The AMP-activated protein kinase (AMPK) is a potential therapeutic target for metabolic diseases based on its reported actions in the liver and skeletal muscle. We evaluated two distinct direct activators of AMPK: a non-selective activator of all AMPK complexes, PF-739, and an activator selective for AMPK β1-containing complexes, PF-249. In cells and animals, both compounds were effective at activating AMPK in hepatocytes, but only PF-739 was capable of activating AMPK in skeletal muscle. In diabetic mice, PF-739, but not PF-249, caused a rapid lowering of plasma glucose levels that was diminished in the absence of skeletal muscle, but not liver, AMPK heterotrimers and was the result of an increase in systemic glucose disposal with no impact on hepatic glucose production. Studies of PF-739 in cynomolgus monkeys confirmed translation of the glucose lowering and established activation of AMPK in skeletal muscle as a potential therapeutic approach to treat diabetic patients.

译文

基于其在肝脏和骨骼肌中的作用,AMP激活的蛋白激酶 (AMPK) 是代谢疾病的潜在治疗靶标。我们评估了AMPK的两种不同的直接激活剂: PF-739,所有AMPK复合物的非选择性激活剂和PF-249对含AMPK β1复合物的选择性激活剂。在细胞和动物中,两种化合物都有效激活肝细胞中的AMPK,但只有PF-739能够激活骨骼肌中的AMPK。在糖尿病小鼠中,PF-739 (但不是PF-249) 引起血浆葡萄糖水平的快速降低,在不存在骨骼肌而非肝脏AMPK异源三聚体的情况下降低,并且是全身葡萄糖处置增加的结果,而对肝葡萄糖产生没有影响。食蟹猴PF-739的研究证实了葡萄糖降低的翻译,并建立了骨骼肌中AMPK的激活,作为治疗糖尿病患者的潜在治疗方法。

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