Evaluation of Funny Current (If) Inhibitor Ivabradine for Reversing Metabolic Dysfunction

Abstract

BACKGROUD AND OBJECTIVE The If (funny) channel inhibitor Ivabradine has been reported to act on JNK signalling ion channels and is important regulators of insulin action through inflammatory pathway in the treatment of T2DM. Therefore, objective of the present study is to repurpose Ivabradin as a JNK antagonist for Type 2 diabetes. MATERIAL AND METHODS Sprague-dawley (SD) rats weighing 200-300 gm were given High-fat diet for ten weeks. Rats were fasted overnight and injected with Streptozotocin (STZ) via intraperitoneal (i.p.) route. Rats were permitted to drink 5% of glucose solution to knockout the STZ induced hypoglycemia. The blood glucose levels of all animals were estimated, and animals with more than 200 mg/dl were considered as diabetic. The animals were divided in different groups, normal control, disease control, disease treated with low dose, mid dose and high dose of ivabradine treatment was carried for two weeks. At the end of the treatment, serum glucose levels and OGTT along with other biochemical parameters like urea, SGPT, SGOT, Creatinine, and serum lipid profiles was performed. At the end animals were sacrificed for histopathology of liver, pancreas and adipose tissue. RESULTS In the present study there was reduction in water intake as well as food intake in disease control animals. Treatment with metformin, high dose of ivabradine showed slight improvement in body weight, water intake as well as food intake. But low dose and mid dose slightly showed improvement. After two weeks of treatment, the high dose of ivabradine exhibited statistical significant (p<0.01) improvement. In OGTT test, Compared to metformin, high dose of ivabradine showed the Insulin resistance. Whereas, low dose and mid dose did not ameliorated the insulin resistance. In the HDL, Cholesterol, as well as triglycerides found to be increased in disease control group, however the low dose and mid dose exhibited slight improvement. TNF-α levels were also found to be improved in the high dose of Ivabradine compared to disease control. CONCLUSIONS Our findings suggest that ivabradine may have anti-hyperglycemic effects by reduction in glucose and lipids In order to treat type 2 diabetes, TNF-α levels which is important mediator of JNK pathway, If (funny current) inhibitor, ivabradine may be used as therapeutic agent for the treatment of metabolic dysfunction.