THE EFFECT OF METFORMIN AND ITS COMBINATION WITH MODULATORS OF HYDROGEN SULPHIDE METABOLISM ON THE LEVEL OF GLYCEMIA AND THE STATE OF THE H2S SYSTEM IN THE KIDNEYS OF RATS WITH STREPTOZOTOCIN-INDUCED DIABETES
Keywords:hydrogen sulfide, glucose, metabolism, kidneys, metformin, NaHS, propargylglycine, nephrotoxicity, diabetes mellitus
Introduction. Diabetic nephropathy belongs to one of the severe microvascular complications of diabetes mellitus (DM) and is one of the causes of patient disability and mortality. An important role in the treatment of diabetic nephropathy belongs to the sugar-lowering drug metformin. The question of the molecular mechanisms of metformin’s action, in particular the role of the H2S signaling system in its pharmacological activity, remains unclear.
The aim of the study – to evaluate the effect of metformin and its combination with modulators of H2S, exchange on the level of glycemia and H2S metabolism in the kidneys of rats with streptozotocin-induced diabetes.
Materials and Methods. The experiments were performed on 75 white non-linear male rats weighing 150–240 g. The animals were divided into five groups: group 1 – control; group 2 – animals with experimental DM, which was initiated by a single intraperitoneal injection of streptozotocin (40 mg/kg of weight) in 0.1 M citrate buffer (pH 4,5); group 3 – animals with experimental DM were treated with metformin (500 mg/kg/day, intragastrically) from the 3rd to the 28th day; group 4 – animals with DM along with metformin were given NaHS (56 μmol/kg/day, intragastrically); group 5 – animals with DM along with metformin, were administered propargylglycine (PPG, 442 μmol/kg/day, intragastrically). The glucose content was determined in the peripheral blood. H2S level, activity of H2S-synthesizing enzymes (cystathionine-γ-lyase – CSE, cystathionine-β-synthase – CBS, cysteineaminotransferase/3-mercaptopyruvate sulfurtransferase – CAT/3-MST), activity of thioredoxin reductase (TRR) and rate of H2S utilization were evaluated in the supernatant of the kidney homogenate,
Results and Discussion. It was established that streptozotocin-induced diabetes (ST-diabetes) causes a significant increase in blood glucose levels (by 4.6 times, p˂0.001), a decrease of H2S contents, activity of H2S-producing enzymes (CSE, CBS and CAT / 3-MST), activity of TRR in the kidney by 33.2–58.1 % (p˂0.001) and an increase of H2S utilization rates by 79.4 % (p˂0.001) compared with control group. The use of metformin in ST-diabetes reveals hypoglycemic activity (glucose level decreases by 25.2 %, p˂0,001, compared with untreated animals), reduces H2S deficiency in the kidneys (H2S level increases by 27.9 %, p˂0.001), increases the activity of H2S-producing enzymes and TRR (by 15.2–60.0 %, p˂0.05), and also reduces the rate of H2S utilization (by 32.7 %, p˂0.001). The introduction of the donor H2S – NaHS potentiates the hypoglycemic activity of metformin and its ability to correct H2S exchange in the kidneys while the introduction of the inhibitor of H2S synthesis – PPG reveals the opposite effect in ST-diabetes.
Conclusion. Metformin exhibits hypoglycemic activity and corrects impaired H2S metabolism in the kidneys in ST-diabetes. The use of NaHS enhanced the hypoglycemic activity of metformin and potentiated its effect on the renal H2S system in the kidneys while the use of PPG reduced the ability of metformin to correct hyperglycemia and renal H2S metabolism in the kidneys.
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