Unimolecular Dual Incretins Maximize Metabolic Benefits in Rodents, Monkeys, and Humans
Unimolecular Dual Incretins Maximize Metabolic Benefits in Rodents, Monkeys, and Humans
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DOI：
10.1126/scitranslmed.3007218
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发表时间：
2013-10-30
影响因子：
17.1
通讯作者：
Tschoep, Matthias H.
中科院分区：
文献类型：
--
作者：
Finan, Brian;Ma, Tao;Tschoep, Matthias H.
我们报告了一种肽的发现和翻译治疗效果，该肽在肠促胰岛素激素胰高血糖素样肽-1（GLP-1）和葡萄糖依赖性促胰岛素多肽（GIP）的受体上具有强效、平衡的共激动作用。这种单分子双重肠促胰岛素衍生自GLP-1和GIP的混合序列，并显示出相对于选择性GLP-1激动剂增强的抗高血糖和促胰岛素功效。值得注意的是，这种上级疗效在肥胖和糖尿病的啮齿动物模型（包括db/db小鼠和ZDF大鼠）中转化为灵长类动物（食蟹猴和人）。此外，这种共激动剂在减少肥胖啮齿动物的脂肪量方面表现出协同作用，而选择性GIP激动剂表现出可忽略不计的减肥功效。单分子双重肠促胰岛素纠正了肥胖的两个原因机制，肥胖诱导的胰岛素抵抗和胰腺胰岛素缺乏，比选择性单激动剂更有效。通过位点特异性脂化或PEG化改进单分子双重肠促胰岛素的作用持续时间，以支持较低的给药频率。这些肽提供了与天然肽相当的药理学，并且相对于类似修饰的选择性GLP-1激动剂具有增强的功效。药代动力学增强降低了药物暴露峰值，并结合对GLP-1介导的药理学的依赖性降低，避免了选择性GLP-1激动剂典型的不良胃肠道作用。平衡且高效的双重肠促胰岛素激动剂的发现和验证使得能够采用更生理的方法来管理与葡萄糖耐量受损相关的疾病。
We report the discovery and translational therapeutic efficacy of a peptide with potent, balanced co-agonism at both of the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This unimolecular dual incretin is derived from an intermixed sequence of GLP-1 and GIP, and demonstrated enhanced antihyperglycemic and insulinotropic efficacy relative to selective GLP-1 agonists. Notably, this superior efficacy translated across rodent models of obesity and diabetes, including db/db mice and ZDF rats, to primates (cynomolgus monkeys and humans). Furthermore, this co-agonist exhibited synergism in reducing fat mass in obese rodents, whereas a selective GIP agonist demonstrated negligible weight-lowering efficacy. The unimolecular dual incretins corrected two causal mechanisms of diabesity, adiposity-induced insulin resistance and pancreatic insulin deficiency, more effectively than did selective mono-agonists. The duration of action of the unimolecular dual incretins was refined through site-specific lipidation or PEGylation to support less frequent administration. These peptides provide comparable pharmacology to the native peptides and enhanced efficacy relative to similarly modified selective GLP-1 agonists. The pharmacokinetic enhancement lessened peak drug exposure and, in combination with less dependence on GLP-1-mediated pharmacology, avoided the adverse gastrointestinal effects that typify selective GLP-1-based agonists. This discovery and validation of a balanced and high-potency dual incretin agonist enables a more physiological approach to management of diseases associated with impaired glucose tolerance.