INFLUENCE OF METFORMIN AND ITS COMBINATION WITH SODIUM HYDROGEN SULPHIDE ON H2 S SYSTEM AND ASSOCIATED BIOCHEMICAL DISORDERS IN MYOCARDIUM AND KIDNEY OF RATS WITH STREPTOZOTOCININDUCED DIABETES

Abstract

Diabetes mellitus (DM) is a recent problem due to the high prevalence of the disease and the high mortality of patients. The most common complications of type I and II diabetes include heart and kidney damage. Metformin, as a first-line drug in the treatment of type 2 diabetes, are known to reduce the risk of cardiovascular and renal complications. Recently, metformin has been shown to increase H2 S in the organs of rats, which is a known cardio- and nephroprotector. However, the effect of metformin on H2 S metabolism in the heart and kidneys in experimental diabetes remains uncertain. The ability of H2 S donors to modify the antidiabetic effect of metformin is also unknown. Objective: to evaluate the effect of metformin and its combination with sodium hydrogen sulfide on H2 S system, the content of profibrogenic mediator galectin-3, the activity of free radical oxidation of lipids and proteins in the heart and kidneys of rats with streptozotocin-induced diabetes. Object and methods of research. The experiments were carried out on 40 white laboratory rats of both sexes, weight 220-280 g. DM model was initiated by a single intraperitoneal injection of streptozotocin (40 mg/kg) in three groups of animals. From the 3rd to the 28th day after streptozotocin injection, one group of animals was administered metformin (500 mg/kg) intragastrically once per day, and the other group along with metformin was administered a H2 S donor – NaHS • H2 O (3 mg/kg) once per day intraperitoneally. Peripheral blood glucose was measured using a glucometer, galectin-3 levels were determined by enzyme-linked immunosorbent assay (ELISA) kit in myocardial and renal homogenates, H2 S content, cystathionine-γ-lyase (CGL) activity, levels of malonic dialdehyde (MDA group) and carbonic acid. Statistical processing of the results was performed using SPSS Statistica 17.0. Research results. According to our results, a single injection of streptozotocin caused a number of metabolic disturbances : an increase in blood glucose by 4.6 times (p <0.05), a decrease in H2 S in the myocardium and kidneys by 32.6-35.4% 0.05), a decrease in H2 S synthesis (in the reaction of hydrolytic cleavage of cysteine catalysed be cystathionine-γ-lyase) in 2.2-2.4 times (p <0.05), an increase in galectin-3 in 5-5.5 times (p <0,05) and increase in lipid peroxidation products and protein peroxidation products – MDA and carbonyl groups – in 1.6-2 times (p <0,05) compared to control. In case of metformin administration to rats with experimental DM were registered significantly higher levels of H2 S (25.8-28.6%), the activity of H2 S – synthesizing enzyme cystathionine-γ-lyase (58.1-60.3%), the content of profibrogenic mediator galectin-3 (1.9-2 times) and lower levels of lipid and protein peroxidation products (21-26.6%), compared with untreated animals. In the group of animals treated with the combination of metformin + NaHS, the blood glucose content was significantly lower by 15.5%, the level of galectin-3 in the heart and kidneys – by 2.7-3 times, compared with rats treated with metformin alone. At the same time, the level of H2 S, cystathionine-γ-lyase activity, the content of lipid and protein peroxidation products in the heart and kidneys did not differ significantly from the control group of animals. Conclusions. The administration of metformin to diabetic rats was accompanied by cardio- and nephroprotective effects, which were associated with its hypoglycemic, antioxidant activity, ability to potentiate H2 S metabolism and reduce the expression of profibrogenic mediator galectin-3. The introduction of H2 S donor significantly reinforced these effects of metformin.

Keywords

• streptozotocin diabetes
• metformin
• hydrogen sulfide
• galectin-3
• oxidative stress.