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从携带MTNR1B风险变体的患者获得的人类诱导多能干细胞中的β细胞功能障碍的遗传风险建模

Tania Singh¹, Sebastian Kalamajski², Joãp P M C M Cunha¹

¹Unit of Molecular Metabolism, Lund University Diabetes Centre, Lund, Sweden.

Journal of pineal research

|September 3, 2025

概括

昼夜节律的干扰与2型糖尿病 (T2D) 有关. 一种特定的基因变异 (MTNR1B G- 基因) 通过影响黑素受体1B增加T2D风险,可能会损害胰腺β细胞功能.

科学领域:

内分泌学
遗传学
干细胞生物学

背景情况:

循环节律障碍和黑激素信号与2型糖尿病 (T2D) 发病有关.
黑素受体1B (MTNR1B) 基因的常见变异 (rs10830963 G- 基因) 与T2D风险的增加有关.
这种SNP是胰腺小岛的表达量特征位点 (eQTL),表明MTNR1B表达变化会影响β细胞功能.

研究的目的:

研究MTNR1BG基因基因风险变异对人类胰腺β类细胞的功能影响.
阐明MTNR1B变异,黑素信号和T2D风险之间的致病机制.

主要方法:

使用CRISPR/Cas9生成具有风险 (G/G) 或无风险 (C/C) MTNR1B基因型的同源人类诱导多能干细胞 (hiPSC) 和人类胚胎干细胞 (hESC) 线.
在50天的时间内将干细胞分化为β类细胞.
通过Western blot分析MTNR1B蛋白水平,并评估胰岛素分泌物对葡萄糖和黑色素刺激的反应.

主要成果:

基因组编辑成功地产生了高于90%的同位细胞系.
西部斑点分析显示,携带β类细胞的G基因基因蛋白质水平略高.
虽然胰岛素分泌在葡萄糖刺激下是可比的,但G单元对黑激素对胰岛素分泌的抑制作用的敏感性增加.
在分化细胞中,MTNR1B mRNA水平太低,无法进行可靠的eQTL分析.

结论:

携带MTNR1B风险等位基因的干细胞衍生的β类细胞显示MTNR1B蛋白的升高和对黑素的敏感性增加.
这些发现表明rs10830963SNP在MTNR1B介导的β细胞功能障碍中的潜在功能作用,有助于T2D风险.
需要对更成熟的β细胞模型进行进一步验证,以确认这些初步结果.

关键词:

黑色素受体1B 单核酸多态性来自干细胞的β细胞 β细胞的功能

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