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 ß 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 ß cells. The study demonstrates prospects of using intranasal insulin for correction of metabolic parameters and reduction of insulin resistance in metabolic syndrome.

[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.

[Total pancreatectomy for pancreatic cancer]. / Total'naya pankreatektomiya pri opukholevom porazhenii podzheludochnoi zhelezy.

AIM: to determine the indications and to evaluate early and long-term outcomes of total pancreatectomy for pancreatic cancer. MATERIAL AND METHODS: Treatment of 29 patients who underwent one- and two-stage pancreatectomy for different malignancies was analyzed. RESULTS: Median of surgery duration and intraoperative blood loss was 280 min and 2200 ml respectively. Postoperative complications were observed in 9 (31%) patients. There were 2 (6.9%) deaths. 1- and 3-year overall actual survival was 61% and 16% respectively in case of ductal adenocarcinoma. Median was 18 months. Patients after surgery for primary multiple lesion (cancer of pancreatic body-tail and major duodenal papilla), pancreatic metastases of renal cancer, mucinous cystadenoma and neuroendocrine cancer are still alive. Follow-up periods are 4, 49, 49 and 65 months respectively. CONCLUSION: Total pancreatectomy is difficult intervention followed by severe metabolic disorders. However it can improve long-term survival with acceptable incidence of postoperative complications and quality of life if clear indications for surgery are present.

Relationships between Mechanical Nociceptive Threshold and Activity of Antioxidant Enzymes in Male Rats with Experimental Type I Diabetes Mellitus.

We analyzed the dynamics of neuropathic pain development and changes in catalase and superoxide dismutase (SOD) activities in the brain, liver, and skeletal muscles of male Wistar rats with 1-month streptozotocin-induced diabetes mellitus. A decrease in mechanical nociceptive threshold was revealed that progressed during the disease progress. Insulin treatment restored nociceptive threshold in diabetic animals to the control values. Catalase activity in the liver and skeletal muscles of diabetic rats increased by 1.5 and 2 times, respectively, in comparison with the control, while insulin treatment reduced enzyme activity to the control level. In the brain, catalase activity was reduced by 1.5 times and insulin therapy did affect this parameter. SOD activity in the studied tissues remained unchanged during diabetes and was not affected by insulin therapy. A strong negative correlation between nociceptive threshold in rats and catalase activity in their liver and skeletal muscles was found.

[THE CHANGES OF NOCICEPTIVE THRESHOLD AND ACTIVITY OF THE ADENYLYL CYCLASE SYSTEM IN THE SKELETAL MUSCLES OF RATS WITH ACUTE AND MILD TYPE 1 DIABETES MELLITUS ].

Diabetic peripheral neuropathy (DPN) is one of the most common complications of the type 1 diabetes mellitus (DM1). The aim of the work was to study the dynamics of a painful DPN and functional state of the hormone-sensitive ACSS in the skeletal muscles of rats with the models of acute and mild DM1, as well as the study of impact on them of insulin therapy with different ways of hormone delivery - intranasal and peripheral. In both models of DM1, the level of nociceptive threshold in rats decreased and the stimulatory effects of guanine nucleotides (GppNHp) and adrenergic agonists (isoproterenol, BRL-37344) on adenylyl cyclase (AC) activity were attenuated. The AC stimulating effect of relaxin decreased in animals with acute DM1, but in mild DM1, the decrease was insignificant. Peripheral administration of insulin in rats with acute DM1 increased the nociceptive threshold and partially restored the AC effect of ß 3-agonist BRL-37344. Intranasal administration of insulin in rats with DM1 also increased the nociceptive threshold and partially restored the basal and BRL-37344-stimulated AC activity in the skeletal muscles of diabetic animals. Thus, in the skeletal muscles of rats with acute and mild DM1 the nociceptive sensitivity and the functions of ACSS were disturbed, and they were partially restored by the treatment with peripheral (acute DM1) or intranasal (mild DM1) insulin.

[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.

[Spatial memory and regulation of brain adenylyl cyclase by serotonin and dopamine in rat with streptozotocin diabetes].

The most common complication of diabetes mellitus of the type 1 (DM1) is a cognitive deficiency, which develops as a result of neurodegenerative changes in the brain. The aim of this work was to study the learning and spatial memory in rats with streptozotocin DM1 with different duration (1.5 and 6 months), as well as the activity of adenylyl cyclase signaling system (ACSS) sensitive to agonists of the serotonin and the dopamine receptors in the brain of diabetic rats. Our experiments demonstrated that rats with 1.5-months DM1 has no changes in spatial memory which were evaluated in a Morris water maze whereas in rats with 6-months DM1 the spatial memory and learning ability were decreased. The alterations of the regulation of adenylyl cyclase by agonists of types 1 and 6 serotonin receptors and type 2 dopamine receptors were found in both the 1.5- and 6-months DM1 which indicates their importance in the development of cognitive deficiency. Abnormalities in the. brain ACSS can be considered as key factors in the etiology and pathogenesis of cognitive dysfunctions in DM1. Hypothesized that cognitive deficiency occurs only in the later stages of DM1 due to alterations in the serotonin and dopamine signaling systems of the brain.

