Metformin is the first-line drug of choice in the treatment of type 2 diabetes mellitus (T2DM). It acts on peripheral tissues as well as different regions of the brain and restores metabolic and hormonal parameters. Insulin administered intranasally (II) enters the brain and normalises the insulin signaling in the central nervous system, including the hypothalamus, which is weakened in T2DM. This improves the central regulation of metabolism, food intake and functions of the endocrine system. We suggested that the combined use of metformin and II should enhance their restorative effect on the metabolic and hormonal parameters in T2DM. The study was conducted on male rats with T2DM2 induced by a high-calorie diet and a low-dose streptozotocin. The male rats with T2DM were administered metformin (4 weeks, 100 mg/kg/day) and II (4 weeks, 0.5 IU/rat/day), separately and together. The aim of the study was to analyse the effect of the treatment on glucose sensitivity and the levels of insulin, leptin, glucagon-like peptide-1 (GLP-1), thyroid hormones and testosterone. Metformin monotherapy improved glucose homeostasis and normalised basal and glucose-stimulated levels of insulin, leptin and GLP-1. Co-administration of metformin with II enhanced the restorative effects of metformin on tissue insulin sensitivity and leptin levels. Metformin and II normalised the levels of thyroid hormones and testosterone, and their combined use caused the activation of the thyroid system, as indicated by an increase in the levels of thyroid hormones. The data obtained indicate the prospects for the combined use of metformin and II for improving metabolic and hormonal parameters. It may also be used to improve the thyroid and androgenic status in patients with T2DM.

The study of the molecular mechanisms of metabolic syndrome (MS) and its complications are among the most acute problems of modern endocrinology. Functional changes in the expression, activity, and regulatory properties of neuronal NO synthase (nNOS), which catalyzes the formation of the most important secondary mediator, nitric oxide (NO), and its dependent NO/cGMP signaling pathways in the brain, myocardium, and skeletal muscles, play a key role among the molecular causes of MS. In the brain, nNOS is associated with NMDA receptors, the hyperactivation of which in MS leads to excessive stimulation of nNOS and hyperproduction of NO, which leads to NO-induced damage to neurons and disruption of the central regulation of physiological processes and neurodegeneration. In the myocardium with MS, there are changes in the expression and localization of nNOS, as well as its functional interaction with cytoskeletal proteins, which leads to disorders of myocardial contraction and hypertrophy. In skeletal muscles, nNOS controls their contraction, oxidative metabolism, is involved in the regulation of vascular relaxation, and also participates in the regulation of glucose transport. A decrease in the expression and activity of nNOS, as well as dysregulation of its activity in MS, cause disturbances of these processes and make a significant contribution to the development of insulin resistance and deterioration of glucose homeostasis. Thus, nNOS can be considered an important therapeutic target in the treatment of MS and other metabolic disorders, as well as to prevent their complications from the nervous and cardiovascular systems and the musculoskeletal system.

This literature review presents the role of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO), as well as arginine, the enzyme substrate, in the disease of metabolic syndrome and COVID-19 (SARS-CoV-2 virus). Metabolic syndrome is a combination of obesity, insulin resistance, hyperglycemia, dyslipidemia and hypertension. It has been shown that in elderly people, patients with obesity, metabolic syndrome, type 2 diabetes mellitus (DM2), and patients with COVID-19, endothelial dysfunction (ED) and vascular endothelial activation are detected. ED is the main cause of a number of pathological conditions during the development of COVID-19 and earlier in patients with metabolic syndrome, while a sharp drop in the level of nitric oxide (NO) is detected due to a decrease in the expression and activity of eNO synthase and enzyme depletion, which leads to a violation of the integrity of bloodvessels, that is, to vasoconstrictive, inflammatory and thrombotic conditions, followed by ischemia of organs and edema of tissues. It should be noted that metabolic syndrome, DM2, hypertension and obesity, in particular, are age-related diseases, and it is known that blood glucose levels increase with age, which reduces the bioavailability of NO in endothelial cells. Defects in the metabolism of NO cause dysfunction in the pulmonary blood vessels, the level of NO decreases, which leads to impaired lung function and coagulopathy. The review presents possible mechanisms of these disorders associated with ED, the release of eNO synthase, changes in phosphorylation and regulation of enzyme activity, as well as insulin resistance. A modern view of the role of the polymorphism of the eNO synthase gene in the development of these pathologies is presented. To increase the level of endothelial NO, drugs are offered that regulate the bioavailability of NO. These include arginine, agonist NO – minoxidil, steroid hormones, statins, metformin. However, further research and clinical trials are needed to develop treatment strategies that increase NO levels in the endothelium.

