| Autor: |
Caspi, Inbal, Tremmel, Daniel M., Pulecio, Julian, Yang, Dapeng, Liu, Dingyu, Yan, Jielin, Odorico, Jon S., Huangfu, Danwei |
| Předmět: |
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| Zdroj: |
Diabetes; Aug2024, Vol. 73 Issue 8, p1336-1351, 16p |
| Abstrakt: |
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. Article Highlights: Normoglycemia of mice and humans falls within different ranges. Transplantation of human islets or stem cell-derived islet-like clusters, but not murine islets, lowered murine blood glucose to the human range, demonstrating the role of β-cells in establishing species-specific glycemia. The distinct expression profiles of GLUT1 and GLUT2 in murine and human β-cells, coupled with their different affinities for glucose, support their roles as species-specific regulators of glucose homeostasis. GLUT1/2 expression is required for human β-cell functionality, suggesting that GLUT1/2 misregulation contributes to diabetes pathogenesis. We further developed a mathematical model predicting insulin secretion as a function of the GLUT1/2 expression profile. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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