[Restriction of breastfeeding in the early postnatal period leads to metabolic and endocrine disorders in eighteen-month-old male rats.]

Breastfeeding deficiency in the early postnatal period can lead to metabolic and hormonal disorders in adulthood. However, there are no studies on the effect of starvation in early ontogeny on metabolic and hormonal parameters in aging animals. The effect of such starvation on the functions of the endocrine system has not been practically studied. The aim of this work was to study how interruption of lactation in lactating female rats (19-21 days of postnatal development of rat pups) affects metabolic parameters, glucose tolerance, insulin sensitivity, and hormonal status of the gonadal and thyroid axes in their offspring, 18-month-old male rats. Inhibition of lactation was induced by treating female rats with bromocriptine (10 mg/kg/day). It has been shown that aging male rats with partial deprivation of breastfeeding have characteristic signs of the metabolic syndrome, such as the increased body weight and adipose tissue, impaired glucose tolerance, insulin resistance, and hyperleptinemia. They have reduced levels of testosterone and thyroid hormones, increased levels of thyroid-stimulating hormone, reduced steroidogenic response to gonadoliberin and a decrease in thyroliberin stimulating effect on thyroxine levels. Thus, short-term deprivation of breastfeeding caused by bromocriptine-induced inhibition of lactation in lactating females leads to the development of metabolic syndrome and hormonal dysregulation of the reproductive and thyroid systems in 18-month-old male rats.

[Influence of intranasally administered insulin on metabolic and hormonal parameters in adult male rats, impaired due to three-day fasting in the early postnatal period]. / Vliianie intranazal'no vvodimogo insulina na metabolicheskie i gormonal'nye pokazateli u vzroslykh samtsov krys, narushennye vsledstvie trekhdnevnogo golodaniia v rannem postnatal'nom periode.

Temporary cessation or restriction of breastfeeding can lead to metabolic disorders in adulthood. However, data on the effect of fasting in the early postnatal period on the functions of the endocrine system in adulthood are rare and contradictory. Approaches for the correction of metabolic and hormonal disorders caused by premature cessation of breastfeeding have not been developed yet. The aim of the work was to study the metabolic and hormonal parameters and changes in the hormonal status of the gonadal and thyroid systems in 10-month-old male rats with interruption of breastfeeding on days P19-P21, as well as to evaluate the restorative effect on them of four weeks of treatment with intranasal insulin (II) administered in the postnatal period (P28-P55) or in adulthood (P183-P210). Lactation interruption has been induced by treatment of lactating females with bromocriptine (10 mg/day/rat, P19-P21). Male rats with temporary cessation of breastfeeding developed characteristic signs of the metabolic syndrome (obesity, dyslipidemia, impaired glucose tolerance, hyperleptinemia), decreased levels of testosterone and thyroid hormones (fT4, tT3) and weakened the synthesis of testosterone and thyroxine, stimulated respectively by GnRH and thyroliberin. This was due to a decrease in the sensitivity of the testes to luteinizing hormone (LH) and the thyroid gland to thyroid-stimulating hormone (TSH). Treatment with II in early ontogenesis reduced body weight and fat, improved lipid profile, sensitivity to insulin, leptin, LH and TSH, restored the levels of testosterone and thyroid hormones and their stimulation by releasing factors. Treatment with II in adulthood normalized the levels of testosterone, thyroid hormones, their stimulation by releasing factors, but had a little effect on metabolic and hormonal parameters. The obtained data point to a wide range of metabolic and hormonal disorders in adult male rats with the "neonatal" model of metabolic syndrome and to the effectiveness of various strategies for their correction using long-term II treatment.

Restoration of ß-Adrenergic Signaling and Activity of Akt-Kinase and AMP-Activated Protein Kinase with Metformin in the Myocardium of Diabetic Rats.

