Amodiaquine improves insulin resistance and lipid metabolism in diabetic model mice

Aims: Although peroxisome proliferator-activated receptors (PPARs)alpha/gamma dual agonists can be beneficial for treatment of dyslipidemia in patients with type 2 diabetes, their use is limited owing to various side effects, including body weight gain, edema, and heart failure. We aimed to demonstrate that amodiaquine, an antimalarial agent, has potential as a PPAR alpha/gamma dual agonist with low risk of adverse effects. Methods: We screened a Prestwick library (Prestwick Chemical; Illkirch, France) to identify novel PPAR alpha/gamma dual agonists and selected amodiaquine (4-[(7-chloroquinolin-4-yl)amino]-2-[(diethylamino)methyl]phenol), which activated both PPAR-alpha & -gamma, for further investigation. We performed both in vitro, including glucose uptake assay and fatty acid oxidation assay, and in vivo studies to elucidate the anti-diabetic and anti-obesity effects of amodiaquine. Results: Amodiaquine selectively activated the transcriptional activities of PPAR alpha/gamma and enhanced both fatty acid oxidation and glucose uptake without altering insulin secretion in vitro. In high-fat diet-induced obese and genetically modified obese/diabetic mice, amodiaquine not only remarkably ameliorated insulin resistance, hyperlipidemia, and fatty liver but also decreased body weight gain. Conclusion: Our findings suggest that amodiaquine exerts beneficial effects on glucose and lipid metabolism by concurrent activation of PPAR alpha/gamma. Furthermore, amodiaquine acts as an alternative insulin-sensitizing agent with a positive influence on lipid metabolism and has potential to prevent and treat type 2 diabetes while reducing the risk of lipid abnormalities.