Metabolic syndrome includes the following symptoms: obesity, hyperlipidemia, hypertension, insulin resistance, and cardiovascular disease. The purpose of this review is to elucidate the role of adipokines in the regulation of the L-arginine-NO-synthas-NO signaling pathway in the pathogenesis of metabolic syndrome. The main questions raised in the review are: how adipokine secretion changes, how the level of their receptors is regulated, and which signaling pathways are involved in the transmission of adipokine signals when coupled to the L-arginine-NO-synthase-NO signaling cascade. Adipokines are peptide hormones that transmit a signal from adipose tissue to targets in the brain, blood vessels, liver, pancreas, muscles, and other tissues. Some adipokines have anti-inflammatory and insulin-sensitive effects: adiponectin, omentin, adipolin, chemerin, progranulin. Others have the negative inflammatory effect in the development ofmetabolic syndrome: visfatin, vaspin, apelin. Adipokines primarily regulate the expression and activity of endothelial NO-synthase. They either activate an enzyme involving 5-AMP protein kinase or Akt kinase, increasing its activity and synthesis of NO in the tissues of healthy patients: adiponectin, adipolin, omentin, or inhibit the activity of eNOS, which leads to a decrease in NO-synthase and suppression of mRNA bioavailability: vaspin, visfatin, apelin in metabolic syndrome, and a decrease in its activity leads to dissociation and endothelial dysfunction. It should be noted that the bioavailability of NO formed by NO-synthase is affected at many levels, including: the expression ofNO-synthase mRNA and its protein; the concentration of L-arginine; the level of cofactors of the reaction; and to detect the maximum activity of endothelial NO-synthase, dimerization of the enzyme is required, posttranslational modifications are important, in particular, phosphorylation of endothelial NO-synthase by serine 1177 with the participation of 5-AMP protein kinase, Akt kinase and other kinases. It should be noted that the participation of adiponectin, omentin, and kemerin in the regulation of the L-arginine-NO-synthase-NO cascade in metabolic syndrom opens up certain opportunities for the development of new approaches for the correction of disorders observed in this disease. The review analyzes the results of research searching in PubMed databases, starting from 2001 and up to 2020 using keywords and adipokine names, more than half of the references of the last 5 years.

The hypothalamus controls food behavior, and the abnormalities in this regulation induce obesity. This is largely due to the changes in the balance of the hypothalamic factors, such as ore-xigenic factors, including orexin (OR), agouti-like peptide (AgRP) and neuropeptide Y (NPY), and anorexigenic factors including the melanocortin peptides generated from pro-opiomelanocortin (POMC). The data on the expression and the ratio of these factors in obesity induced by the high-calorie diet are few and contradictory. The aim was to study the expression of POMC, OR of the A-type (OR-A), AgRP and NPY in the hypothalamic structures of male rats with cafeteria diet-induced obesity as compared to control animals. Starting the 26-day-old age, the rats consumed a cafeteria diet for 12 weeks, which leads to obesity, insulin resistance, the changes in the carbohydrate and lipid metabolism, and hyperleptinemia. In the perifornical area of the hypothalamus of obese rats, a significant decrease in the number of OR-A and the mRNA expression for the gene encoding pre-proorexin, the OR-A precursor, was shown. In the hypothalamic arcuate nuclei of obese rats, the expression of the gene for AgRP, the antagonist of type 4 melanocortin receptor, was decreased, the expression of the gene for POMC was increased, and the expression of the gene for NPY changed to a small extent. Thus, in different areas of the hypothalamus of rats with cafeteria diet-induced obesity, the compensatory processes are triggered to increase anorexigenic effects and suppress orexigenic effects, which should weaken hyperphagia and prevent the negative metabolic and hormonal changes caused by excessive caloric intake

