Ameliorative Effect And Mechanism Of Chiglitazar, A Novel PPAR α/γ Dual Agonist, On Insulin Resistance And Dyslipidemia

Type 2 diabetes mellitus is a chronic disease characterized by glucose intolerance, hyperglycemia, hyperinsulinemia, and dyslipidemia. The World Health Organization estimated that by the year 2025, up to 300 million people will suffer from type 2 diabetes. Blood glucose levels and insulin sensitivity can be improved by treating patients with thiazolidinediones (TZDs) such as pioglitazone and rosiglitazone which act by binding and activating a transcription factor known as peroxisome proliferators-activated receptor gamma (PPARγ). Whereas rosiglitazone can markedly reduce insulin resistance, it has modest effects on plasma lipids and increases fat mass and body weight associated with adipocyte proliferation in type 2 diabetic patients. On the other hand, the increased triglycerides and decreased high-density lipoprotein cholesterol (HDL-C) levels, the most common lipid abnormalities in patients with insulin resistance, can be effectively altered by treatment with fibrates such as fenofibrate and gemfibrozil which have been used to treat hypertriglyceridaemia and reduce cardiovascular risk. The fibrates act by binding and activating PPARα. Both PPARa and PPARγ agonists have actions with distinct benefits for T2DM.PPARs are a class of nuclear transcription factors that have been found to be very important in various aspects of metabolism, including lipids, adipogenesis, and glucose control. PPARs have three subtypes:α,δ (β), and γ. PPARα is predominantly expressed in the liver and regulates the transcription of genes involved in hepatic fatty acid uptake and oxidation. PPARγ is present mainly in white adipose tissue (WAT), where its activation stimulates the expression of genes involved in fatty acid uptake and storage. In skeletal muscle, significant levels of PPARa and PPARγ proteins are...