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Glucose transporters are key components of the human glucostat

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posted on 2024-05-22, 02:34 authored by Inbal Caspi, Daniel M. Tremmel, Julian Pulecio, Dapeng Yang, Dingyu Liu, Jielin Yan, Jon S. Odorico, Danwei Huangfu

Mouse models are extensively utilized 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 setpoints.

Funding

This study was supported in part by grants to D.H. from NIH (R01DK096239) and the American Diabetes Association (1-19-IBS-125); grants to J.S.O. and D.H. from JDRF (3-SRA-2021-1060-S-B) and DoD PRMRP (W81XWH-20-1-0670); and the University of Wisconsin-Madison, Office of the Vice Chancellor for Research and Graduate Education with funding from the Wisconsin Alumni Research Foundation; a MSKCC Cancer Center Support Grant from the NIH (P30CA008748); a General Atlantic Graduate Research Fellowship (to I.C.); a Beatrice P. K. Palestin Fellowship and a Bruce Charles Forbes Fellowship (to D.L.); and a postdoctoral fellowship from a NYSTEM training grant from the Center for Stem Cell Biology of the Sloan Kettering Institute (DOH01-TRAIN3-2015-2016-00006, to D.Y.).

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