The effect of the two-month metformin treatment (200 mg/kg/day) of rats with the neonatal model of type 2 diabetes mellitus on the functional activity of hypothalamic signaling systems was studied. It was shown that metformin treatment restored the sensitivity of hypothalamic adenylyl cyclase signaling system to agonists of the type 4 melanocortin receptor and the type 2 dopamine receptor but did not influence significantly the functions of the insulin signaling system. These data suggest new targets and mechanisms of metformin action in the CNS, which may mediate its restoring effect on energy homeostasis impaired in diabetic pathology.

The biguanide metformin, which is widely used for the treatment of type 2 diabetes, improves carbohydrate and lipid metabolism and has substantial cardioand neuroprotective effects. The positive effects of metformin on the activity of NO synthases catalyzing the synthesis of NO, a major vasodilator, and that of the hormone-sensitive adenylyl cyclase signaling system (ACSS) are believed to play an important role in the mediation of these effects. To prove this hypothesis, we initiated a study addressing the effect of prolonged metformin treatment of obese rats on metabolic parameters and the activity of ACSS and NO synthases in the myocardium and brain of the animals. Obesity was induced in Wistar rats by a high-fat diet, and the animals were subsequently treated with metformin for 2 months (the daily dose was 200 mg/kg). Metformin treatment induced a decrease in adipose tissue mass, total body mass, levels of insulin and glucose, and the insulin resistance index HOMA-IR, as well as improved glucose tolerance, and led to a decrease of the content of atherogenic forms of cholesterol. ACSS stimulation by agonists of β1/β2-adrenergic receptors (ARs) and enhancement of β3-AR signaling was detected in the myocardium of obese rats, while metformin treatment restored ACSS regulation by adrenergic agonists in the myocardium and normalized the balance between β-AR-signaling pathways. The stimulating effects of serotonin and agonists of type 4 melanocortin receptors on adenylyl cyclase, which are attenuated in obesity, were restored in the brain of rats treated with metformin. The treatment completely restored the total activity of NO synthases and the activity of endothelial NO synthase in the myocardium, which are reduced in obesity. Metformin treatment was also shown to induce hyperactivation of NO synthases in the brain and myocardium of healthy animals. It is proposed the effects of prolonged treatment of obese rats with metformin underlie the cardioand neuroprotective actions of this drug.

Biguanide metformin, which is widely used for the treatment of type 2 diabetes mellitus, improves carbohydrate and lipid metabolism and shows a pronounced cardio- and neuroprotective effects. It is assumed that an important role in these effects of metformin plays its ability to positively influence the activity of NO-synthase catalyzing the synthesis of NO, the most important vasodilator, and the activity of hormone-sensitive adenylyl cyclase signaling system (ACSS. To prove this, we have carried out a study whose purpose was to study the effect of long-term metformin treatment on the metabolic rates in obese rats, as well as on the activity of ACSS and NO-synthase in the myocardium and the brain of these animals. The metformin treatment of Wistar rats with obesity induced by high-fat diet was carried out for 2 months (daily dose of 200 mg/kg). The treatment with metformin led to a decrease in body weight and body fat, reduced glucose and insulin levels as well as reduced insulin resistance index HOMA-IR, improved glucose tolerance, and decreased the level of atherogenic forms of cholesterol. In the myocardium of obese rats, the attenuation of ACSS stimulation induced by the agonists of β1/β2-adrenergic receptors (AR) and the strengthening of β3-AR signaling has been found. At the same time, in the myocardium of animals treated with metformin, the regulation of ACSS by adrenergic agonists was restored, and the ratio of β-AR-signaling pathways returned to normal. In the brain of rats treated with metformin, adenylyl cyclase stimulating effects of serotonin and agonists of type 4 melanocortin receptors, which had been weakenend for obesity, were restored. Metformin treatment completely restored activity of total and endothelial NO-synthase in the myocardium decreased in obesity. It as also shown that metformin treatment induced hyperactivation of NO-synthase in the myocardium and brain of healthy animals. Thus, we conclude that the effects of metformin identified by us in rats with long-term treatment of obesity may explain cardio- and neuroprotective influence of this drug.

