Sanofi Research and Development, Frankfurt, Germany.
Experimental Pharmacology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
Diabetes Obes Metab. 2020 Aug;22(8):1328-1338. doi: 10.1111/dom.14035. Epub 2020 Apr 12.
To test specific mono-agonists to the glucagon-like peptide-1 receptor (GLP-1R), glucagon receptor (GCGR) and glucose-dependent insulinotropic peptide receptor (GIPR), individually and in combination, in a mouse model of diet-induced non-alcoholic steatohepatitis (NASH) and fibrosis in order to decipher the contribution of their activities and potential additive effects to improving systemic and hepatic metabolism.
We induced NASH by pre-feeding C57BL/6J mice a diet rich in fat, fructose and cholesterol for 36 weeks. This was followed by 8 weeks of treatment with the receptor-specific agonists 1-GCG (20 μg/kg twice daily), 2-GLP1 (3 μg/kg twice daily) or 3-GIP (30 μg/kg twice daily), or the dual (1 + 2) or triple (1 + 2 + 3) combinations thereof. A dual GLP-1R/GCGR agonistic peptide, 4-dual-GLP1/GCGR (30 μg/kg twice daily), and liraglutide (100 μg/kg twice daily) were included as references.
Whereas low-dose 1-GCG or 3-GIP alone did not influence body weight, liver lipids and histology, their combination with 2-GLP1 provided additional weight loss, reduction in liver triglycerides and improvement in histological disease activity score. Notably, 4-dual-GLP-1R/GCGR and the triple combination of selective mono-agonists led to a significantly stronger reduction in the histological non-alcoholic fatty liver disease activity score compared to high-dose liraglutide, at the same extent of body weight loss.
GCGR and GIPR agonism provide additional, body weight-independent improvements on top of GLP-1R agonism in a murine model of manifest NASH with fibrosis.
在饮食诱导的非酒精性脂肪性肝炎（NASH）和纤维化的小鼠模型中，分别测试和组合测试胰高血糖素样肽-1 受体（GLP-1R）、胰高血糖素受体（GCGR）和葡萄糖依赖性胰岛素释放肽受体（GIPR）的特异性单激动剂，以解析其活性和潜在的协同作用对改善全身和肝脏代谢的贡献。
我们通过预饲 C57BL/6J 小鼠富含脂肪、果糖和胆固醇的饮食 36 周来诱导 NASH。随后，用受体特异性激动剂 1-GCG（20μg/kg，每日两次）、2-GLP1（3μg/kg，每日两次）或 3-GIP（30μg/kg，每日两次），或双重（1+2）或三重（1+2+3）组合进行 8 周的治疗。包含双重 GLP-1R/GCGR 激动肽 4-双重-GLP1/GCGR（30μg/kg，每日两次）和利拉鲁肽（100μg/kg，每日两次）作为参考。
虽然低剂量的 1-GCG 或 3-GIP 单独使用不会影响体重、肝脏脂质和组织学，但它们与 2-GLP1 的联合使用可提供额外的体重减轻、肝甘油三酯减少和组织学疾病活动评分的改善。值得注意的是，与高剂量利拉鲁肽相比，4-双重-GLP-1R/GCGR 和选择性单激动剂的三重组合在相同程度的体重减轻下，可显著降低组织学非酒精性脂肪性肝病活动评分。
在有纤维化的明显 NASH 小鼠模型中，GCGR 和 GIPR 激动剂除了 GLP-1R 激动剂之外，还提供了额外的、与体重无关的改善。
