Selective PPAR Agonists for the Treatment of Type 2 Diabetes

Abstract

Type 2 diabetes is a metabolic disease characterized by increased plasma glucose and insulin as well as dyslipidemia. If left untreated, chronic diseases will develop that are associated with neuropathic damage and higher mortality risk. Using a rational drug design, novel compounds have been developed that selectively activate the human PPAR receptors, leading to lessening of hyperglycemia and hyperinsulinemia as well as reduction of lipid levels in conjunction with an increase of the beneficial HDL-cholesterol. These PPAR agonists showed increased potency and efficacy compared to previously marketed insulin sensitizers. Lead compounds with desirable pharmacokinetic properties were chosen for further testing in several animal models. The in vivo activity of some synthetic ligands, capable of activating two or all three members of peroxisome proliferator-activated receptors (PPAR) family of receptors, suggested that they may have improved efficacy in type 2 diabetes therapy. Here, we briefly summarize the development of some novel PPAR agonists identified by our group in recent years.

PGC‐1α activation as a therapeutic approach in mitochondrial disease

“…Via PGC-1a activation, the PPARs thereby link external stimuli and metabolic changes to mitochondrial function. The role of PPARs in modulating fatty acid oxidation made them therapeutic targets for the treatment of diabetes (57)(58)(59), and metabolic syndrome (60)(61)(62). Hence, many PPAR agonists to stimulate PPAR-activated gene transcription as available and well studied (60).…”

Blueberries’ Impact on Insulin Resistance and Glucose Intolerance

“…The transcription factor PPAR was also observed and whole blueberries, isolated anthocyanins, and anthocyanin-rich extracts increased its activity [18,51,52,53]. PPARs are nuclear fatty acid receptors that play an important role in obesity-related metabolic diseases and PPAR agonist drugs have been used to improve insulin resistance [54]. In addition, the Chinese blueberry has been found to effectively protect β-cells against glucolipotoxicity when compared to metformin in vitro by reducing intracellular triglyceride levels, restoring intracellular insulin content, lowering basal insulin secretion, and increasing glucose-stimulated insulin secretion [55].…”

Peroxisome Proliferator-Activated ReceptorγRegulates the Expression of Lipid Phosphate Phosphohydrolase 1 in Human Vascular Endothelial Cells

“…PPAR γ forms a heterodimer with RXR and binds to the PPAR response elements (PPREs) in the promoter region of target genes [13]. When activated by various natural and synthetic ligands such as prostaglandin metabolite 15d-PGJ2 [14] and the insulin sensitizer rosiglitazone [15], PPAR γ transactivates the gene expression and regulates adipogenesis [16] and insulin response [17]. In addition, PPAR γ possesses antiatherogenic and anti-inflammatory actions in ECs [18, 19].…”