The stimulating effect of norepinephrine, isoproterenol and selective β-adrenoceptor (β3-AR) agonists BRL 37344 and CL 316.243 on the adenylyl cyclase signaling system (ACSS) in the brain and myocardium of young and mature rats (disease induction at 2 and 4 months, respectively) with experimental obesity and type 2 diabetes mellitus (DM2), and the influence of long-term treatment of animals with intranasal insulin (I-I) were studied. The AC stimulatory effects of β-agonist isoproterenol in animals with obesity and DM2 was shown to be practically unchanged. The respective effects of norepinephrine on the AC activity were attenuated in the brain of young and mature rats and in the myocardium if mature rats, and the I-I treatment led to their partial recovery. In the brain and myocardium of mature rats with obesity and DM2, the enhancement of the AC stimulatory effects of β3-AR agonists was observed, white in young rats the influence of the same pathological conditions was lacking. The I-I treatment decreased the AC stimulatory effects of β3-agonists to their levels in the control. Since functional disruption of the adrenergic agonist-sensitive ACSS can lead to metabolic syndrome and DM2, the recovery of this system by the I-I treatment offers one of the ways to correct these diseases and their complications in the nervous and cardiovascular systems.

Снижение функций щитовидной железы (ЩЖ), часто наблюдаемое при ожирении и метаболическом синдроме, приводит к развитию гипотиреоидного состояния и является одной из причин метаболических и функциональных нарушений. Предполагается, что терапия тиреоидными гормонами, нормализующая их уровень в организме, способна предотвратить эти нарушения. Однако исследования влияния такой терапии на метаболические показатели у животных с экспериментальным ожирением немногочисленны, а данные о ее влиянии на активность аденилатциклазной сигнальной системы (АЦСС) отсутствуют. Известно, что нарушения чувствительности АЦСС к гормонам играют ключевую роль в этиологии и патогенезе заболеваний, ассоциированных с метаболическими расстройствами. В представленной работе изучали влияние длительного приема левотироксина на показатели углеводного и липидного обмена, тиреоидный статус, активность АЦСС и ее регуляцию гормонами в головном мозге, миокарде, эпидидимальном жире и ЩЖ самцов крыс с ожирением. Крысы с ожирением, вызванным высокожировой диетой в течение 3 мес., на протяжении 4 недель получали левотироксин (перорально, в суточной дозе 20 мкг/кг) (группа ОЖ + ЛТ), в то время как контрольные животные и крысы с ожирением без лечения вместо гормона получали плацебо. Прием левотироксина приводил к восстановлению уровня тиреоидных гормонов, снижению массы тела и жировой ткани, а также уровней триглицеридов, общего и атерогенного холестерина, усилениию утилизации глюкозы. Наряду с этим в мозге, миокарде и эпидидимальном жире восстанавливалась активность АЦСС, нарушенная при ожирении. Левотироксин восстанавливал стимулирующие эффекты серотонина и дофамина в мозге, а также ингибирующие эффекты агонистов серотониновых рецепторов подтипа 1B и дофаминовых рецепторов типа 2 на активность аденилатциклазы (АЦ). В миокарде восстанавливались сниженные при ожирении стимулирующие эффекты -агонистов и релаксина. Следует, однако, отметить, что в группе ОЖ + ЛТ повышенные в условиях ожирения эффекты -агонистов не менялись, что приводило к усилению активирующего влияния -агонистов на АЦ и создавало определенные риски для развития сердечно-сосудистой патологии. В эпидидимальном жире наблюдали усиление липолитических эффектов -агонистов и ослабление антилиполитического эффекта агониста аденозинового рецептора типа 1, N6-циклопентиладенозина, что указывает на усиление липолиза в жировой ткани. Чувствительность АЦ к тиреотропному гормону в ЩЖ в группе ОЖ + ЛТ в условиях избытка тиреоидных гормонов снижалась. Таким образом, лечение левотироксином не только улучшает энергетический обмен и предотвращает дефицит тиреоидных гормонов в условиях экспериментального ожирения, но и восстанавливает гормональную регуляцию АЦСС, что может быть одним из механизмов действия тиреоидных гормонов на функции мозга и периферических тканей в условиях ожирения и других метаболических расстройств, сопровождаемых гипотиреоидными состояниями.

