Normalization of Testicular Steroidogenesis and Spermatogenesis in Male Rats with Type 2 Diabetes Mellitus under the Conditions of Metformin Therapy.

One of the complications of type 2 diabetes mellitus in men is steroidogenic and spermatogenic dysfunctions. There is evidence of a restoring effect of the antidiabetic drug metformin on them. We studied the effect of MF therapy (4 weeks, 200 mg/kg/day) on the hormonal parameters of the gonad axis and on the morphological characteristics of epididymal spermatozoa in male rats with a severe form of T2DM caused by a high-fat diet and a low-dose streptozotocin. It has been shown that MF therapy, along with the restoration of the metabolic parameters, normalizes the plasma levels of testosterone and leptin and the content of testosterone, its precursors, leptin and its receptors in the testes, and also increases sperm motility, which is reduced in T2DM. This is the result of both the systemic action of MF and its direct effect on testicular cells.

Intranasal Administration of Insulin and Gangliosides Improves Spatial Memory in Rats with Neonatal Type 2 Diabetes Mellitus.

We analyzed the effects of intranasal administration of insulin (0.48 U/rat) and gangliosides (6 mg/kg) on spatial memory in rats with the neonatal model of the type 2 diabetes mellitus. The development of diabetes was verified by the glucose tolerance test. Insulin and gangliosides improved training and reversal training in diabetic rats in a modified version of Morris water maze test and reduced the time of finding the hidden platform. High effectiveness of intranasal administration of gangliosides to animals for the normalization of cognitive functions was shown for the first time. The effects of insulin and gangliosides were similar during training, but during reversal training, gangliosides were more effective. At the same time, intranasally administered insulin, unlike gangliosides, partially normalized glucose tolerance in rats with type 2 diabetes mellitus.

[The effect of high-dose metformin on the metabolic parameters and functional state of the liver of agouti-mice with the melanocortin obesity.]

In recent years, the effectiveness of high-dose metformin (MF) to treat the endocrine and oncological diseases has been shown. However, the use of high-dose MF may be associated with the lactic acidosis and the liver dysfunctions. The aim of the work was to study the effect of long-term (10 days) oral administration of a relatively high dose of MF (600 mg/kg per day) into yellow C57Bl/6J (Ay/a) Agouti line mice with the melanocortin type obesity on the liver function, which was evaluated by the morphology of hepatocytes and the severity of steatosis, the expression of the inflammatory and apoptotic factors of and the activity of aminotransferases, as well as on the plasma lactate level in the animals. In Agouti line mice, MF (600 mg/kg per day) caused a decrease in the body and fat weight, led to the reduced hyperglycemia, hyperinsulinemia and hyperleptinemia, and restored the sensitivity to glucose and insulin. At the same time, in the liver of Agouti line mice treated with MF, the small-drop and large-drop fatty degeneration and the hydropic degeneration were attenuated, and the expression of pro-inflammatory IL-1ß and pro-apoptotic Bax protein and the Bax/Bcl-2 ratio did not differ from the control C57Bl/6J (a/a) mice. In the blood of Agouti line mice treated with MF, the activity of alanine aminotransferase was normalized, and the lactate levels was increased, but to a moderate degree. It was concluded that the high-dose MF did not induce the lactic acidosis in Agouti line mice, and at the same time it restored the liver functions impaired in the melanocortin obesity. This allows us to consider the use of the high doses of MF as one of the possible ways to treat obesity and metabolic disorders that are associated with the hepatic steatosis.

[The effect of different types of bariatric surgery on the metabolic and hormonal parameters in rats with decompensed form of type 2 diabetes mellitus.]

