胰淀素（一种单分子胰高血糖素样肽-1和胰淀素受体激动剂）对小鼠和大鼠体重及代谢功能障碍的影响。
The effect of amycretin, a unimolecular glucagon-like peptide-1 and amylin receptor agonist, on body weight and metabolic dysfunction in mice and rats.
作者信息
Kuhre Rune Ehrenreich, Ballarín-González Borja, Brand Christian Lehn, Glendorf Tine, Madsen Kim Grimstrup, Hjøllund Karina Rahr, Hogendorf Wouter Frederik Johan, Ipsen David Højland, Lundh Sofia, Kruse Thomas, Petersen Signe Beck, Secher Anna, Vegge Andreas, Raun Kirsten
机构信息
Novo Nordisk A/S, Research and Early Development, Måløv, Denmark.
Novo Nordisk A/S, Research and Early Development, Måløv, Denmark; Novo Nordisk A/S, Development, Søborg, Denmark.
出版信息
EBioMedicine. 2025 Jul 23;118:105862. doi: 10.1016/j.ebiom.2025.105862.
BACKGROUND
Amycretin is a novel unimolecular glucagon-like peptide-1 (GLP-1) and amylin receptor agonist. This study aimed to determine its role in mitigating diet-induced metabolic disorders, such as obesity, insulin resistance, and fatty liver disease, in mice and rats.
METHODS
Preclinical studies were conducted to characterise amycretin activation of GLP-1, amylin and calcitonin receptors, and determine the effects of amycretin administration on the metabolic health of mice and rats. Investigations included measurements of body weight and body composition, energy intake and energy expenditure, insulin sensitivity, metabolic dysfunction-associated steatotic liver disease (MASLD), and access in the mouse brain.
FINDINGS
Amycretin activated human, mouse and rat GLP-1, amylin and calcitonin receptors in cell-based systems. In diet-induced obese (DIO) rats, amycretin administration for 21 days reduced total energy intake by 47% (95% CI (mean), kcal: vehicle: 2132-2493 vs. amycretin: 1044-1390) and lowered body weight by 18% (95% CI (mean), % change relative to pre-treatment: vehicle: 6.56-8.47 vs. amycretin: -10.48 to -12.74, p < 0.0001), while maintaining energy expenditure. Amycretin targeted key areas of the mouse brain that regulate food intake. Insulin sensitivity improved significantly with amycretin administration in DIO rats compared with vehicle controls, shown by higher glucose infusion rates during a hyperinsulinaemic euglycemic clamp. Additionally, amycretin improved histological hallmarks of MASLD, primarily by reducing steatosis.
INTERPRETATION
Amycretin had various beneficial effects on metabolic health in mice and rats; effectively reducing body weight, enhancing insulin sensitivity, and improving MASLD activity scores. Thus, amycretin could be a promising therapeutic option for metabolic diseases including obesity and type 2 diabetes, warranting further clinical trials assessing its efficacy in humans.
FUNDING
Novo Nordisk A/S.
背景
艾美克肽是一种新型的单分子胰高血糖素样肽-1（GLP-1）和胰淀素受体激动剂。本研究旨在确定其在减轻小鼠和大鼠饮食诱导的代谢紊乱（如肥胖、胰岛素抵抗和脂肪肝疾病）中的作用。
方法
进行临床前研究以表征艾美克肽对GLP-1、胰淀素和降钙素受体的激活作用，并确定给予艾美克肽对小鼠和大鼠代谢健康的影响。研究包括测量体重和身体组成、能量摄入和能量消耗、胰岛素敏感性、代谢功能障碍相关脂肪性肝病（MASLD）以及小鼠大脑中的通路。
研究结果
在基于细胞的系统中，艾美克肽激活了人、小鼠和大鼠的GLP-1、胰淀素和降钙素受体。在饮食诱导的肥胖（DIO）大鼠中，给予艾美克肽21天可使总能量摄入减少47%（95%置信区间（均值），千卡：载体组：2132 - 2493 vs. 艾美克肽组：1044 - 1390），体重降低18%（95%置信区间（均值），相对于治疗前的变化百分比：载体组：6.56 - 8.47 vs. 艾美克肽组：-10.48至-12.74，p < 0.0001），同时维持能量消耗。艾美克肽作用于小鼠大脑中调节食物摄入的关键区域。与载体对照组相比，在DIO大鼠中给予艾美克肽后胰岛素敏感性显著改善，这在高胰岛素正常血糖钳夹期间较高的葡萄糖输注率中得到体现。此外，艾美克肽改善了MASLD的组织学特征，主要是通过减少脂肪变性。
解读
艾美克肽对小鼠和大鼠的代谢健康具有多种有益作用；有效减轻体重、增强胰岛素敏感性并改善MASLD活性评分。因此，艾美克肽可能是包括肥胖和2型糖尿病在内的代谢性疾病的一种有前景的治疗选择，值得进一步进行临床试验以评估其在人类中的疗效。
资助
诺和诺德公司。
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