation in the hypothalamus, including the obesity conditions.

Orexin-A is one of the regulators of food intake and energy metabolism. In the brain, this peptide is formed in the neurons of the perifornical hypothalamic area from prepro-orexin, and its action is realized through two types of orexin receptors (OX1R, OX2R). In the diet-induced obesity (DIO), the activity of the hypothalamic orexin system changes, but the data on the orexin-А level and the expression of OX1R and OX2R are few and contradictory. In the case of melanocortin obesity, these data are not available. The aim of the work was to study the orexinergic system in the hypothalamus of mice with the different forms of obesity: with DIO, induced by a high-calorie diet (8 and 16 weeks) in C57Bl/6J (a/a) mice, and agouti mice, C57Bl/6J (Ay/a), with genetically determined melanocortin obesity. The level of orexin-A in neurons was evaluated in brain sections by immunohistochemistry; the gene expression of prepro-orexin (pOx), Ox1r and Ox2r in the hypothalamus was measured by quantitative PCR. In DIO mice, the level of orexin-A and the expression of the pOx and Ox1r genes in the hypothalamus were changed depending on the duration of the diet: increased after 8 weeks and returned to the control values after 16 weeks. At the same time, the expression of the Ox2r gene did not change. In agouti mice, a decrease in the immunopositive orexin-A level in the perifornical area neurons of the hypothalamus was shown. The expression of the pOx, Ox1r and Ox2r genes in the hypothalamus of agouti mice did not change significantly. The findings suggest that reducing orexin-A level in conditions of prolonged, heavy obesity may be a compensatory response aimed at reducing calorie intake, and the orexin system of the hypothalamus can be considered as one of the targets for correcting and preventing the different forms of obesity.

The metabolic syndrome (MS) is characterized by chronic mild inflammation that is a consequence of complex interaction between the genetic and environmental factors. The review presents the current view on the role of inflammation and oxidative stress in the development of MS and pathology associated with it. The contribution of adipokines and adipocytokines, such as tumor necrosis factor-б (TNF-б), interleukin-6 (IL-6), leptin, adiponectin and plasminogen activator inhibitor-1 (PAI-1), in the development of inflammation, obesity and insulin resistance is discussed. The molecular mechanisms of formation of oxidative stress in MS are considered. The review provides information on the redox-sensitive transcription factors such as FoxO, NF-кB and AP-1, and also on the Keap1/Nrf2/ARE system which play an important role in the integration of the intracellular signal systems participating in the inflammatory processes and responsible for the decrease in insulin sensitivity. A conclusion was made on the functional interrelation between the oxidative stress, inflammation, obesity and MS.

Background. Metabolic syndrome (MS) is closely associated with the development of diseases of the cardiovascular system, one of the causes of which are changes in the hormonal system, including adenylyl cyclase signaling system (ACSS), which is sensitive to agonists of adrenergic receptors (AR) and the other hormones and plays a key role in the regulation of myocardial function. However, the functional state of the myocardial ACSS in MS is currently poorly understood. Objective. The aim of the work was to study the hormone sensitivity of ACSS in the myocardium of rats with MS and the influence of metformin (MF) and intranasally administered insulin (I-I) treatment on it. Design and methods. The MS in rats was caused by two-month consumption of 30% sucrose solution and diet enriched by saturated fat. The treatment of the MS-rats with MF (200 mg/kg/day) and I-I (0.5 IU/rat/day) was performed for 5 weeks. Results. The MF and I-I treatment of MS-rats led to restoration of glucose tolerance, insulin sensitivity and lipid metabolism. In the myocardium of MS-rats the adenylyl cyclase (AC) stimulating effects of s1/s2-AR agonists, relaxin and glucagon-like peptide-1 were decreased, the relationship between s1/s2- and s3-AR was shifted to s3-AR, and the inhibitory effect of 2-chloro-N 6 -cyclopentyl adenosine, an agonist of A 1 -adenosine receptors, was reduced. The treatment with MF and, to a lesser extent, with I-I restored the hormonal regulation of AC in the myocardium. Conclusion. Thus, in the myocardium of MS-rats the hormonal sensitivity of ACSS was impaired, and the MF and I-I treatment led to its complete or partial restoration, which is one of the mechanisms of cardioprotective effect of these drugs.

Glucose-6-phosphate dehydrogenase (G6PD) play an important role in the pathogenesis of type 2 diabetes mellitus (T2DM) and metabolic syndrome (MS), and it can be regarded as one of the targets in their treatment. However, the data on changes in the G6PD activity in these diseases are scarce. The aim of this work was to study the G6PD activity in the brain, myocardium and epididymal fat (EF) in male rats with T2DM and MS and the influence of long-term treatment with antidiabetic drug metformin (MF) on it. To induce T2DM, five-day rat pups were treated with streptozotocin (75 mg/kg). The MS in rats was induced by diet consisting of 30% glucose solution and saturated fats. The treatment of T2DM and MS was carried out at a daily dose 200 mg/kg for 5 or 10 weeks. It was shown that in the brain of rats with T2DM and MS the G6PD activity changed weakly. In the myocardium and EF in rats with T2DM and MS the G6PD activity significantly increased. The treatment of animals with MF led to decrease of this activity, and in the myocardium of rats with T2DM the enzyme activity reached its level in control. Thus, we showed that in the myocardium and EF of rats with T2DM and MS the G6PD activity was significantly increased, and the MF treatment normalized it, which is one of the mechanisms of therapeutic action of MF.

Background. The abnormalities of micro- and macrocirculation in obesity are associated with the changes in the activity of NO-synthases, the enzymes catalyzing synthesis of endogenous NO. However, in experimental obesity they are not well understood. There are no data on the influence of long-term treatment with intranasally administered insulin (I-I) that is used for the treatment of pre-diabetic states on NO-synthase activity. Objective. The aim of this work was to study the activity of NO-synthases in the tissues of rats with obesity induced by high- fat diet and the influence of long-term I-I treatment on them. Design and methods. To induce the obesity, Wistar male rats received a high-fat diet during 4 months. The I-I treatment was started on the 60 th day of the diet, and carried out for two months at a daily dose 0.48 IU/rat. The activity of total, neuronal and endothelial isoforms of NO-synthase in the brain, myocardium and skeletal muscles was evaluated. Results. It was shown that in the myocardium and skeletal muscles of obese rats the activity of total and endothelial NO-synthases was decreased, and in the brain it has not significantly changed. The treatment of obese rats with II resulted in partial or complete restoration of the activity of total and endothelial NO-synthases in the myocardium and skeletal muscles, and caused an increase of NO-synthase activity in the brain above this level in control. Conclusion. Summing up, long-term I-I treatment restores insulin signaling system in the brain and positively affect the NO-synthase system in CNS and periphery, attenuated in the obesity, which can lead to improved blood circulation and to prevent the development of dysfunctions of the nervous, the cardiovascular and other systems.