Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY.
Developmental Biology Program, Sloan Kettering Institute, New York, NY.
Diabetes. 2024 Aug 1;73(8):1336-1351. doi: 10.2337/db23-0508.
Mouse models are extensively used in metabolic studies. However, inherent differences between the species, notably their blood glucose levels, hampered data translation into clinical settings. In this study, we confirmed GLUT1 to be the predominantly expressed glucose transporter in both adult and fetal human β-cells. In comparison, GLUT2 is detected in a small yet significant subpopulation of adult β-cells and is expressed to a greater extent in fetal β-cells. Notably, GLUT1/2 expression in INS+ cells from human stem cell-derived islet-like clusters (SC-islets) exhibited a closer resemblance to that observed in fetal islets. Transplantation of primary human islets or SC-islets, but not murine islets, lowered murine blood glucose to the human glycemic range, emphasizing the critical role of β-cells in establishing species-specific glycemia. We further demonstrate the functional requirements of GLUT1 and GLUT2 in glucose uptake and insulin secretion through chemically inhibiting GLUT1 in primary islets and SC-islets and genetically disrupting GLUT2 in SC-islets. Finally, we developed a mathematical model to predict changes in glucose uptake and insulin secretion as a function of GLUT1/2 expression. Collectively, our findings illustrate the crucial roles of GLUTs in human β-cells, and identify them as key components in establishing species-specific glycemic set points.
小鼠模型广泛应用于代谢研究。然而，由于物种之间存在固有差异，特别是血糖水平的差异，这阻碍了数据向临床环境的转化。在这项研究中，我们证实 GLUT1 是成年和胎儿人β细胞中主要表达的葡萄糖转运体。相比之下，GLUT2 在一小部分成年β细胞中被检测到，并且在胎儿β细胞中表达更为显著。值得注意的是，源自人干细胞的胰岛样簇（SC-islets）中的 INS+细胞中 GLUT1/2 的表达与在胎儿胰岛中观察到的表达更为相似。原发性人胰岛或 SC-islets 的移植可以将小鼠的血糖降低到人类的血糖范围，这强调了β细胞在建立物种特异性血糖方面的关键作用。我们进一步通过在原发性胰岛和 SC-islets 中化学抑制 GLUT1 以及在 SC-islets 中遗传破坏 GLUT2 来证明 GLUT1 和 GLUT2 在葡萄糖摄取和胰岛素分泌中的功能需求。最后，我们开发了一个数学模型来预测 GLUT1/2 表达变化对葡萄糖摄取和胰岛素分泌的影响。总之，我们的研究结果阐明了 GLUTs 在人β细胞中的关键作用，并确定它们是建立物种特异性血糖设定点的关键组成部分。
