新激素疗法有望同时治疗肥胖糖尿病

一个由美国、中国、德国等国研究人员组成的科研小组10月30日在美国期刊《科学-转化医学》上报告说，动物及人类临床试验表明，可激活两种内分泌激素的一种人工合成分子能缓解糖尿病患者的血糖水平并有效降低体重。

该科研小组当天此前许多激素疗法只能激活某个单一激素，不但需要大剂量治疗才可见效，还往往带来严重恶心等副作用。他们研制的合成分子，可同时激活对机体代谢调节起重要作用的GLP-1与GIP这两种激素。

研究人员首先针对患糖尿病的肥胖老鼠及猴子进行治疗试验。结果发现，这种合成分子比现有药物更能有效降低体重并改善血糖。

在为期6周的临床试验中，研究人员给53名患糖尿病的肥胖患者使用以这种分子制成的药物。与未经治疗者相比，接受治疗的患者可分泌更多胰岛素，其血糖水平及肥胖问题均得到改善。尽管有些患者感到恶心，但没有观察到严重副作用。

报告作者们认为，他们研制的新分子或许是治疗糖尿病及肥胖症的新选择。

原文阅读：Unimolecular Dual Incretins Maximize Metabolic Benefits in Rodents,Monkeys,and Humans

Abstract

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.