I. B. Sukhov

Long-term intranasal insulin administration improves spatial memory in male rats with prolonged type 1 diabetes mellitus and in healthy rats

349 Type 1 diabetes mellitus (DM1) is a severe endo crine disease with a wide spectrum of complications in the CNS and peripheral organs leading to disability and premature death of patients. Though neurodegen erative diseases and related to them cognitive deficit are observed in many DM1 patients, physiological and biochemical processes of their development remain poorly studied [1, 2]. The approaches to prevention and treatment of diabetic encephalopathy are poorly developed; however, it is important for timely rehabil itation of DM1 patients and maintenance of their psy chosocial status.

Effect of intranasal insulin and serotonin on functional activity of the adenylyl cyclase system in myocardium, ovary, and uterus of rats with prolonged neonatal model of diabetes mellitus

The disturbances in hormonal signaling systems, adenylyl cyclase system (ACS) in particular, occur at the early stages of diabetes mellitus (DM) being one of the key causes of its complications. Since the correlation between the severity of DM and severity of disturbances in ACS is established, studying ACS activity can be used for monitoring DM and its complications and evaluating the effectiveness of their treatment. Recently, intranasal insulin (I-I) and the drugs increasing brain serotonin level, thus effectively restoring CNS functions, have begun to be used for the treatment of type 2 DM. However, the mechanisms of their action on peripheral tissues and organs at DM are not understood. The aim of this work was to study an influence of I-I and intranasal serotonin (I-S) on the functional activity of ACS in myocardium, ovary and uterus of rats with a neonatal model of type 2 DM. In the tissues of diabetic rats the changes in the regulation of adenylate cyclase (AC) by guanine nucleotides and hormones acting on enzyme in stimulatory and inhibitory manner were found, and these changes were characterized by receptor and tissue specificity. In diabetic rats I-I restored AC-stimulating effects of isoproterenol in the myocardium, that of guanine nucleotides and gonadotropin in the ovaries and relaxin in the uterus, as well as AC-inhibiting effects of somatostatin in all tissues and norepinephrine in the myocardium. Treatment with I-S led to a partial recovery of AC-inhibiting effect of norepinephrine in the diabetic myocardium, but did not affect the regulation of AC by other hormones. These data indicate that I-I normalizes the functional activity of ACS in the myocardium and in the tissues of reproductive system of female rats with neonatal DM, whereas the effect of I-S on ACS in the studied tissues is less pronounced. These results should be considered for the design and optimization of the strategy of I-I and I-S application for the treatment of DM and its complications.

Functional state of hypothalamic signaling systems in rats with type 2 diabetes mellitus treated with intranasal insulin

Intranasal insulin (II) administration is widely used in the last years to treat Alzheimer’s disease and other cognitive disorders. Meanwhile, it is almost not used to treat type 2 diabetes mellitus (DM2), mainly due to insufficiently studied molecular mechanisms of its effect on the hormonal and metabolic status of the organism. The effect of II on activity of the hypothalamic signaling systems playing a key role in central regulation of energy metabolism is also poorly studied. The aim of this work was to study the effect of 5-week II treatment of male rats with the neonatal model of DM2 (0.48 ME/rat) both on the metabolic parameters and functional activity of the hypothalamic signaling systems. II treatment of diabetic rats (DI group) was shown to normalize the blood glucose level and restore glucose tolerance and utilization. In the hypothalamus of the DI group, the regulatory effects of agonists of the type 4 melanocortin receptor (MC4R), type 2 dopamine receptor (D2-DAR) and serotonin 1B receptor (S1BR) on adenylyl cyclase (AC) activity, reduced under DM2, were found to be restored; moreover, the inhibitory effect of S1BR agonists became even stronger as compared to control. In the DI group, the restoration of AC hormonal regulation was associated with a considerable increase in expression of the genes encoding S1BR and MC4R. Besides, the attenuation of the AC-stimulating effect of D2-DAR agonists against the background of decreasing expression of the Drd1 gene was found to promote the enhancement of the negative effect of dopamine on AC activity. II treatment did not have a considerable effect on expression of the genes encoding the insulin receptor and insulin receptor substrate-2, which was slightly reduced in the hypothalamus of diabetic rats. Thus, II treatment of rats with the neonatal model of DM2 partially restores the hypothalamic AC signaling pathways regulated by melanocortin, serotonin and dopamine, demonstrating thereby one of the mechanisms of the positive influence of II on energy metabolism and insulin sensitivity in peripheral tissues.