Currently, one of the approaches to correct metabolic disorders in the type 2 diabetes mellitus (DM2) with obesity are bariatric surgery (BS), including sleeve gastrectomy (SG), gastric bypass (GB) and ileal transposition (IT). However, their effectiveness and impact on the hypothalamic signaling and hormonal status in severe forms of DM2 without obesity remain little studied. The aim of the work was to study the effect of IT, SG and GB on the insulin, leptin, ghrelin and glucagon-like peptide-1 (GLP-1) levels in the blood and on the expression of the genes encoding the main components of the hypothalamic signaling systems in rats with decompensated form of DM2, which was induced by a high-fat diet (3 months) and a single low dose of streptozotocin (25 mg/kg, 2 months after the start of the diet). In diabetic rats, a significantly expressed hyperglycemia, an impaired glucose tolerance, a decrease in glucose-stimulated GLP-1 level, a slight decrease in the insulin and leptin levels and an slight increase in ghrelin level were detected. In the hypothalamus, the expression of the genes encoding GLP-1 receptor, orexigenic agouti-related peptide (AgRP), as well as phosphotyrosine phosphatase 1B and SOCS3, the negative regulators of the leptin and insulin pathways was increased. In diabetic rats, the IT reduced the glucose levels 120 minutes after glucose load, increased the basal and glucose-stimulated GLP-1 levels, normalized the gene expression for phosphotyrosine phosphatase 1B, SOCS3, AgRP and GLP-1 receptor, which indicates the restoration of the hypothalamic signaling responsible for the control of energy metabolism and insulin sensitivity. In the case of SG and GB, an improvement in the glucose tolerance was found, and in the case of SG, an increase in the basal and glucose-stimulated GLP-1 levels was shown. However, no significant effect on the expression of the hypothalamic genes in SG and GB was found. Thus, IT is the most effective of all studied BS in the treatment of severe forms of DM2 without obesity.

[Features of the changes in lipid peroxidation and activity of Na+/K+-ATPase in the brain of the aged rats in the conditions of two-vessel cerebral ischemia/reperfusion.]

The success of preclinical neuroprotection studies depends on the model used in animal research. The methodological approaches developed on young animals and widely used for modeling cerebral ischemia/reperfusion injury may not be so effective or not suitable for its modeling on senescent animals, which usage is recommended for preclinical trials. The aim of this study was to investigate the age-related features on the effect of brain reperfusion with different duration (1 and 3 h) after 2-vessel forebrain ischemia on the level of lipid peroxidation (LPO) products and on the activity of Na+/K+-ATPase in the cerebral cortex of rats aged 22-24 months. We found a later accumulation of LPO products (3 h instead of 1 h after blood recirculation), specifically triene conjugates and Schiff bases, and a decrease in the activity of Na+/K+-ATPase in the cerebral cortex of aged rats compared to young animals. The data obtained reveal the difference in the molecular and physiological mechanisms of the development of disorders in the brain during ischemia/reperfusion in aged and young animals. The revealed differences in these mechanisms should be consider in developing and testing compounds, which will be further used for the treatment of elderly patients with stroke and ischemic brain damage.

Insulin Increases Viability of Neurons in Rat Cerebral Cortex and Normalizes Bax/Bcl-2 Ratio under Conditions of Oxidative Stress.

We studied the protective effect of insulin in various concentrations and its effect on the Bax/ Bcl-2 ratio in neurons of rat cerebral cortex under conditions of oxidative stress. The protective effect of insulin was dose-dependent within the nanomolar range (1 nM<10 nM<100 nM). Preincubation with insulin in concentrations of 100 nM and 1 µM significantly increased Bcl-2 content in neurons in 5, 30, and 45 min and 1, 2, and 4 h after the start of cell exposure to H2O2. This prooxidant increased the Bax/Bcl-2 ratio in neurons to 141-164% in comparison with the control (100%); preincubation of neurons with insulin returned this ratio to normal.

Metabolic parameters and functional state of hypothalamic signaling systems in AY/a mice with genetic predisposition to obesity and the effect of metformin.

The metabolic parameters and functional state of hypothalamic systems in mice with the Yellow mutation in the Agouti locus and with obesity of the melanocortin type and the effect of metformin (MF) treatment (9 days, 200 mg/kg/day) were studied. The MF treatment led to decreased body weight and to normalization of glucose tolerance in mice. In the hypothalamus, MF restored the decreased activity of Akt kinase, the main component of leptin pathway, and normalized the increased expression of subtype 1B serotonin receptor. The obtained data suggest the efficiency of MF to treat obesity of the melanocortin type.

[Catecholamine content in the adrenal gland of rat offspring in the model of prenatal hyperhomocysteinemia].

Catecholamine content has been studied in the adrenal gland of rat females whose pregnant mothers were loaded daily with L-methionine administered per os during all the pregnancy period, on the first day of postnatal life, and in one and two months after birth. The animal model of hyperhomocysteinemia used in the experiment has been shown to result in the catecholamine content decreasing in the adrenal gland of both newly born rat offspring with high serum level of homocysteine and one-month old offspring with their homocysteine level decreased to the normal values. It was found that nitrotyrosine level increased significantly in the blood serum of the offspring aged one and two months. The data obtained may testify to oxidative stress development.