We studied the effect of metformin (100 and 200 mg/kg/day, 4 weeks) on the adenylyl cyclasestimulating effects of ß-agonists and relaxin in the myocardial membranes and on activities of Akt-kinase, an effector component of insulin signaling, and AMP-activated protein kinase (AMPK), a cellular energy sensor, in the myocardium of rats with type 2 diabetes mellitus induced by high-fat diet and streptozotocin. Metformin normalized the ratio of adenylyl cyclase effects of ß1/2- and ß3-agonists in the myocardial membranes, that is reduced in DM2, and restored phosphorylation of Akt-kinase by Ser473 and AMPK by Thr172 in the myocardium of diabetic rats. The effect of metformin in a dose of 200 mg/kg/day was more pronounced. Thus, the cardioprotective effect of metformin is due to its ability to restore the adrenergic and insulin regulation in cardiomyocytes and their energy status.

[The effect of Metformin on metabolic parameters and hypothalamic signaling systems in rats with obesity induced by a high-carbohydrate/high-fat diet.]

Metformin (MF), a first-line drug in the treatment of diabetes mellitus, has been used in the recent years to treat obesity. Its therapeutic effect is due not only to the influence on the peripheral tissues, but also on the hypothalamus, which controls food behavior and energy metabolism. The aim was to study the effect of MF therapy (200 mg/kg/day, 8 weeks) in rats with obesity caused by a high-carbohydrate/high-fat diet on the metabolic and hormonal parameters and functional state of the hypothalamic signaling systems. The MF treatment of obese rats (the group ObM) normalized the food behavior, reduced the body and fat weight and the glucose, insulin and leptin levels, increased the sensitivity to glucose and insulin, improved the lipid metabolism, and restored the Ser473-phosphorylation of Akt-kinase in the liver. In the hypothalamus, the stimulating adenylyl cyclase (AC) effects of the agonists of type 4 melanocortin receptor and type 1 dopamine receptor were partially restored, the inhibitory AC effect of the agonists of subtype 1B serotonin receptor (5-HT1BR) was increased, which was associated with an increase in Htr1b gene expression, and the stimulating effect of the 5-HT6R-agonist EMD-386088 was normalized. At the same time, the differences in the activity of the leptin and insulin systems and the ratio of anorexigenic and orexigenic factors in the hypothalamus of the rat groups Ob and ObM were insignificant. Thus, MF treatment changes functional activity of the hypothalamic melanocortin, dopamine and serotonin systems in obese rats, which is one of the reasons to decrease their food intake and to restore the metabolic indicators and insulin sensitivity.

The evolution of the M1 local structure during preparation of VMoNbTeO catalysts for ethane oxidative dehydrogenation to ethylene.

The so-called M1 phase (the common formula (TeO) x (Mo, V, Nb)5O14) is a very promising catalyst for ethane oxidative dehydrogenation (ODE). It shows 90% selectivity to ethylene at 78% ethane conversion (400 °C, contact time - 5.5 s). The active crystal structure is formed under certain synthetic conditions in VMoNbTe mixed oxides. This paper is devoted to the analysis of how the local and average structure of the M1 phase is developed during the synthesis and what happens at particular synthetic steps. The analysis of the local structure was performed using the EXAFS and pair distribution function (PDF) methods. The EXAFS analysis of the initial VMoTe water solution and VMoNbTe slurry showed that Anderson-type heteropoly anions are formed in the solution and are preserved after fast spray-drying of the slurry. Nb cations do not enter the structure of the polyanions, but form an extended hydrated oxide matrix, where distorted NbO6 and NbO7 polyhedrons are connected to each other. The hydrated oxide matrix with captured polyanions provides the compositional homogeneity of the precursor. The distances in the second coordination shell are redistributed after thermal treatment at 310 °C. After being heated at T > 350°, the local structure of the M1 phase is organized and pentagonal domains are formed. These domains consist of a NbO7 pentagonal bipyramid and five MeO6 adjacent octahedra (Me = Mo, V). In the first stages, the building blocks are stacked along the [001] direction. The crystallization process results in the connection of the pentagonal domains to the extended polygonal grid. The formation of the regular grid with TeO x containing channels is accompanied by the increase in ethane conversion and ethylene selectivity of the catalysts.