Intranasal administration of insulin eliminates the deficit of long-term spatial memory in rats with neonatal diabetes mellitus

216 Insulin has a regulatory effect on the metabolic and growth processes not only in peripheral tissues but also in the central nervous system (CNS). It had been shown that insulin controls the energy homeostasis in the brain tissue, affects the proliferation and differen tiation of neuronal cells, and is involved in the regula tion of learning and memory [1, 2]. Abnormalities in the insulin signaling system, resulting in type 2 diabe tes mellitus, which is characterized by insulin resis tance of tissues and moderate hyperglycemia, induce neurodegenerative processes in the CNS [3]. A reduced functional activity of the brain and cognitive deficits in patients with type 2 diabetes mellitus asso ciated with it is not only a medical but a social problem because its solution largely depends on the adaptation of patients in the community and their ability to work.

The effect of prolonged intranasal administration of serotonin on the activity of hypothalamic signaling systems in male rats with neonatal diabetes

The functioning of the serotonergic system of the brain is impaired in type II diabetes (T2D), and this leads to metabolic and hormonal dysfunction. The elevation of serotonin level in the CNS is one of the approaches for correcting of the serotonergic system of the brain. The aim of the present work was to investigate the effect of intranasal serotonin (InS) administration for 5 weeks at a daily dose of 20 μg on the metabolic parameters and functional activity of adenylate cyclase signaling system (ACSS) sensitive to peptide hormones and biogenic amines in the hypothalamus of male rats with neonatal T2D. Neonatal model of T2D was induced by injecting streptozotocin (70 mg/kg) into 5-day-old rat pups. Four-month-old animals with apparent T2D manifestations were divided into two groups: an untreated group (D0, n = 6) and a group that received InS treatment (DIS, n = 6). InS administration to diabetic rats restored ACSS regulation by the agonists of type 2 dopamine receptors (DA2R) and type 4 melanocortin receptors (MC4R) and enhanced the inhibitory effect of serotonin on adenylate cyclase activity. Elevated expression of genes encoding DA2R, MC4R, and serotonin receptor of the 1B subtype (5-HT1BR) was among the main causes of this change. The relative activity of signaling cascades involving various types of serotonin (Gs-coupled 5-HT4,6,7R/Gi-coupled 5-HT1R), dopamine (DA1R/ DA2R), and melanocortin (MC3R/MC4R) receptors involved in ACSS regulation was also altered in the animals of the DIS group. InS administration restored hormonal regulation in the hypothalamus, improved glucose tolerance, and increased the sensitivity of tissues to insulin. The data obtained show that the elevation of serotonin level in the CNS is a promising approach for the recovery of hypothalamic signaling pathways in T2D and correction of the metabolic disturbances dependent on these pathways.

Restoration of hypothalamic signaling systems as a cause of improved metabolic parameters in rats with neonatal diabetes model during treatment with bromocriptine mesylate

One approach to correction of diabetes mellitus 2 type (DM2) and its complications is the use of bromocriptine mesylate (BCM), a selective agonist of the dopamine receptor type 2 (DA2R). However, the effectiveness and mechanisms of the action of BCM in the treatment of severe forms of DM2 forms currently not understood. The purpose of this study was to investigate the influence of 4-week treatment of male rats with neonatal DM2 model using BCM (300 mg/kg daily) on their metabolic parameters and on the activity of the adenylyl cyclase signaling system (ACSS) in the hypothalamus. Exposure to BCM restored glucose tolerance and glucose utilization by exogenous insulin, normalized lipid metabolism, and lowered triglycerides and atherogenic cholesterol levels, which are elevated in DM2. In the hypothalamus of diabetic rats treated with BCM, the regulation of ACSS by agonists of melanocortin receptors type 4 (MC4R), DA2R, and serotonin 1B-subtype receptors and expression of the Mc4r gene encoding MC4R were restored. Furthermore, BCM treatment did not influence the insulin levels in the blood and its production by pancreatic β-cells. The data indicate that the use of BCM to correct severe forms of experimental DM2 holds promise and show that the therapeutic potential of this drug is based on its ability to restore signaling systems of the hypothalamus that are sensitive to monoamines and peptides of the melanocortin family, which are responsible for the control of energy metabolism and insulin sensitivity.

