影响GLP1R细胞表面表达的人类GLP1R变异与血糖控制受损和脂肪增加有关
Wenwen Gao1,2, Lei Liu1,3, Eunna Huh4
1Université Paris Cité, Institut Cochin, INSERM, CNRS, Paris, France.
Nature metabolism
|September 14, 2023
概括
葡萄糖类1受体 (GLP1R) 的遗传变异影响其功能,影响2型糖尿病和肥胖风险. 缺陷GLP1R细胞表面表达是一种危险因素,但有些缺陷是可以治疗的.
科学领域:
- 内分泌学 在内分泌学.
- 分子药理学分子药理学
- 遗传学 是一个遗传学.
背景情况:
- 葡萄糖类1受体 (GLP1R) 是2型糖尿病和肥胖症的关键治疗标.
- 之前对GLP1R基因变异及其代谢关联的研究已经产生了相互矛盾的结果.
研究的目的:
- 为了从功能上描述各种GLP1R变异,并研究它们与代谢特征的关联.
- 澄清GLP1R遗传变异对受体功能和相关健康状况的影响.
主要方法:
- 在四个信号通路中对60个GLP1R变体进行功能分析.
- 使用INS-1 823/3细胞进行体外研究以评估胰岛素分泌救援.
- 在20万名英国生物库参与者中进行遗传关联研究.
主要成果:
- 观察到多种不同的GLP1R表型,包括缺陷的细胞表面表达,功能增益和功能丧失变体.
- 在GLP1R功能丧失的变体中,通过使用全osteric配体或高度激动剂,证明了缺陷胰岛素分泌的救援.
- 在一个大型的人群中,与GLP1R细胞表面表达受损与较差的葡萄糖控制和增加脂肪度 (较高的HbA1c和BMI) 有关.
结论:
- 损害GLP1R细胞表面表达被确定为2型糖尿病和肥胖特征的危险因素.
- GLP1R基因变异表现出广泛的功能后果,影响受体活性.
- 对于携带GLP1R功能丧失变体的个体,存在潜在的治疗策略.
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