[Metabolic and hormonal indices in rats with prolonged model of metabolic syndrome induced by high-carbohydrate and high-fat diet].

To develop the approaches for the prevention and treatment of metabolic syndrome (MS), a pathological state widespread in modern population, that involves a complex of metabolic and functional disorders, appropriate animal models of MS are required. One of these models is induced by the consumption of combined high-carbohydrate and high-fat (HC/HF) diet consisting of excess amount of easily digestible carbohydrates and saturated fats. At the same time, the character, temporal dynamics and severity of metabolic abnormalities in MS induced by HC/HF diet are still poorly understood. The aim of work was the characterization of metabolic changes in Wistar rats with MS induced by 10- and 15-week HC/HF diet that includes the consumption of 30% sucrose solution (instead of drinking water) and food rich in saturated fats. Rats that received HC/HF diet for 15 weeks had a number of features characteristic of MS, such as increased body weight and content of abdominal fat, hyperglycemia, hyperinsulinaemia, impaired glucose tolerance, insulin resistance, dyslipidemia, as well as the markers of impaired function of the cardiovascular system (hyperhomocysteinemia, the reduced level of vasodilator nitric oxide, the increased concentration of vasoconstrictor endothelin 1). In rats, which were on the diet for 10 weeks, the metabolic abnormalities were less pronounced, indicating an insufficiency of 10-week duration of HC/HF diet for MS induction. Thus, the model of MS induced by 15-week HC/HF diet has the characteristic features that allow for extrapolation of the obtained data to similar pathologic changes in human, and can be used to study the etiology and pathogenesis of MS and the search of effective ways of MS prevention and treatment.

[Co-administration of intranasally delivered insulin and proinsulin C-peptide to rats with the types 1 and 2 diabetes mellitus restores their metabolic parameters.]

The C-peptide, the product of proinsulin proteolysis, not only is a signal molecule, but also, forming a complex with insulin, is able to modulate the signaling functions of insulin. The signaling systems sensitive to insulin in the hypothalamus and other brain areas are among the targets of insulin. We hypothesized that in systemic deficiency of insulin and C-peptide in the type 1 diabetes mellitus (DM) and in severe forms of the type 2 DM, the increase in the level of C-peptide in the CNS will improve central effects of insulin, including its influence on peripheral metabolism. To verify this, the influence of separate and co-administration of intranasal insulin (II) and C-peptide (IP) on their metabolic parameters and sensitivity to insulin in rats with acute and mild type 1 DM induced by the treatment with streptozotocin at the doses of 60 and 35 mg/kg and in rats with neonatal type 2 DM corresponding to severe long-term form of type 2 DM in human was studied. The treatment of animals with II and IP was carried out for 7 days in the daily doses of 20 and 10 µg/rat, respectively. The co-administration of II and IP leading to an increase of insulin and C-peptide levels in the brain was most effective. In rats with type 1 DM treated with the combination of II plus IP, hyperglycemia was decreased and weight loss was prevented. In rats with type 2 DM, co-administration of II and IP led to the normalization of glucose homeostasis and the increase in insulin sensitivity, as shown by glucose-tolerance and insulin-glucose tolerance tests, and to improvement of lipid metabolism, as demonstrated by the decrease in the atherogenic index. The effectiveness of monotherapy with II was lower than in the case of a combination of II+IP, while monotherapy with C-peptide had little effect on the indicators studied. Thus, the simultaneous increase of insulin and C-peptide levels in the brain in the conditions of their deficiency in diabetic pathology can be considered as one of the promising approaches to restore the central insulin-dependent regulation of peripheral metabolism and to improve the utilization of glucose in different forms of DM.