Obesity, a metabolic syndrome (MS) component, disturbs macro- and microcirculation largely due to the attenuation of NO-dependent cascades leading to pathology of the cardiovascular system. Among the activators of NO-synthases (NOS), the enzymes catalyzing NO synthesis, are thyroid hormones. Since obesity and MS are characterized by reduced functions of the thyroid gland, the replacement therapy with thyroid hormones exhibiting vasodilator properties is one of the approaches to functional recovery of the cardiovascular system. However, there is no information so far about the effect of thyroid hormones on NOS activity in obesity. The aim of this work was to study the effect of 4-week treatment of rats with high-fat diet induced obesity with L-thyroxine (20 μg/kg daily) on functional activity of total NOS as well as its endothelial (eNOS) and neuronal (nNOS) isoforms in the brain, myocardium and skeletal muscles. Obese rats were found to exhibit the reduced level of thyroid hormones, impaired glucose tolerance and dyslipidemia. In the myocardium and skeletal muscles of obese rats, total NOS and eNOS activities were considerably reduces, while in the brain they did not alter very much. Long-term treatment of obese rats with L-thyroxine led to a substantial increase in total NOS and eNOS activities in the myocardium and skeletal muscles as well as to an increase in total NOS and nNOS activities in the brain with enzyme activities exceeding those in control. In healthy rats treated with L-thyroxine, total NOS and eNOS activities in the myocardium and skeletal muscles as well as total NOS in the brain were also substantially increased. The inducible NOS isoform (iNOS) was found to contribute significantly to an increase in total NOS activity both in obese rats and healthy rats treated with L-thyroxine; its activity was determined by calculation. Thus, 4-week L-thyroxine treatment of obese rats deficient in thyroid hormones led to a recovery of total NOS and eNOS activities in the myocardium and skeletal muscles reduced in obesity. This suggests a promising future for thyroxine therapy of vascular pathology in obesity and MS.

The decrease in the function of thyroid gland (TG), which is often observed in obesity and metabolic syndrome, results in the hypothyroid state and is one of the causes of metabolic and functional disorders. It is assumed that thyroid hormone treatment normalizing hormone levels in an organism is able to prevent these disorders. However, studies of the effect of this therapy on metabolic parameters in animals with experimental obesity are very scarce, and data concerning its influence on the activity of the adenylyl cyclase signaling system (ACSS) are absent. At the same time, it is known that disturbances in the hormonal regulation of ACSS play a key role in etiology and pathogenesis of diseases associated with metabolic disorders. This work was aimed at studying the effect of long-term levothyroxine treatment of obese male rats on their carbohydrate and lipid metabolism, thyroid status, and the activity of ACSS and its hormonal regulation in the brain, myocardium, epididymal fat, and TG. The rats with obesity caused by a three-month high-fat diet received levothyroxine for four weeks (orally, with a daily dose of 20 μg/kg) (group OB + LT), whereas the control animals and untreated obese rats received placebo instead of the hormone. As a result of the treatment, the levels of thyroid hormones increased, the body and adipose tissue weight decreased, the levels of triglycerides, total and atherogenic cholesterol decreased, and glucose utilization increased. In addition, the ACSS activity impaired in obesity was restored in the brain, myocardium, and epididymal fat tissue. In the brain, the levothyroxine treatment restored the stimulatory effects of serotonin and dopamine, as well as the inhibitory effects of the agonists of the subtype 1B 5-hydroxytryptamine receptor and type-2 dopamine receptor on the adenylyl cyclase (AC) activity. In the myocardium, the stimulatory effects of β1/β2-agonists and relaxin reduced in obesity were also restored. It should be noted, however, that the effects of β3-agonists augmented in obesity did not change in group OB + LT, resulting in the enhanced activating influence of β-agonists on AC and creating certain risks of the development of cardiovascular diseases. The increase in the lipolytic effect of β-agonists and the weakening of the antilipolytic effect of N6-cyclopentyladenosine, an agonist of type 1 adenosine receptor, was found in the epididymal fat, indicating the increased lipolysis in adipose tissue. The sensitivity of AC to the thyroid-stimulating hormone in TG decreased in group OB + LT with an excess of thyroid hormones. Thus, the treatment with levothyroxine not only improves the energy metabolism and prevents the deficiency of thyroid hormones in experimental obesity but also restores the hormonal regulation of ACSS, which can be one of the mechanisms of action of thyroid hormones on the brain and peripheral tissue functions in obesity and other metabolic disorders associated with the hypothyroid state.

