Innovation Center, Shanghai Benemae Pharmaceutical Corporation, 916 Ziping Road, Zhoupu, PuDong, Shanghai, China.
Innovation Center, Shanghai Benemae Pharmaceutical Corporation, 916 Ziping Road, Zhoupu, PuDong, Shanghai, China.
Life Sci. 2021 Apr 1;270:118966. doi: 10.1016/j.lfs.2020.118966. Epub 2021 Jan 19.
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.
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.
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 β-oxidation (Ppara, Acadl, 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.
贝那鲁肽已在中国获批用于 2 型糖尿病（T2DM）的血糖控制。除了血糖控制，从真实世界数据中观察到显著的体重减轻。本研究旨在研究贝那鲁肽在不同模型中的药理学和药代动力学特征。
单次给药后，在 C57BL/6 和 ob/ob 小鼠中评估贝那鲁肽的药效学。单次或多次给药后研究药代动力学特征。在 ob/ob 小鼠中进行两周的亚慢性药效学研究，以及在非酒精性脂肪性肝炎（NASH）的饮食诱导 ob/ob 小鼠模型中进行四周的治疗。
贝那鲁肽可剂量依赖性降低葡萄糖水平并改善葡萄糖耐量试验中的胰岛素分泌，单次给药后抑制摄食和胃排空。在较高剂量下，贝那鲁肽可在 4 小时以上抑制摄食，导致 ob/ob 小鼠约两周治疗后体重减轻。重复给药时，贝那鲁肽在摄食方面没有出现脱敏现象。在 NASH 模型中，贝那鲁肽可降低肝重和肝脂肪变性，并改善胰岛素敏感性。观察到脂肪酸β氧化（Ppara、Acadl、Acox1）、线粒体功能（Mfn1、Mfn2）、抗氧化（Sod2）、Sirt1 等基因水平的显著变化。
我们的结果描述了贝那鲁肽在小鼠中的药理学和药代动力学特征，并支持慢性使用贝那鲁肽可导致体重减轻和减少肝脂肪变性，这表明贝那鲁肽可能是肥胖和 NASH 治疗的有效疗法。