[FUNCTIONAL STATE OF THE HYPOTHALAMIC SIGNALING SYSTEMS IN RATS WITH TYPE 2 DIABETES MELLITUS TREATED WITH INTRANASAL INSULIN].

In the last years intranasally administered insulin (II) is widely used to treat Alzheimer's disease and other cognitive disorders. Meanwhile, it is little used to treat the type 2 diabetes mellitus (DM2); which is due to insufficient knowledge of molecular mechanisms of its action on hormonal and metabolic status of an organism. The effect of II on the activity of hypothalamic signaling systems, which plays a key role in the central regulation of energy metabolism, is still poorly understood. The aim of the present work was to study the effect of five-week treatment of male rats with neonatal model of DM2 using 11 (0.48 IU/rat) on metabolic parameters and on functional activity of the hypothalamic signaling systems. It was shown that treatment of diabetic rats with II'(Group DI) normalized plasma glucose level, restored glucose tolerance and its utilization. In the hypothalamus of rats of the Group DI the-regulatory effects of agonists of type 4 melanocortin receptors (MC4R), type 2 dopamine receptor (D2-DAR) and subtype 1B serotonin receptor (5-HTIBR) on adenylyl cyclase (AC) activity, which were reduced in DM2, restored. Moreover, the inhibitory effect of 5-HTIR agonists even was increased as compared to control. In the Group DI, the res- toration of AC regulation by hormones was accompanied by a significant increase in the expression of genes encoding 5-HTIBR and MC4R. Along with this, the attenuation of the AC stimulating effect of D1-DAR agonists and the decreased expression of Drdl gene were found, promoting the enhancement of the negative dopamine effect on AC activity. The II treatment did not significantly affect the expression of genes encoding insulin receptor and insulin receptor substrate 2, which was reduced, though to a small extent, in the hypothalamus of diabetic rats. Thus, the II treatment of rats with the neonatal model of DM2 partially restores the hypothalamic AC signaling pathways regulated by melanocortins, serotonin and do- pamine, which is one of the mechanisms of positive influence of II on energy metabolism and insulin sensitivity in the peripheral tissues.

[THE EFFECTS OF LONG-TERM METFORMIN TREATMENT ON THE ACTIVITY OF ADENYLYL CYCLASE SYSTEM AND NO-SYNTHASES IN THE BRAIN AND THE MYOCARDIUM OF RATS WITH OBESITY].

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 ß1/ß2-adrenergic receptors (AR) and the strengthening of ß3-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 ß-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 INFLUENCE OF LONG-TERM THYROXINE TREATMENT ON THE ACTIVITY OF NO-SYNTHASES IN TISSUES OF RATS WITH OBESITY INDUCED BY HIGH-FAT DIET].

Under obesity, a component of metabolic syndrome (MS), macro- and microcirculation are attenuated, which is associated with abnormalities of NO-dependent cascades and leads 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, possessing the properties of vasodilators, is one of approached to restore functioning of the cardiovascular system. However, data on influence of thyroid hormones on NOS activity in obesity are not currently available. The aim of this work was to study the effect of four-week treatment of rats with obesity induced by high-fat diet with L-thyroxine (at a daily dose of 20 mg-kg) on functional activity of total NOS, as well as one endothelial (eNOS) and neuronal (nNOS) isoforms of the enzyme in the brain, myocardium and skeletal muscles of animals. In obese rats the decrease of thyroid hormones level, impaired glucose toleranse, and dyslipidemia were detected. In the myocardium and skeletal muscles of obese rats the activity of total NOS and eNOS was strongly decreased, whereas in the brain the activity of these enzymes was not significantly changed. Long-term treatment of obese rats with thyroxine led to a significant increase in activity of total NOS and eNOS in the myocardium and skeletal muscles and to an increase in activity of total NOS and nNOS in the brain, with the enzyme activity exceeding that in control. In healthy animals treated with thyroxine a significant increase in activity of total NOS and eNOS in the myocardium and skeletal muscles and in activity of total NOS in the brain was also eNOS in the myocardium and skeletal muscles and in activity of total NOS in the brain was also found. A significant contribution to the increasing activity of total NOS in obese rats and healthy animals treated with thyroxine belonged to the inducible isoform of the enzyme whose activity was found by calculation. Thus, the four-week thyroxine treatment of obese rats with deficiency of thyroid hormones led to a complete restoration of activity of total NOS and eNOS, reduced in obesity, in the myocardium and skeletal muscles which indicated the prospects of thyroxine therapy for treatment of vascular pathology in obesity and MS.