Intranasal Insulin Restores Metabolic Parameters and Insulin Sensitivity in Rats with Metabolic Syndrome

We studied the effect of 10-week treatment with intranasal insulin (0.5 IU/day) on glucose tolerance, glucose utilization, lipid metabolism, functions of pancreatic β cells, and insulin system in the liver of rats with cafeteria diet-induced metabolic syndrome. The therapy reduced body weight and blood levels of insulin, triglycerides, and atherogenic cholesterol that are typically increased in metabolic syndrome, normalized glucose tolerance and its utilization, and increased activity of insulin signaling system in the liver, thus reducing insulin resistance. The therapy did not affect the number of pancreatic islets and β cells. The study demonstrates prospects of using intranasal insulin for correction of metabolic parameters and reduction of insulin resistance in metabolic syndrome.

Comparative study of functional activity of the D2-dopaminergic system in the hypothalamus of rats with different models of diabetes mellitus

patients with DM2 and metabolic syndrome have begun to be treated with bromocriptine (Cyclo-set), a selective D 2-DR agonist, functional characterization of its targets, D 2-DR, is one of the topical problems of biochemistry and experimental medicine [2]. The aim of this study was to explore D 2-DR expression and their functional activity in the hypothalamus of rats with DM1 and DM2 experimental models. Prolonged DM1 (180 days) was induced by successive treatment of 1.5-and 5-month-old Wis-tar male rats with medium streptozotocin (STZ) doses, as described previously [3]. Animals were sorted out into two groups (DM1-1 1/2, n = 5, and DM1-5, n = 5), characterized by a pronounced hy-perglycemia (fasting glucose level above 15 mM) and relative insulin deficit (blood plasma insulin level below 0.6 ng/ml). The neonatal DM2 model was induced by treatment of 5-day-old rat pups with STZ at a dose of 75 mg/kg [4]. Animals were studied at ages of 4 (DM2-1), 5 (DM2-2) and 6 (DM2-3) months, in all groups n = 5. Since the DM2 typical traits developed at the age of three months, the duration of the disease in these groups was 1, 2 and 3 months, respectively. In DM2 rats, impaired glucose tolerance was observed, as evi-Dopamine (DA) is a major neurotransmit-ter in the CNS, which controls a wide range of physiological functions including motor activity, cognition, emotions and feeding behavior. In hy-pothalamic neurons, the dopaminergic system is involved in regulation of peripheral metabolism, functional activity of the endocrine and cardio-vascular systems. The regulatory effects of DA are actualized mainly via type 1 dopamine receptors (D 1-DR), which mediate stimulation of anenylyl cyclase (AC), and D 2-DR receptors, which inhibit AC. Functional state of D2-DR influences feeding behavior, metabolic status, activity of the sympathetic nervous system, and resultant impairments in the D 2-DR-dependent cascades in the CNS are among the causes of metabolic disorders and cardiovascular diseases [1]. Under types 1 and 2 diabetes mellitus (DM1 and DM2), the central D2-dopaminergic system, including that localized in hypothalamic neurons, undergoes substantial changes [2]. However, the molecular mechanisms behind these changes are studied not well enough. There are no works addressing comparative aspects of changes in the D 2-DR-dependent pathways under different diabetic pathologies. Since in the recent years SHORT COMMUNICATIONS

The Functional Activity of Hypothalamic Signaling Systems in Rats with Neonatal Diabetes Mellitus Treated with Metformin

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.