The functional state of adenylyl cyclase signaling system (ACSS) and its regulation by the hormones and the inhibitor of adenylyl cyclase (AC), somatostatine (SST), in the brain and myocardium and by 5-nonyloxytryptamine (5-NOT) in the brain of rats of different ages (2- and 7-month-old) with experimental obesity and combination of obesity and type 2 diabetes mellitus (DM2), as well as the effect of the long-term treatment with intranasally administered insulin (II) on ACSS were studied. It was shown that the basal AC activity in obese and DM2 rats increases in the myocardium and, to a lesser extent, in the brain and decreases under the II treatment. The AC stimulating effect of forskolin decreases in the myocardium, but not in the brain of obese and DM2 rats. The II treatment recovers the AC stimulating effect of forskolin in 7-month-old animals, but has little effect in 5-month-old rats. In obesity as well as under the II treatment, the basal AC activity and its stimulation by forskolin change insignificantly. The AC inhibitory effects of 5-NOT and, particularly, SST are strongly attenuated in the investigated pathology, supposedly due to a reduction in the functional activity of Gi-proteins. The treatment of obesity and its combination with DM2 recovers, completely or partially, the AC inhibitory effects of hormones, most of all in the brain. Since the ACSS dysfunctions are causal to metabolic syndrome and DM2, their elimination by the II treatment promises an effective approach to combat these pathologies and their CNS and cardiovascular complications.

In the smooth muscles of mollusc Anodonta cygnea the regulatory action of hormones on adenylyl cyclase signaling system (ACSS) are realized through the receptors of serpentine type (biogenic amines, isoproterenol, glucagon) and receptor tyrosine kinase (insulin) type. Intracellular mechanisms of their interaction are interconnected. Application of hormones, their antagonists and pertussis toxin in combination with insulin and biogenic amines or glucagon on adenylyl cyclase (AC) activity allows revealing the possible sites of cross-linking in the mechanisms of their action. Combined influence of insulin and serotonin or glucagon leads to decreased stimulation of adenylyl cyclase (AC) by these hormones, whereas combined application of insulin and isoproterenol suppresses AC-stimulating effect of insulin, but AC-inhibiting effect of isoproterenol is maintained in the presence and absence of non-hydrolysable analog of GTP—guanylyl imido diphosphate (GIDP). The specific blockage of AC-stimulating effect of serotonin by cyproheptadine—antagonist of serotonin receptors, did not change AC stimulation by insulin. Beta-adrenoblockers (propranolol and alprenolol) prevent inhibition of AC activity by isoproterenol, but did not change AC stimulation by insulin. Pertussis toxin blocked AC-inhibiting effect of isoproterenol and weakened AC-stimulating action of insulin. Thus, in the muscles of Anodonta cygnea negative interaction between ACS have been revealed, which are realized under combined influence of insulin and serotonin or glucagon, most probably, at the level of receptor of serpentine type (serotonin, glucagon), whereas under action of insulin and isoproterenol at the level of Gi protein and AC interaction.

