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一个微生理学模型的渐进的人类肝脏胰岛素耐药性

Dominick J Hellen¹, Jessica Ungerleider¹, Erin Tevonian¹

¹Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139 US.

bioRxiv : the preprint server for biology

|January 20, 2025

概括

高水平的胰岛素会导致肝细胞的胰岛素抵抗,高葡萄糖和脂肪会使情况恶化. 这种情况在2型糖尿病 (T2D) 和脂肪肝中见到,部分可逆.

科学领域:

肝病学肝病学是一种肝病学.
代谢疾病代谢疾病
内分泌学在内分泌学.

背景情况:

肝脏抗胰岛素是2型糖尿病 (T2D) 和代谢功能障碍相关的脂肪肝疾病 (MAFLD) 的关键.
由于复杂的系统相互作用,体内研究难以分离营养素,激素和炎症等因素.
人类肝脏微生理系统 (MPS) 用于建模胰岛素反应和营养干扰.

研究的目的:

为了在人类肝脏MPS.中建立一个生理学上相关的,对胰岛素有反应的代谢基线.
研究肝细胞对胰岛素,葡萄糖和自由脂肪酸 (FFAs) 控制变化的反应.
了解T2D和MAFLD中肝脏胰岛素抵抗背后的机制.

主要方法:

肝脏MPS被培养长达3周的正常 (200 pM) 或T2D水平 (800 pM) 胰岛素.
细胞暴露于正常/高血糖葡萄糖和正常/升高的FFA水平,单独或组合.
关键评估包括葡萄糖生产,信号通路,胰岛素清除,转录组学和脂质/胆酸积累.

主要成果:

单独高胰岛素血症会在一周内引起胰岛素抵抗.
过高血糖和升高的FFAs显著恶化了胰岛素抵抗表型.
结合的高胰岛素血症,高血糖和高的FFAs改变了代谢和免疫信号,使肝细胞易于产生胰岛素抵抗.
观察到的表型在恢复正常条件后是部分可逆的.

结论:

增强的肝脏MPS模型准确地复制了人类胰岛素耐药性的关键方面.
这个模型为T2D和MAFLD的机制提供了有价值的见解.
这些发现强调了肝细胞代谢功能障碍的部分可逆性.

关键词:

微流体学微流体学 2 型糖尿病 2 型糖尿病肝细胞肝细胞肝细胞非酒精性脂肪性肝病是非酒精性脂肪性肝病.组织工程是组织工程.

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