An antifibrotic compound that ameliorates hyperglycaemia and fat accumulation in cell and HFD mouse models

IF 8.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Tsugumasa Toma, Nobukazu Miyakawa, Yuiichi Arakaki, Takuro Watanabe, Ryosei Nakahara, Taha F. S. Ali, Tanima Biswas, Mikio Todaka, Tatsuya Kondo, Mikako Fujita, Masami Otsuka, Eiichi Araki, Hiroshi Tateishi
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引用次数: 0

Abstract

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

Abstract Image

一种抗纤维化化合物,可改善细胞和高密度脂蛋白胆固醇(HFD)小鼠模型中的高血糖和脂肪堆积状况
目的/假设适当控制血糖水平和预防并发症是治疗糖尿病的重要手段。我们曾报道过一种名为 HPH-15 的化合物,它不仅能抗纤维化,还能激活 AMP 激活蛋白激酶 (AMPK)。我们研究了 HPH-15 对分别作为肌肉、肝脏和脂肪组织模型的 L6-GLUT4、HepG2 和 3T3-L1 细胞中 AMPK 激活、葡萄糖摄取、脂肪积累和乳酸生成的影响。此外,我们还研究了 HPH-15 在高脂饮食(HFD)小鼠体内的降糖、抑制脂肪积累、抗纤维化和 AMPK 激活作用。结果 HPH-15 浓度为 10 µmol/l 时,在每种细胞模型中都能增加 AMPK 激活、葡萄糖摄取和 GLUT4 的膜转位,其增加程度与二甲双胍浓度为 2 mmol/l 时相同。经 HPH-15 处理的细胞产生的乳酸(导致乳酸酸中毒)与二甲双胍处理的细胞相同或更少。在高密度脂蛋白喂养的小鼠中,HPH-15可将血糖从11.1±0.3毫摩尔/升降至8.2±0.4毫摩尔/升(10毫克/千克)和7.9±0.4毫摩尔/升(100毫克/千克),并改善胰岛素抵抗。HPH-15(10毫克/千克)组与二甲双胍(300毫克/千克)组在所有器官中的AMPK激活水平相同。经 HPH-15 处理的高密度脂蛋白胆固醇喂养小鼠还显示出抑制肝脏和脂肪组织中脂肪堆积和纤维化的作用;这些作用比二甲双胍的作用更为显著。结论/解释HPH-15在体外和体内激活AMPK的浓度低于二甲双胍,并能改善体内血糖水平和胰岛素抵抗。此外,HPH-15 比二甲双胍更有效地改善高密度脂蛋白胆固醇喂养小鼠的脂肪肝和脂肪细胞肥大。HPH-15可有效预防糖尿病患者常见的并发症--脂肪肝。此外,与二甲双胍相反,高剂量的HPH-15可减少高密度脂蛋白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更强,这也是皮下脂肪减少的原因。因此,HPH-15是一种潜在的降糖药物,可以降低血糖、抑制脂肪堆积和改善肝纤维化。 图文摘要
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Diabetologia
Diabetologia 医学-内分泌学与代谢
CiteScore
18.10
自引率
2.40%
发文量
193
审稿时长
1 months
期刊介绍: Diabetologia, the authoritative journal dedicated to diabetes research, holds high visibility through society membership, libraries, and social media. As the official journal of the European Association for the Study of Diabetes, it is ranked in the top quartile of the 2019 JCR Impact Factors in the Endocrinology & Metabolism category. The journal boasts dedicated and expert editorial teams committed to supporting authors throughout the peer review process.
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