Peptides of the insulin superfamily (insulin, insulin-like growth factor, relaxin), epidermal.growth factor (ECF) and biogenic amines (isoproterenol, adrenalin, noradrenalin, serotonin) stimulate the adenylyl cyclase signaling system (ACSS). In erythrocyte membranes from a control group of patients, the hormone activating affect on ACSS was potentiated in the presence of guanylylimidinodiphosphate (CppNHp). In erythrocyte membranes from patients of various severity of type 2 diabetes mellitus (DM2, early, medium and severe), the basal activity of AC was higher than in the control group and its responsiveness to hormones was different. It was reduced in patients with early and severe forms of DM2 both in the presence and absence of CppNHp. In patients with the medium severity of the disease, the stimulating effect of biogenic amines was not changed but there was no potentiating effect of CppNHp. The insulin superfamily peptides and ECF stimulated AC in the erythrocyte membranes of patients with the medium severity of DM2 to the same extent as in the control while, at the early and severe stages of the disease, the AC sensitivity to these hormones was significantly reduced. These data suggest that DM2 results in disturbances of the hormone stimulating properties of ACSS by insulin superfamily peptides, ECF and biogenic amines. In erythrocyte membranes, DM2 disturbs ACSS functions at the level of the catalytic component and its responsiveness to hormone action at the level of interactions between CG, and AC.

The regulatory effect of peptides of the insulin superfamily—insulin, insulin-like growth factor (IGF-1), and relaxin, as well as of epidermal growth factor (EGF) on activity of glycogen synthase (GS) in rat skeletal muscles was studied in normal state and in experimental diabetes mellitus types 1 and 2 (DM1, DM2). Normally, the peptides stimulated GS activity to the maximum at a concentration of 10−8 M in vitro. The efficiency ranking of the peptide action was as follows: insulin > IGF-1 > relaxin. In DM1 the basal GS activity did not change, while the effect of insulin in vitro decreased more sharply on the 30th day of diabetes as compared to IGF-1 and relaxin, i.e. the efficiency ranking was as follows: IGF-1 = relaxin > insulin. Administration of insulin in vivo did not recover the sensitivity of the enzyme to the action of the hormone in DM1. In DM2, GS activity (both in total and in the active form) decreased while the stimulatory effect of the peptides and EGF on the enzyme was absent. Insulin administered in vivo did not lead to the recovery of the enzyme activity. We conclude that it is insulin resistance pronounced in DM2 that mostly affects the basal GS activity as well as the enzyme regulation by peptides of insulin type and EGF in rat skeletal muscles, while insulin deficiency in DM1 is of lesser importance.

Cytoskeleton plays a key role in the functioning of hormonal signaling systems in vertebrate animals. However, data on the effect of cytoskeletal components, in particular microtubules, on the functional activity of chemosignaling systems of unicellular organisms are currently lacking. The goal of this work consisted of studying the effects of microtubule-disrupting agents, colchicine and vinblastine, on the adenylyl cyclase system of free living infusoria Dileptus anser. The incubation of D. anser with colchicine and vinblastine (10−5–10−6 M) weakly affected the basal activity of adenylyl cyclase (AC), but led to a significant decrease in or complete block of AC stimulation with nonhormonal (GppNHp, sodium fluoride) and hormonal agents (adrenaline, serotonin, glucagon). The basal level of GTP binding in heterotrimeric G proteins decreased and there was observed inhibition of stimulation of G proteins by hormones. Colchicine and vinblastine have been shown to interrupt adrenalin-produced AC stimulation achieved through Gs-protein, but weakly affect its inhibiting AC effect caused by the Gi-protein. Thus, it has been established for the first time that, in unicellular organisms, i.e., infusoria D. anser, microtubules are involved in the regulation of the functional activity of the AC system and their action is realized at the level of G proteins, which is similar to Gs-proteins in vertebrate animals.