Surgical and combined treatment of patients with cholangiocellular carcinoma.

INTRODUCTION: Liver resection is the essential method of cholangiocellular carcinoma treatment. However due to low resectability and high incidence of recurrences search for additional curative methods is necessary. AIM: To improve the results of surgical treatment of patients with cholangiocellular carcinoma especially with complications and poor prognosis. MATERIAL AND METHODS: A total of 95 surgical procedures for intrahepatic cholangiocarcinoma have been performed in the department of liver andpancreatic tumors at N.N. Blokhin Russian Cancer Research Center since 1998 to 2014. 11 patients had obstructive jaundice as the first symptom of the disease. Extended liver resections were done in most cases (84.2%). Preoperative treatment was performed in 3 patients. Adjuvant chemotherapy after R0-resection was applied in 15 patients. RESULTS: The postoperative mortality rate was 4.2%. Postoperative complications were observed in 51 (53.7%) patients. Complication grade III after adjuvant chemotherapy was observed in one (6.7%) patient. Median survival after liver resection was 25 months, 5-year survival rate - 25.3%. In stage I-II five-year survival reached 66.7%. In patients with obstructive jaundice 5-year survival rate was 26.7%, median survival - 37 months. There was no improvement of survival in case of adjuvant therapy. CONCLUSION: Liver resection remains essential treatment of cholangiocellular carcinoma including patients with obstructive jaundice. Additional curative methods are necessary to increase resectability and decrease the risk of recurrence.

[A change of hormonal regulation of adenylyl cyclase in the epididymal adipose tissue of rats with experimental models of diabetes mellitus].

One of the key causes of diabetes mellitus (DM) and its complications are hormonal disturbances in functioning of hormonal signaling systems, including the adenylyl cyclase signaling system (ACSS). The goal of this work was to study the functional state and hormonal sensitivity of ACSS in the epididymal adipose tissue of male rats in the 7-month model of mild type 1 DM (DM1), in the 18-month neonatal model of type 2 DM (DM2), and in the taken for comparison model of the 30-day acute DM1. It is shown for the first time that in adipocytes from the epididymal fat of rats with the studied DM models the basal AC activity and its stimulation by forskolin were decreased, which indicates a weakening of the catalytic function of the enzyme adenylyl cyclase (AC). Stimulation of AC by guanine nucleotides in DM changed to the lesser extent, which speaks in favor of preservation of functions of heterotrimeric G(s)-proteins in the epididymal fat. In rats with DM1 the sensitivity of AC of adipocytes to agonists of ß-adrenergic receptors (ß-AR), activators of lipolysis, remained practically unchanged, while in animals with DM2 the AC stimulating effects of ß-AR-agonists were reduced or completely blocked, like in the case of ß3-AR-agonist BRL-37344 and CL-316243. In adipocytes of rats with DM1 the AC inhibitory effect of N6-cyclopentyladenosine, agonist of type 1 adenosine receptors (Aden1R), an inhibitor of lipolysis, was attenuated, whe- reas in DM2 this effect was completely preserved. Thus, in the epididymal adipose tissue of rats with DM1 the antilipolytic AC cascades including Aden1R were decreased and the stimulation of AC by ß-AR-agonists was preserved, whereas in rats with DM2 the ß-AR-mediated AC cascades activating lipolysis were reduced, but Aden1R-mediated AC cascades inhibiting lipolysis did not change. The changes of hormonal regulation of ACSS in adipocytes from the epididymal fat lead to disturbances of the metabolic status of animal with DM1 and DM2 and should be considered in the diagnostics and treatment of DM and its complications.

Androgen deficiency in male rats with prolonged neonatal streptozotocin diabetes.

We studied the diurnal dynamics of testosterone concentration in male rats with 240-day neonatal streptozotocin-induced diabetes mellitus, which is similar to human type 2 diabetes mellitus. We also studied the effects of intranasal administration of luliberin on testosterone level and the regulation of activities of adenylate cyclase and stimulatory G-proteins in the testicles of diabetic and intact animals by human chorionic gonadotropin. In rats with neonatal diabetes, a decrease in the mean diurnal level of testosterone and its morning rise were observed. The increase in testosterone level 30 min after luliberin administration was significantly reduced in diabetic animals, but no differences in the response to luliberin were observed in intact and diabetic rats 2-6 h after the treatment. The stimulatory effects of human chorionic gonadotropin on adenylate cyclase activity and binding of guanosine triphosphate by stimulatory G-proteins were reduced in the plasma membranes from the testicles of rats with neonatal diabetes in comparison with control specimens. Therefore, rats with neonatal diabetes were characterized by androgen deficiency, which can be related to the impairment of hypothalamic-pituitary-gonadal axis and reduced sensitivity of the adenylate cyclase system in the testicles of diabetic rats to human chorionic gonadotropin.

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.