[The influence of immunization of rats with BSA-conjugated peptide 269-280 of type 3 melanocortin receptor on the metabolic parameters and thyroid functions].

One of the approaches to study the role of the brain hormonal signaling systems in the regulation of biochemical and physiological processes is their shutdown using the antibodies generated to peptides corresponding to extracellular regions of receptors. The brain type 3 melanocortin receptors (M3R) play an important role in the central regulation of the metabolism and the endocrine system. However, the influence of prolonged inhibition of M3R on energy metabolism, insulin resistance, and thyroid gland (TG) function is practically not studied. The aim of the study was to investigate the influence of prolonged repeated immunization of male rats with the BSA-conjugated peptide Ala-[Pro-Thr-Asn-Pro-Tyr-Cys-Ile-Cys-Thr-Thr-Ala-His269-280]-Ala (A[269- 280]A) corresponding to the third extracellular loop of M3R on their metabolic parameters and functional activity of TG. 9 months after the first immunization, the weight of rats was reduced and after 12-13 months was significantly lower than in controls. The weight of abdominal and brown adipose tissues, on the contrary, increased. At the same timeline there was an increase in the fasting glucose and insulin levels, and increase of the HOMA-IR index (by 75%) indicating that immunized animals develop insulin resistance. The rats have increased glucose utilization due to an increase of insulin production by pancreatic ß-cells. 12 months after the first immunization, the increase of the triglycerides level (by 74%) and the ratio of LDL- and HDL-cholesterol (by 36%) were revealed. 13 months after the start of immunization, the levels of free and total thyroxine and total triiodothyronine significantly decreased. In the TG plasma membranes of immunized rats the weakening adenylyl cyclase stimulating effect of thyroid-stimulating hormone was detected. Thus, long-term decrease in the bra- in M3R activity due to repeated immunization of rats with BSA-conjugated peptide A[269-280]A induces the disturbances of the peripheral metabolism and TG function.

[The influence of two-month treatment with bromocryptine on activity of the adenylyl cyclase signaling system in the myocardium and testes of rats with type 2 diabetes mellitus].

One of the common complications of type 2 diabetes mellitus (DM2) are cardiovascular diseases and dysfunctions of the reproductive system, indicating the urgency of developing new approaches to their correction. Last years for the treatment of DM2 began to use bromocryptine (BC), the agonist of type 2 dopamine receptors, which not only restores the energy metabolism, but also prevents the development of cardiovascular diseases. However, the mechanisms and targets of BC action are poorly understood. The purpose of this study was to investigate the effect of BC treatment on functional activity of adenylyl cyclase signaling system (ACSS) in the myocardium and testes of male rats with DM2, which is caused by high-fat diet and treatment with streptozotocin (25 mg/kg). The treatment with BC (60 days, orally at a dose of 0.6 mg/kg once every two days) was started 90 days after the beginning of high-fat diet. Diabetic rats had an increased body weight, elevated triglycerides level, impaired glucose tolerance, and insulin resistance. The treatment with BC resulted in the restoration of glycometabolic indicators and in the improvement of insulin sensitivity. Adenylyl cyclase (AC) stimulating effects of guanylylimidodiphosphate (GppNHp), relaxin, and agonists of ß-adrenergic receptors (ß3-AR)--isoproterenol and norepinephrine were decreased in the miocardium of the diabetic rats. The corresponding effects of the ß-agonists BRL-37344 and CL-316243 was preserved. The inhibitory effect of somatostatin on forskolin-stimulated AC activity was attenuated, while the inhibitory effect of noradrenaline mediated through α2-AR increased. The treatment with BC resulted in the normalization of the adrenergic signaling in the myocardium and partially restoration of AC effects of relaxin and somatostatin. In the testes of diabetic rats, the basal and stimulated by GppNHp, forskolin, human chorionic gonadotropin and pituitary AC-activating polypeptide AC activity were decreased, and the inhibitory effect of somatostatin was attenuated. The changes in testicular ACSS in the case of BC treatment were weakly expressed. Thus, long-term BC treatment restores the functional activity of ACSS in the myocardium and testes of diabetic rats that underlies the therapeutic effect of BC on functions of the cardiovascular and reproductive systems disturbed in DM2 and should be considered when developing strategies for treatment type 2 diabetes and its complications.

