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适应葡萄糖的PAGR1-调节的骨肌肉基因程序控制全身葡萄糖恒温和肝脏代谢

Chenyun Ding¹, Yuhuan Jia¹, Lin Liu¹

¹The State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Chemistry and Biomedicine Innovation Center (ChemBIC), Model Animal Research Center, Medical School of Nanjing University, Nanjing University, Nanjing, 210061, China.

Advanced science (Weinheim, Baden-Wurttemberg, Germany)

|July 24, 2025

概括

高血糖水平增加PAXIP1相关的富含谷氨酸蛋白1 (PAGR1) 在肌肉中,恶化胰岛素抵抗. 移除PAGR1可以改善葡萄糖的吸收,并防止代谢功能障碍,这表明PAGR1是2型糖尿病的治疗点.

科学领域:

代谢性疾病研究研究.
分子内分泌学分子内分泌学
骨肌肉生理学骨肌肉生理学

背景情况:

2型糖尿病 (T2D) 中的慢性高血糖会导致胰岛素抵抗,并损害肌肉的葡萄糖吸收,导致代谢功能障碍.
高血糖症对骨肌肉产生负面影响的分子机制尚不清楚.
骨肌肉对于葡萄糖平衡至关重要,调节食后葡萄糖吸收.

研究的目的:

为了识别骨肌肉中的新型葡萄糖反应调节剂.
研究PAGR1在调解高血糖引起的胰岛素抵抗中的作用.
探索PAGR1作为T2D和代谢障碍的潜在治疗标.

主要方法:

使用肌肉特定的PAGR1-淘汰赛小鼠模型.
评估了胰岛素信号传递,葡萄糖载体4 (GLUT4) 转位,以及骨肌肉中的葡萄糖吸收.
研究了PAGR1对TBC1D4表达作用的分子机制.
评估了对高脂肪饮食诱导的代谢功能障碍的保护作用.

主要成果:

PAXIP1相关的富含谷氨酸蛋白1 (PAGR1) 表达是由骨肌肉中的高葡萄糖诱导的.
肌肉特异性PAGR1缺乏改善了胰岛素信号传递,增强了GLUT4转位,并增加了葡萄糖吸收.
PAGR1直接激活TBC1D4表达,这是GLUT4的负调节者.
保护PAGR1删除免受饮食诱导的胰岛素耐药性和肝硬化.

结论:

PAGR1是骨肌肉中一种关键的葡萄糖反应调节剂.
PAGR1调解了对高血糖的不适应反应,从而导致胰岛素抵抗.
向PAGR1可能为2型糖尿病和相关代谢疾病提供治疗策略.

关键词:

葡萄糖的恒常性是葡萄糖的恒常性.肝脏代谢肝脏代谢肥胖肥胖肥胖肥胖肥胖肥胖肥胖肥胖这是骨肌肉的骨架肌肉.

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