Diabetologia ( IF 8.4 ) Pub Date : 2024-09-09 , DOI: 10.1007/s00125-024-06260-y Tsugumasa Toma 1 , Nobukazu Miyakawa 2 , Yuiichi Arakaki 1 , Takuro Watanabe 2 , Ryosei Nakahara 1 , Taha F S Ali 1, 3 , Tanima Biswas 1 , Mikio Todaka 4 , Tatsuya Kondo 2 , Mikako Fujita 1 , Masami Otsuka 1, 5 , Eiichi Araki 2, 6, 7 , Hiroshi Tateishi 1, 8
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Aims/hypothesis
Appropriate management of blood glucose levels and the prevention of complications are important in the treatment of diabetes. We have previously reported on a compound named HPH-15 that is not only antifibrotic but also AMP-activated protein kinase (AMPK)-activating. In this study, we evaluated whether HPH-15 is useful as a therapeutic medication for diabetes.
Methods
We examined the effects of HPH-15 on AMPK activation, glucose uptake, fat accumulation and lactic acid production in L6-GLUT4, HepG2 and 3T3-L1 cells, as a model of muscle, liver and fat tissue, respectively. Additionally, we investigated the glucose-lowering, fat-accumulation-suppressing, antifibrotic and AMPK-activating effect of HPH-15 in mice fed a high-fat diet (HFD).
Results
HPH-15 at a concentration of 10 µmol/l increased AMPK activation, glucose uptake and membrane translocation of GLUT4 in each cell model to the same extent as metformin at 2 mmol/l. The production of lactic acid (which causes lactic acidosis) in HPH-15-treated cells was equal to or less than that observed in metformin-treated cells. In HFD-fed mice, HPH-15 lowered blood glucose from 11.1±0.3 mmol/l to 8.2±0.4 mmol/l (10 mg/kg) and 7.9±0.4 mmol/l (100 mg/kg) and improved insulin resistance. The HPH-15 (10 mg/kg) group showed the same level of AMPK activation as the metformin (300 mg/kg) group in all organs. The HPH-15-treated HFD-fed mice also showed suppression of fat accumulation and fibrosis in the liver and fat tissue; these effects were more significant than those obtained with metformin. Mice treated with high doses of HPH-15 also exhibited a 44% reduction in subcutaneous fat.
Conclusions/interpretation
HPH-15 activated AMPK at lower concentrations than metformin in vitro and in vivo and improved blood glucose levels and insulin resistance in vivo. In addition, HPH-15 was more effective than metformin at ameliorating fatty liver and adipocyte hypertrophy in HFD-fed mice. HPH-15 could be effective in preventing fatty liver, a common complication in diabetic individuals. Additionally, in contrast to metformin, high doses of HPH-15 reduced subcutaneous fat in HFD-fed mice. Presumably, HPH-15 has a stronger inhibitory effect on fat accumulation and fibrosis than metformin, accounting for the reduction of subcutaneous fat. Therefore, HPH-15 is potentially a glucose-lowering medication that can lower blood glucose, inhibit fat accumulation and ameliorate liver fibrosis.
Graphical Abstract
中文翻译：
一种抗纤维化化合物，可改善细胞和 HFD 小鼠模型中的高血糖和脂肪堆积
目标/假设
适当管理血糖水平和预防并发症在糖尿病治疗中很重要。我们之前报道过一种名为 HPH-15 的化合物，它不仅具有抗纤维化作用，而且还具有 AMP 活化蛋白激酶 （AMPK） 激活作用。在这项研究中，我们评估了 HPH-15 是否可用作糖尿病的治疗药物。
方法
我们分别作为肌肉、肝脏和脂肪组织模型，研究了 HPH-15 对 L6-GLUT4 、 HepG2 和 3T3-L1 细胞中 AMPK 活化、葡萄糖摄取、脂肪积累和乳酸产生的影响。此外，我们研究了 HPH-15 在喂食高脂饮食 （HFD） 的小鼠中的降糖、抑制脂肪堆积、抗纤维化和 AMPK 激活作用。
结果
浓度为 10 μmol/l 的 HPH-15 增加了每个细胞模型中 GLUT4 的 AMPK 活化、葡萄糖摄取和膜易位，其程度与 2 mmol/l 的二甲双胍相同。HPH-15 处理的细胞中乳酸（导致乳酸性酸中毒）的产生等于或少于在二甲双胍处理的细胞中观察到的。在 HFD 喂养的小鼠中，HPH-15 将血糖从 11.1±0.3 mmol/l 降低到 8.2±0.4 mmol/l （10 mg/kg） 和 7.9±0.4 mmol/l （100 mg/kg） 并改善了胰岛素抵抗。HPH-15 （10 mg/kg） 组在所有器官中显示出与二甲双胍 （300 mg/kg） 组相同的 AMPK 活化水平。HPH-15 处理的 HFD 喂养小鼠也显示出对肝脏和脂肪组织中脂肪堆积和纤维化的抑制;这些效果比使用二甲双胍获得的效果更显著。用高剂量 HPH-15 治疗的小鼠也表现出皮下脂肪减少 44%。
结论/解释
HPH-15 在体外和体内以低于二甲双胍的浓度激活 AMPK，并改善体内血糖水平和胰岛素抵抗。此外，HPH-15 在改善 HFD 喂养小鼠的脂肪肝和脂肪细胞肥大方面比二甲双胍更有效。HPH-15 可有效预防脂肪肝，脂肪肝是糖尿病患者的常见并发症。此外，与二甲双胍相比，高剂量的 HPH-15 减少了 HFD 喂养小鼠的皮下脂肪。据推测，HPH-15 对脂肪堆积和纤维化的抑制作用比二甲双胍强，解释了皮下脂肪的减少。因此，HPH-15 可能是一种降糖药物，可以降低血糖、抑制脂肪堆积和改善肝纤维化。
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