Amodiaquine improves insulin resistance and lipid metabolism in diabetic model mice.

Abstract

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.

• Authors: Hoe-Yune Jung, Bobae Kim, Hye Guk Ryu, Yosep Ji, Soyoung Park, Seung Hee Choi, Dohyun Lee, In-Kyu Lee, Munki Kim, You Jeong Lee, Woojin Song, Young Hee Lee, Hyung Jin Choi, Chang-Kee Hyun, Wilhelm H Holzapfel, Kyong-Tai Kim
• Journal: Diabetes, obesity & metabolism (Diabetes Obes Metab) Vol. 20 Issue 7 Pg. 1688-1701 (07 2018) ISSN: 1463-1326 [Electronic] England
• PMID: 29516607 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 John Wiley & Sons Ltd.

Chemical References

• Antimalarials
• Blood Glucose
• Fatty Acids
• PPAR alpha
• PPAR gamma
• Triglycerides
• Amodiaquine

Topics

• 3T3-L1 Cells
• Amodiaquine (pharmacology)
• Animals
• Antimalarials (pharmacology)
• Blood Glucose (drug effects, metabolism)
• Body Weight
• Cell Proliferation
• Diet, High-Fat
• Disease Models, Animal
• Fatty Acids (metabolism)
• Fatty Liver
• Hyperlipidemias
• In Vitro Techniques
• Insulin Resistance
• Lipid Metabolism (drug effects)
• Liver (drug effects, metabolism)
• Mice
• Mice, Obese
• Oxidation-Reduction
• PPAR alpha (agonists)
• PPAR gamma (agonists)
• Triglycerides (metabolism)