Bukhtiyarova I.P., Shchekina K.G., Pozdniakova A.Yu.

Department of Pharmacology, National University of Pharmacy,

Kharkiv, Ukraine

Influence of interleukin-1 receptor antagonist on the

development of the metabolic syndrome in rats

Due to the high prevalence and high mortality of metabolic syndrome (MS) it became one of important medical and social problem of our time. The prevalence of MS is twice higher of diabetes mellitus. This disease affects about 25% of the adult population and in the next 25 years is expected to increase its growth on 50%. World Health Organization experts consider MS as a new pandemic of the XXI century.

The leading role of inflammatory cytokines, namely interleukin-1 (IL-1), interleukin-6 and tumor necrosis factor (TNF-α) in the development of MS and its complications is proved today. Therefore, medicines that can inhibit the synthesis and activity of IL-1, normalize the functional activity of β-cells of the pancreas, and improve sensitivity of tissues to insulin are promising medicines for MS treatment.

The previous studies have found that the original recombinant receptor antagonist IL-1 raleukin obtained at the Research Institute of Pure Biochemicals (St. Petersburg, Russia) has a strong hypoglycemic and anti-inflammatory effect. That is why the aim of this study is an experimental study of raleukin effect on carbohydrate metabolism on a model of metabolic syndrome in rats.

Model pathology was reproduced by the introduction of fructose to adult white male rats (body weight 220-280 g) in a dose of 200 mg/l in drinking water for two months. As reference medicines metformin (Diaformin produced by «Farmak» (Ukraine) and anakinra (Kineret produced by «Swedish Orphan Biovitrum» (Sweden) were chosen.

The drugs under study were administered in prophylactic-therapeutical regimen beginning with the first day of the model pathology conducting during 2 months, 1 time a day: raleukin in a dose of 7 mg/kg and anakinra in a dose of 8 mg/kg were used subcutaneously, metformin – in a dose of 30 mg/kg – intragastrically.

After the last administration of fructose and medicines under research intraperitoneal glucose tolerance test was carried out that was reproduced by intraperitoneal administration of glucose (2 g/kg of rats’ body weight).

Blood samples for analysis from the vessels of experimental animals’ tails were taken, before and in 30, 60, 120 and 180 minutes after the intraperitoneal glucose tolerance test. The effect of studied medicines on carbohydrate metabolism in a model of MS was evaluated by the following factors: changes in the dynamics of blood glucose during the intraperitoneal glucose tolerance test (in 30, 60, 120 and 180 minutes), basal glycemia, basal insulinemia, coefficient of insulin resistance – an index of HOMA-IR and the area of underglycemic curve.

The results of our research show that after chronic administration of fructose the level of basal glucose in the blood serum of rats from the control pathology group increase in 1.2 times, but did not differ significantly from the corresponding markers in blood serum of intact control group of animals. That is why, we can only assert about a tendency to the increase of basal glycemia level. The level of basal insulinemia was significantly increased in 1.5 times, insulin resistance index HOMA-IR was increased in 2.3 times, the area of underglycemic curve enhanced in 1.8 times in comparison with the same markers from the intact control group of rats. The above results show a decrease in insulin sensitivity in animal with control pathology.

Under the influence of raleukin and anakinra the level of basal insulinemia in the blood serum of rats was significantly reduced in 1.3 times, insulin resistance index was decreased in 1.8 times, the area of underglycemic curve diminished in 1.4 times comparing to the rats in the control pathology group. Against the background of metformin administration, HOMA-IR was significantly reduced in 1.4 times, the area of underglycemic curve diminished in 1.3 times comparing with the animals from the control group of pathology. By normalizing effect on the index of insulin resistance metformin was significantly inferior to raleukin, according to its effect on the area of underglycemic curve, metformin was inferior to anakinra. In 30 minutes after reproduction of intraperitoneal glucose tolerance test the glucose level in the blood serum of rats from the control pathology group increased in 1.7 times comparing with the group of intact animals. At the end of the test (in 180 minutes), the level of glycemia was twice higher than the markers of the group of normoglycemic animals. Under the influence of raleukin and anakinra the level of basal insulinemia in the blood serum of experimental animals was significantly reduced in 1.3 times, HOMA-IR – in 1.8 times, the area of underglycemic curve diminished in 1.4 times comparing with the rats from control pathology group.

Against the background of metformin administration, insulin resistance index was significantly decreased in 1.4 times, the area of underglycemic curve was reduced in 1.3 times comparing with the rats from control pathology group. By the ability to normalize HOMA-IR metformin was significantly inferior to raleukin, the area of underglycemic curve – to anakinra.

Against the background of raleukin in intraperitoneal glucose tolerance test the glycemia level in 30 minutes was in 1.1 times lower, in 60 minutes in 1.2 times lower, in 120 minutes in 1.5 times lower, in 180 minutes in 1.7 times lower than the same marker in animals from the control pathology group.

Under the influence of anakinra the level of glycemia declined in 1.1, 1.3, 1.5 and 1.8 times respectively in 30, 60, 120 and 180 minutes of the experiment. After administration of metformin, blood glucose level in serum of experimental animals decreased in 1.2, 1.2, 1.4 and 1.5 times respectively comparing with the same markers of rats from the control pathology group. These results indicate the ability of all investigated medicines to cause a hypoglycemic effect when intraperitoneal glucose tolerance test is carried out.

Thus, in terms of insulin resistance caused by chronic administration of fructose, original interleukin-1 receptor antagonist raleukin in a dose of 7 mg/kg inhibits the development of insulin resistance, as evidenced by the significant decrease in basal insulinemia, insulin resistance index and the area under the glycemia curve, and has a hypoglycemic effect, which is not inferior to the action of the reference medicines. It is the reason why the recombinant receptor antagonist IL-1 is a promising drug for further study with the aim of its use in combined therapy of metabolic syndrome.