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Amodiaquine improves insulin resistance and lipid metabolism in diabetic model mice
Author(s) -
Jung HoeYune,
Kim Bobae,
Ryu Hye Guk,
Ji Yosep,
Park Soyoung,
Choi Seung Hee,
Lee Dohyun,
Lee InKyu,
Kim Munki,
Lee You Jeong,
Song Woojin,
Lee Young Hee,
Choi Hyung Jin,
Hyun ChangKee,
Holzapfel Wilhelm H,
Kim KyongTai
Publication year - 2018
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/dom.13284
Subject(s) - amodiaquine , insulin resistance , endocrinology , medicine , lipid metabolism , dyslipidemia , pharmacology , hyperlipidemia , carbohydrate metabolism , peroxisome proliferator activated receptor , insulin , type 2 diabetes , diabetes mellitus , chemistry , receptor , chloroquine , immunology , malaria
Aims Although peroxisome proliferator‐activated receptors (PPARs)α/γ 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 PPARα/γ dual agonist with low risk of adverse effects. Methods We screened a Prestwick library (Prestwick Chemical; Illkirch, France) to identify novel PPARα/γ dual agonists and selected amodiaquine (4‐[(7‐chloroquinolin‐4‐yl)amino]‐2‐[(diethylamino)methyl]phenol), which activated both PPAR‐α & ‐γ, 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 PPARα/γ 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 PPARα/γ. 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.