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Diabetes Obes Metab. 2018 Jul;20(7):1688-1701. doi: 10.1111/dom.13284. Epub 2018 Apr 14.

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

Author information

1
Department of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea.
2
R&D Center, NovMetaPharma Co., Ltd., Pohang, Republic of Korea.
3
Department of Advanced Green Energy and Environment, Handong Global University, Pohang, Republic of Korea.
4
School of Life Science, Handong Global University, Pohang, Republic of Korea.
5
Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea.
6
Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea.
7
Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
8
Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, Republic of Korea.
9
Bio Convergence Team, Advanced Bio Convergence Center, Pohang, Republic of Korea.
10
Academy of Immunology and Microbiology, Institute for Basic Science (IBS), Pohang, Republic of Korea.
11
Functional Neuroanatomy of Metabolism Regulation Laboratory, Department of Anatomy, Division of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.

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.

KEYWORDS:

antidiabetic drug; dyslipidaemia; fatty liver; glucose metabolism; glycaemic control; insulin resistance

PMID:
29516607
DOI:
10.1111/dom.13284
[Indexed for MEDLINE]

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