Development of a physiological insulin resistance model in human stem cell-derived adipocytes

Adipocytes are key regulators of human metabolism, and their dysfunction in insulin signaling is central to metabolic diseases including type II diabetes mellitus (T2D). However, the progression of insulin resistance into T2D is still poorly understood. This limited understanding is due, in part, to the dearth of suitable models of insulin signaling in human adipocytes. Traditionally, adipocyte models fail to recapitulate in vivo insulin signaling, possibly due to exposure to supraphysiological nutrient and hormone conditions. We developed a protocol for hPSC-derived adipocytes that uses physiological nutrient conditions to produce a potent insulin response comparable to in vivo adipocytes. After systematic optimization, this protocol allows robust insulin-stimulated glucose uptake and transcriptional insulin response. Furthermore, exposure of sensitized adipocytes to physiological hyperinsulinemia dampens insulin-stimulated glucose uptake and dysregulates insulin-responsive transcription. Overall, our methodology provides a novel platform for the mechanistic study of insulin signaling and resistance using human pluripotent stem cell-derived adipocytes. Overall design: Development of a physiological insulin resistance model in human stem cell-derived adipocytes

脂肪细胞（adipocytes）是人体代谢的关键调控因子，其胰岛素信号通路（insulin signaling）功能异常是包括2型糖尿病（type II diabetes mellitus, T2D）在内的代谢疾病的核心致病环节。然而，胰岛素抵抗进展为T2D的具体机制仍有待阐明。这一认知局限部分源于人类脂肪细胞中胰岛素信号通路研究的合适模型匮乏。传统脂肪细胞模型无法重现体内的胰岛素信号通路特征，这可能是因为模型采用了超生理剂量的营养与激素培养条件。
本研究开发了一套基于人类多能干细胞（human pluripotent stem cell, hPSC）诱导分化脂肪细胞的培养方案，该方案采用生理浓度的营养条件，可使脂肪细胞产生与体内脂肪细胞相当的强效胰岛素应答反应。经过系统性优化后，该方案可实现稳定的胰岛素刺激葡萄糖摄取以及转录层面的胰岛素应答。此外，将致敏后的脂肪细胞暴露于生理性高胰岛素环境中，会抑制胰岛素刺激的葡萄糖摄取，并扰乱胰岛素应答相关的转录调控。综上，本研究建立的方法为利用人类多能干细胞诱导分化的脂肪细胞开展胰岛素信号通路及抵抗的机制研究提供了全新的实验平台。
实验设计概述：基于人类干细胞诱导分化脂肪细胞构建生理性胰岛素抵抗模型。