Adenosine Monophosphate-Activated Protein Kinase (AMPK) as a New Target for Antidiabetic Drugs: A Review on Metabolic, Pharmacological and Chemical Considerations.
Adenosine Monophosphate-Activated Protein Kinase (AMPK) as a New Target for Antidiabetic Drugs: A Review on Metabolic, Pharmacological and Chemical Considerations.
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DOI：
10.1900/rds.2009.6.13
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发表时间：
2009-01-01
期刊：
影响因子：
--
通讯作者：
Sasson, Shlomo
中科院分区：
文献类型：
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作者：
Gruzman, Arie;Babai, Gali;Sasson, Shlomo
鉴于2型糖尿病的流行性质和目前口服降糖药的失败率很高，对新疗法的探索是密集的。腺苷单磷酸活化蛋白激酶（adenosine monophospate -activated protein kinase， AMPK）是细胞能量平衡的重要调节蛋白，被认为是各器官，尤其是骨骼肌和肝脏中糖脂代谢的主开关。在骨骼肌中，AMPK刺激葡萄糖运输和脂肪酸氧化。在肝脏中，它增加脂肪酸氧化，减少葡萄糖输出，胆固醇和甘油三酯合成。AMPK诱导的这些代谢作用与降低高血糖个体的血糖水平有关。两类口服降糖药物（双胍类和噻唑烷二酮类）已被证明通过直接或间接激活AMPK来发挥一些治疗作用。然而，副作用和对这些药物的获得性耐药强调需要开发新型有效的AMPK激活剂。我们最近发现了一类新的疏水d -木糖衍生物，以非胰岛素依赖的方式激活骨骼肌中的AMPK。其中一种衍生物（2,4;3,5-二苄基-d -木糖-二乙基-二硫缩醛）通过激活AMPK，增加质膜中葡萄糖转运蛋白-4 （GLUT-4）的丰度，从而刺激骨骼肌细胞中己糖的运输速率。该化合物降低了糖尿病小鼠的血糖水平，因此为2型糖尿病的治疗干预策略提供了一种新的策略。本文介绍了通过直接或间接相互作用激活AMPK的各种化学相关化合物，并讨论了它们作为候选抗高血糖药物开发的潜力。
In view of the epidemic nature of type 2 diabetes and the substantial rate of failure of current oral antidiabetic drugs the quest for new therapeutics is intensive. The adenosine monophosphate-activated protein kinase (AMPK) is an important regulatory protein for cellular energy balance and is considered a master switch of glucose and lipid metabolism in various organs, especially in skeletal muscle and liver. In skeletal muscles, AMPK stimulates glucose transport and fatty acid oxidation. In the liver, it augments fatty acid oxidation and decreases glucose output, cholesterol and triglyceride synthesis. These metabolic effects induced by AMPK are associated with lowering blood glucose levels in hyperglycemic individuals. Two classes of oral antihyperglycemic drugs (biguanidines and thiazolidinediones) have been shown to exert some of their therapeutic effects by directly or indirectly activating AMPK. However, side effects and an acquired resistance to these drugs emphasize the need for the development of novel and efficacious AMPK activators. We have recently discovered a new class of hydrophobic D-xylose derivatives that activates AMPK in skeletal muscles in a non insulin-dependent manner. One of these derivatives (2,4;3,5-dibenzylidene-D-xylose-diethyl-dithioacetal) stimulates the rate of hexose transport in skeletal muscle cells by increasing the abundance of glucose transporter-4 (GLUT-4) in the plasma membrane through activation of AMPK. This compound reduces blood glucose levels in diabetic mice and therefore offers a novel strategy of therapeutic intervention strategy in type 2 diabetes. The present review describes various classes of chemically-related compounds that activate AMPK by direct or indirect interactions and discusses their potential for candidate antihyperglycemic drug development.