The Metabolic Effect of Cellular Protein Kinases Blockade on the Experimental Diabetes

Abstract

Prospective use of receptor protein kinase inhibitors (PKI) for the prevention and/or treatment of diabetic complications necessitates the study of their effect on carbohydrate, lipid, and protein metabolism in experimental models of type 1 (DM1) and type 2 (DM2) diabetes. DM1 was modeled in male Wistar rats with streptozotocin administration (50 mg/ kg), DM2 – by long-term (180 days) maintenance on a highcalorie fat diet (HFD; 56,7% fat) with the introduction of a lower dose of streptozotocin (25 mg/kg). For the treatment, we used insulin (“Actrapid Novo Nordisk”, Denmark) and a PKI inhibitor Sorafenib (“Cipla”, India), added orally in sachet form (150 mg/kg). Regardless of the diet type, the streptozotocin administration led to hyperglycemia, weight loss, glucose- and ketonuria, polyuria, and polydipsia. The severity of these manifestations was heightened in HFD rats, with a mortality rate of 53.3% observed (when modeling DM1 – 12%), likely attributed to the onset of liver failure. In HFD rats, slight hyperglycemia was noted only on the 150th day. All the diabetes models used were accompanied by significant hypercholesterolemia and hyperlipidemia. The addition of glucose to HFD rats increased the cholesterol content. HFD caused hypoproteinemia, metabolism suppression and increased transaminases activity. The established violations were largely restored with the use of PKI: glycemia level, body weight loss, the content of triglycerides and very low-density lipoproteins decreased; an increase in high-density lipoproteins and the normalization of pigment metabolism were observed.