Beinaglutide shows significantly beneficial effects in diabetes/obesity-induced nonalcoholic steatohepatitis in ob/ob mouse model
Beinaglutide shows significantly beneficial effects in diabetes/obesity-induced nonalcoholic steatohepatitis in ob/ob mouse model
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DOI：
10.1016/j.lfs.2020.118966
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发表时间：
2021-01-29
期刊：
影响因子：
6.1
通讯作者：
Zuo, Yajun
中科院分区：
文献类型：
--
作者：
Fang, Xiankang;Du, Zhiqiang;Zuo, Yajun
目的：贝那鲁肽已被批准用于2型糖尿病（T2DM）的降糖治疗。除了血糖控制外，从现实世界的数据中还观察到显著的体重减轻。本研究旨在探讨贝那鲁肽在不同模型中的药理学和药代动力学特征。方法：观察贝那鲁肽单次给药后C57BL/6和ob/ob小鼠的药理作用。研究了单次或多次给药后小鼠的药代动力学特征。研究了ob/ob小鼠治疗2周和饮食诱导的非酒精性脂肪性肝炎（NASH） ob/ob小鼠模型治疗4周的亚慢性药理疗效。主要发现：贝那鲁肽能剂量依赖性地降低葡萄糖水平，改善糖耐量试验中胰岛素分泌，单次给药后抑制食物摄入和胃排空。在高剂量下，beinaglutide可以抑制食物摄入超过4小时，在大约两周的治疗后，ob/ob小鼠体重减轻。在重复给药的情况下，没有观察到贝纳鲁肽在食物摄入中的快速反应。在NASH模型中，贝纳鲁肽可减轻肝脏重量和肝脏脂肪变性，改善胰岛素敏感性。在脂肪酸β -氧化（Ppara, Acad1, Acox1），线粒体功能（Mfn1, Mfn2），抗氧化（Sod2）， Sirt1等方面观察到显著的基因水平变化。意义：我们的研究结果表征了贝因纳鲁肽在小鼠体内的药理学和药代动力学特征，并支持长期使用贝因纳鲁肽可导致体重减轻和减少肝脂肪变性，这表明贝因纳鲁肽可能是治疗肥胖和NASH的有效药物。
Aims: Beinaglutide has been approved for glucose lowering in type 2 diabetes mellitus (T2DM) in China. In addition to glycemic control, significant weight loss is observed from real world data. This study is designed to investigate the pharmacological and pharmacokinetic profiles of beinaglutide in different models.Methods: The pharmacological efficacy of beinaglutide was evaluated in C57BL/6 and ob/ob mice after single administration. Pharmacokinetic profiles in mice were investigated after single or multiple administration. Sub-chronic pharmacological efficacy was investigated in ob/ob mice for two weeks treatment and diet-induced ob/ob mice model of nonalcoholic steatohepatitis (NASH) for four weeks treatment.Key findings: Beinaglutide could dose-dependently reduce the glucose levels and improve insulin secretion in glucose tolerance tests, inhibit food intake and gastric emptying after single administration. At higher doses, beinaglutide could inhibit food intake over 4 h, which results in weight loss in ob/ob mice after about two weeks treatment. No tachyphylaxis is observed for beinaglutide in food intake with repeated administration. In NASH model, beinaglutide could reduce liver weight and hepatic steatosis and improve insulin sensitivity. Signiant changes of gene levels were observed in fatty acid beta-oxidation (Ppara, Acad1, Acox1), mitochondrial function (Mfn1, Mfn2), antioxidation (Sod2), Sirt1, and et al.Significance: Our results characterize the pharmacological and pharmacokinetic profiles of beinaglutide in mice and supported that chronic use of beinaglutde could lead to weight loss and reduce hepatic steatosis, which suggest beinaglutide may be effective therapy for the treatment of obesity and NASH.