MEDI0382, a GLP-1/Glucagon Receptor Dual Agonist, Dramatically Reduces Hepatic Collagen in a Mouse Model of NASH
MEDI0382, a GLP-1/Glucagon Receptor Dual Agonist, Dramatically Reduces Hepatic Collagen in a Mouse Model of NASH
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DOI：
10.2337/db18-1841-p
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发表时间：
2018-06
期刊：
影响因子：
7.7
通讯作者：
M. Beaton;S. Guionaud;James Conway;J. Grimsby;C. Rhodes;L. Jermutus;James L. Trevaskis
中科院分区：
文献类型：
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作者：
M. Beaton;S. Guionaud;James Conway;J. Grimsby;C. Rhodes;L. Jermutus;James L. Trevaskis
以肝脏脂肪变性、炎症和纤维化为特征的非酒精性脂肪性肝炎（NASH）是一个尚未得到满足的医疗需求。MEDI0382是一种平衡的GLP-1/胰高血糖素双受体激动剂，正在开发用于治疗T2DM。在这里，我们比较了MEDI0382与GLP-1类似物利拉鲁肽对NASH的影响。瘦素缺乏的ob/ob小鼠在高反式脂肪、果糖和胆固醇饮食中维持8周以诱导NASH，然后随机分为四个治疗组：对照物、MEDI0382 （30 nmol/kg）、利拉鲁肽（30 nmol/kg）或对照物治疗后转为低脂饮食（LFD）。使用MEDI0382和利拉鲁肽治疗可降低体重并改善葡萄糖耐量。使用MEDI0382治疗后，肝脏脂质降低了40% (p)。综上所述，MEDI0382与利拉鲁肽具有相似的代谢控制作用，但在主要NASH终点上表现出更好的效果。M. Beaton：雇员；自我;落实的。员工;配偶/伴侣;落实的。S.吉奥诺：没有。j·p·康威：没有。格里姆斯比：雇员；自我;阿斯利康。C.J.罗兹：股票/股东；自我;阿斯利康。L.耶尔穆图斯：雇员；自我;阿斯利康。股票/股东;自我;阿斯利康。J. Trevaskis：员工；自我;落实的。股票/股东;自我;阿斯利康。
Nonalcoholic steatohepatitis (NASH), characterized by hepatic steatosis, inflammation and fibrosis is an unmet medical need. MEDI0382, a balanced GLP-1/glucagon dual receptor agonist, is under development for the treatment of T2DM. Here we examined the effects of MEDI0382 on NASH compared to liraglutide, a GLP-1 analog. Leptin-deficient ob/ob mice were maintained on high trans-fat, fructose and cholesterol diet for 8 weeks to induce NASH then randomized to four treatment groups: vehicle, MEDI0382 (30 nmol/kg), liraglutide (30 nmol/kg) or vehicle-treated and switched to low-fat diet (LFD). Treatment with MEDI0382 and liraglutide reduced body weight and improved glucose tolerance. Hepatic lipid was reduced by 40% with MEDI0382 treatment (p In conclusion, MEDI0382 exerted similar metabolic control relative to liraglutide, but exhibited superior effects on primary NASH endpoints. Disclosure M. Beaton: Employee; Self; MedImmune. Employee; Spouse/Partner; MedImmune. S. Guionaud: None. J.P. Conway: None. J. Grimsby: Employee; Self; AstraZeneca. C.J. Rhodes: Stock/Shareholder; Self; AstraZeneca. L. Jermutus: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. J. Trevaskis: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca.