Tyrosine Kinase Inhibitor in Combination with PPAR-y Agonist: Directing Metabolic Dysfunction Throgh AMPK Pathway

Abstract

1.1 AIM AND OBJECTIVE—Diabetes presently impacts over 425 million people across the world. Tyrosine kinase inhibitors have been reported to reverse type 2 diabetes in chronic myeloid leukemia patients. Thiazolidenediones exhibits potential improvement in glycemic control and insulin sensitivity in type 2 diabetes. Molecular docking studies suggest that tyrosine kinase inhibitors interact with PPAR-γ in ligand binding domain with high predictive values. These in silico investigations warranted us further evaluation of tyrosine kinase inhibitor in combination with PPAR-γ agonist in in vivo animal models. Therefore, present study focuses on pharmacological evaluation of combination of tyrosine kinase inhibitor with PPAR-γ agonist in treatment of type 2 diabetes. 1.2 MATERIAL AND METHOD—The current study evaluated the effect of Tyrosine Kinase Inhibitor and combination on diabetes in db/db mice and investigated possible mechanism’s underlying improved glycemic control. Dasatinib was administered at the dose of 2.5mg/kg p.o., gallic acid 100mg/kg p.o. and pioglitazone 20mg/kg p.o. and their combinations into db/db mice for 4 weeks. At the end of treatment, effect on glucose homeostasis was measured using an intraperitoneal glucose tolerance test and assessment of insulin sensitivity test. The blood glucose levels and body weight were monitored on weekly basis. The liver inflammation and lipid infiltration in adipocytes were assessed by histopathology using H & E staining. Akt phosphorylation and AMPK expressions were studied by western blotting. Ki76 and p-AMPK expression were determined by immunohistochemistry analysis.