[Effects of intranasal insulin and serotonin on functional activity of the adenylyl cyclase system in the myocardium, ovaries, and uterus of rats with prolonged neonatal model of diabetes mellitus].

Disturbances in hormonal signaling systems, in the adenylyl cyclase system (ACS) in particular, occur at early stages of diabetes mellitus (DM) and are one of the key causes of its complications. Since there is a correlation between the severity of DM and of disturbances in the ACS, the study of the ACS activity can be used to monitor DM and its complications and to evaluate effectiveness of their treatment. Comparatively recently, for treatment of the type 2 DM, there began to be used the intranasal insulin (I-I) and drugs increasing brain serotonin level, which effectively restore CNS functions. However, mechanisms of their action on peripheral tissues and organs with DM remain to be not understood. The goal of this work was to study effects. of I-I and intranasal serotonin (I-S) on the ACS functional activity in myocardium, ovary, and uterus of rats with a neonatal model of the type 2 DM. In tissues of diabetic rats there were revealed changes in regulation of adenylyl cyclase (AC) by guanine nucleotides and hormones that both stimulated and inhibited this enzyme, such changes being characterized by the receptor and tissue specificity. In diabetic rats, I-I restored the AC stimulating effects of isoproterenol in the myocardium, guanine nucleotides and gonadotropin in ovaries and relaxin in uterus, as well as the AC inhibitory effects of somatostatin in all tissues, and of noradrenaline in myocardium. Treatment with IS led to a partial restoration of the AC-inhibitory effect of noradrenalin in the diabetic myocardium, but did not affect regulation of AC by other hormones. These data indicate that I-I normalizes the ACS functional activity in myocardium and in tissues of the reproductive system of female rats with neonatal DM, whereas the effect of I-S on in the studied tissues is less pronounced. These results are necessary to be taken into account at development and optimization of strategy of use of I-I and I-S for treatment of DM and of its complications.

[The influence of long-term diabetes mellitus induced by streptozotocin treatment of six-week rats on the functional activity of adenylyl cyclase system].

