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小檗碱及衍生物通过激活一磷酸腺苷激活蛋白激酶改善胰岛素敏感性机制研究——线粒体呼吸链复合物抑制
发表日期: 2008-05-22
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    小檗碱,也称黄连素,最新发现具有降低血糖和改善胰岛素抵抗的治疗作用。研究表明,小檗碱通过抑制线粒体内呼吸链上复合物一的活性,从而激活能量代谢感应器一磷酸腺苷激活蛋白激酶AMPK,改善胰岛素抵抗啮齿动物的胰岛素敏感性。基于小檗碱的不良口服利用度,对小檗碱进行结构修饰获得的二氢小檗碱在保持生物活性基础上,大大提高了小檗碱在生物体内的生物利用度,对肥胖鼠的胰岛素抵抗和肥胖症状具有显著的改善作用。
    该研究由上海药物研究所李佳研究员课题组和胡立宏研究员课题组与国外研究者共同完成,该项结果为小檗碱在抗2型糖尿病治疗领域的应用提供重要依据,并预示经合理设计并改造修饰的小檗碱,将成为治疗2型糖尿病的具有应用前景的自主创新药物。
 
Berberine, and its more Biologically Available Derivative Dihydroberberine,
Inhibit Mitochondrial Respiratory Complex I: A Mechanism for the Action of
Berberine to Activate AMPK and Improve Insulin Action
 
Nigel Turner1* (PhD), Jing-Ya Li2* (PhD), Alison Gosby1* (PhD), Sabrina W.C. To1 (BSc),Zhe Cheng2 (MSc), Hiroyuki Miyoshi3 (PhD), Makoto M. Taketo3 (PhD), Gregory J.
Cooney1 (PhD), Edward W. Kraegen1 (PhD), David E. James1 (PhD), Li-Hong Hu2† (PhD),
Jia Li 2† (PhD) and Ji-Ming Ye1† (PhD)
 
*These authors contributed equally to this work
 
1Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia;
2Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China;
3Department of Pharmacology, Graduate School of Medicine, Kyoto University, Japan
 
Objective: Berberine (BBR) activates AMP-activated protein kinase (AMPK) and improves insulin sensitivity in rodent models of insulin resistance. We investigated the mechanism of activation of AMPK by BBR and explored whether derivatization of BBR could improve its in vivo efficacy.
 
Methods: AMPK phosphorylation was examined in L6 myotubes and LKB1-/- cells, with or without the CAMKK inhibitor STO-609. Oxygen consumption was measured in L6 myotubes and isolated muscle mitochondria. The effect of a BBR derivative,
dihydroberberine (dhBBR), on adiposity and glucose metabolism was examined in rodents fed a high-fat diet (HFD).
 
Results: We have made the following novel observations: (1) BBR dose-ependently
inhibited respiration in L6 myotubes and muscle mitochondria, through a specific effect on respiratory Complex 1, similar to that observed with metformin and rosiglitazone. (2) Activation of AMPK by BBR did not rely on the activity of either LKB1 or CAMKKβ, consistent with major regulation at the level of the AMPK phosphatase. (3) A novel BBR derivative, dhBBR, was identified that displayed improved in vivo efficacy in terms of counteracting increased adiposity, tissue triglyceride accumulation and insulin resistance in HFD rodents. This effect is likely due to enhanced oral bioavailability.
 
Conclusions: Complex 1 of the respiratory chain represents a major target for compounds that improve whole body insulin sensitivity through increased AMPK activity. The identification of a novel derivative of BBR with improved in vivo efficacy highlights the potential importance of BBR as a novel therapy for the treatment of type 2 diabetes.
 
Diabetes 57: 1414-1418; published online before print as 10.2337/db07-1552
 

   

(供稿部门:李佳课题组;)

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