A novel glucagon-like peptide-1/glucagon receptor dual agonist exhibits weight-lowering and diabetes-protective effects
A novel glucagon-like peptide-1/glucagon receptor dual agonist exhibits weight-lowering and diabetes-protective effects
复制标题
一种新型胰高血糖素样肽-1/胰高血糖素受体双重激动剂具有减肥和糖尿病保护作用
DOI：
10.1016/j.ejmech.2017.07.046
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发表时间：
2017
影响因子：
6.7
通讯作者：
Qian Hai
中科院分区：
文献类型：
--
作者：
Zhou Jie;Cai Xingguang;Huang Xun;Dai Yuxuan;Sun Lidan;Zhang Bo;Yang Bo;Lin Haiyan;Huang Wenlong;Qian Hai
胰高血糖素通过其特异性的胰高血糖素受体（GCGR）发挥多种作用，如升高血糖、改善脂肪酸代谢、能量消耗和增加脂肪组织的脂解。胰高血糖素最重要的作用是调节血糖，但也存在高血糖症的可能性。胰高血糖素还可轻度激活胰高血糖素样肽-1受体（GLP-1 R），从而产生降血糖作用。本研究旨在通过改善GLP-1 R活化和恶化GCGR活化来消除高血糖症的可能性并保持固有的分解代谢作用，从而降低体重并显示糖尿病保护作用。首先，合成了十二种半胱氨酸修饰的GLP-1/GCGR双重激动剂（1-12）。然后，在正常ICR小鼠中全面地进行GLP-1 R/GCGR介导的活化和生物活性。观察到胰高血糖素中位置22、23和25处被半胱氨酸取代的化合物是体重和血糖的更好调节剂。为了延长衍生物的半衰期，对各种脂肪侧链马来酰亚胺进行了修饰，以获得最佳的胰高血糖素类似物。月桂酸马来酰亚胺共轭物4d的抗氧化能力最强。在饮食诱导的肥胖（DIO）小鼠中，每两天给予一次1000 nmol/kg 4d，持续一个月，使肥胖和葡萄糖耐量正常化。观察到包括胰岛素、瘦素和脂联素在内的血浆代谢参数的改善。这些研究表明，化合物4d在降低体重和维持能量消耗方面表现良好，而没有高血脂症的机会，4d作为有效的GLP-1/GCGR激动剂在预防和治疗肥胖和血脂异常中具有很强的临床潜力。
Glucagon has plenty of effects via a specific glucagon receptor(GCGR) like elevating the blood glucose, improving fatty acids metabolism, energy expenditure and increasing lipolysis in adipose tissue. The most important role of glucagon is to regulate the blood glucose, but the emergent possibilities of hyperglycaemia is exist. Glucagon could also slightly activate glucagon-like peptide-1 receptor(GLP-1R), which lead to blood glucose lowering effect. This study aims to erase the likelihood of hyperglycaemia and to remain the inherent catabolic effects through improving GLP-1R activation and deteriorating GCGR activation so as to lower the bodyweight and show diabetes-protective effects. Firstly, twelve cysteine modified GLP-1/GCGR dual agonists were synthesized (1–12). Then, the GLP-1R/GCGR mediated activation and biological activity in normal ICR mice were comprehensively performed. Compounds substituted by cysteine at positions 22, 23 and 25 in glucagon were observed to be better regulators of the body weight and blood glucose. To prolong the half-lives of derivatives, various fatty side chain maleimides were modified to optimal glucagon analogues. Laurate maleimide conjugate4dwas the most potent. Administration of 1000 nmol/kg4donce every two days for a month normalized adiposity and glucose tolerance in diet-induced obese (DIO) mice. Improvements in plasma metabolic parameters including insulin, leptin, and adiponectin were observed. These studies suggest that compound4dbehaves well in lowering body weight and maintaining energy expenditure without a chance of hyperglycaemia,4dhas strong clinical potential as an efficient GLP-1/GCGR agonist in the prevention and treatment of obesity and dyslipidemia.