The alterations occurring in diabetes mellitus (DM) of the type 1 in the adenylyl cyclase signaling system (ACSS) are one of the key causes of complications of the disease. As type 1 DM most often diagnosed in childhood and adolescence, the actual problem is the study of alterations in ACSS in the early development of the disease. For this we developed a prolonged model of type 1 DM, which was induced by treatment of six-week-old rats with moderate doses of streptozotocin (1 ½M-DM), and studied the functional state of ACSS in the brain, myocardium, and testes of rats with this model of the disease, seven months after its initiation. Model 1 ½-DM was compared with the seven-month model of type 1 DM, which was induced by streptozotocin treatment of adults, five-month-old, animals (5M-DM). It is shown that in 1 ½M-DM in the tissues of diabetic rats the functional activity of ACSS sensitive to biogenic amines and polypeptide hormones was significantly changed. In rats with 1 ½M-DM the adenylyl cyclase (AC) inhibiting effects of somatostatin (in all studied tissues), norepinephrine (in the myocardium and brain), and agonists of type 1 serotonin receptor (in the brain) were weakened the most. In the brain also decreased AC stimulating effects of relaxin, isoproterenol and agonists of G(s)-protein-coupled serotonin receptors, in the myocardium--corresponding effects of GppNHp, relaxin and ß-adrenergic agonists, and in the testes--AC effects of GppNHp and chorionic gonadotropin. When comparing the models 1 ½M-DM and 5M-DM, the most pronounced differences between them were found in the influence of DM on hormonal regulation of ACSS in the brain, and this refers both to AC stimulating effects of dopamine and PACAP-38, and to AC inhibiting effects of bromocryptine and somatostatin. These results indicate significant alterations in the hormonal regulation of the nervous, cardiovascular and reproductive systems in rats with early induction of type 1 DM, in some cases more severe compared with late model of 5M-DM. These alterations can be the basis for the development of diabetic cardiomyopathy, cognitive deficits and hypogonadotropic states, which are often detected in children and adolescents with type 1 DM.

Initial stages of the insulin signaling system in the brain of rats with experimental diabetes mellitus.

We studied reactivity of insulin signal pathway elements, insulin receptor and insulin receptor substrate protein-2 (IRS2 protein), in rat brain in response to insulin insufficiency and insulin resistance during the development of experimental type 1 or type 2 diabetes mellitus. In type 1 diabetes mellitus characterized by acute insulin insufficiency, specific binding of insulin in rat brain increased 2-fold in comparison with the control and IRS2-gene expression in rat hypothalamus and cortex 2-4 fold surpassed the normal values. In type 2 diabetes mellitus (110 and 190 days of development), changes in the test parameters in rat brain were less pronounced. These findings attest to involvement of the brain insulin signal pathway into the response to systemic insulin deficiency in type 1 diabetes mellitus.

[The activity of receptor guanylyl cyclases in tissues of rats with neonatal streptozotocin diabetus mellitus and the influence of intranasal administration of insulin and serotonin].

Functional activity of hormanal signaling systems and their sensitivity to regulatory actions of hormones in diabetes mellitus (DM) and its complications are altered. The activity of receptor forms of guanylyl cyclases (rGC) sensitive to natriuretic peptides, ANP and CNP, in tissues of female rats with 240-days neonatal streptozotocin DM and the influence of intranasal administration of insulin and serotonin (6 weeks, daily dose is 0.48 IU of insulin or 20 microg of serotonin to rat) on this activity were studied. In diabetic animals, the increase of the basal activity of rGC in the myocardium and its decrease in the uterus and ovaries were found, whereas the brain showed no differences from control animals. The treatment of diabetic rats with insulin led to a decrease in the basal activity of rGC in the myocardium and to its restoration to normal level in the ovaries. Serotonin treatment induced a less pronounced compared with insulin decrease in the basal activity of the enzyme in the myocardium and also a slight increase the activity in the brain. In the myocardium of diabetic rats, the weakening of GC stimulating effect of ANP and, on the contrary, the strengthening of CNP effect were observed. In the ovaries, GC stimulating effect of CNP and, to a lesser degree, the corresponding effect of ANP were decreased. In the uterus and the brain, the sensitivity of rGC to hormones was practically not changed. The administration of insulin to diabetic rats induced an increase in GC effect of ANP in the myocardium to its values in control animals and a decrease in CNP effect as well as in partially restored GC effect of CNP in the ovaries. Serotonin treatment led to some increase in the effects of natriuretic peptides in the brain of both control and diabetic animals. Summing up, in neonatal model of type 2 DM in the myocardium and the tissues of reproductive system of rats the functioning of natriuretic peptide-sensitive rGC is altered in the myocardium and the tissues of reproductive system of model rats with neonatal type 2 DM. Treatment of animals with insulin substantially restores rGC activity while intranasal administration of serotonin has little effect.