Umeå Centre for Molecular Medicine, Umeå University, SE-901 87 Umeå, Sweden.
Betagenon AB, Tvistevägen 48, SE-907 36 Umeå, Sweden.
JCI Insight. 2018 Jun 21;3(12). doi: 10.1172/jci.insight.99114.
AMPK activated protein kinase (AMPK), a master regulator of energy homeostasis, is activated in response to an energy shortage imposed by physical activity and caloric restriction. We here report on the identification of PAN-AMPK activator O304, which - in diet-induced obese mice - increased glucose uptake in skeletal muscle, reduced β cell stress, and promoted β cell rest. Accordingly, O304 reduced fasting plasma glucose levels and homeostasis model assessment of insulin resistance (HOMA-IR) in a proof-of-concept phase IIa clinical trial in type 2 diabetes (T2D) patients on Metformin. T2D is associated with devastating micro- and macrovascular complications, and O304 improved peripheral microvascular perfusion and reduced blood pressure both in animals and T2D patients. Moreover, like exercise, O304 activated AMPK in the heart, increased cardiac glucose uptake, reduced cardiac glycogen levels, and improved left ventricular stroke volume in mice, but it did not increase heart weight in mice or rats. Thus, O304 exhibits a great potential as a novel drug to treat T2D and associated cardiovascular complications.
腺苷酸活化蛋白激酶（AMPK）是能量稳态的主要调节因子，它会在体力活动和热量限制引起的能量短缺时被激活。我们在此报告了 PAN-AMPK 激活剂 O304 的鉴定，它在饮食诱导的肥胖小鼠中增加了骨骼肌中的葡萄糖摄取，减少了β细胞的应激，并促进了β细胞的休息。因此，O304 在二甲双胍治疗的 2 型糖尿病（T2D）患者的概念验证性 IIa 期临床试验中降低了空腹血糖水平和稳态模型评估的胰岛素抵抗（HOMA-IR）。T2D 与严重的微血管和大血管并发症有关，O304 改善了动物和 T2D 患者的外周微血管灌注和血压。此外，与运动一样，O304 激活了心脏中的 AMPK，增加了心脏的葡萄糖摄取，降低了心脏糖原水平，并改善了小鼠的左心室射血容量，但它没有增加小鼠或大鼠的心脏重量。因此，O304 作为一种治疗 T2D 及其相关心血管并发症的新型药物具有巨大的潜力。
