Davis Jeffrey C, Alves Tiago C, Helman Aharon, Chen Jonathan C, Kenty Jennifer H, Cardone Rebecca L, Liu David R, Kibbey Richard G, Melton Douglas A
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.
Department of Internal Medicine (Endocrinology), Yale University, New Haven, CT, USA; Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany.
Cell Rep. 2020 May 12;31(6):107623. doi: 10.1016/j.celrep.2020.107623.
Stem cell-derived β (SC-β) cells could provide unlimited human β cells toward a curative diabetes treatment. Differentiation of SC-β cells yields transplantable islets that secrete insulin in response to glucose challenges. Following transplantation into mice, SC-β cell function is comparable to human islets, but the magnitude and consistency of response in vitro are less robust than observed in cadaveric islets. Here, we profile metabolism of SC-β cells and islets to quantify their capacity to sense glucose and identify reduced anaplerotic cycling in the mitochondria as the cause of reduced glucose-stimulated insulin secretion in SC-β cells. This activity can be rescued by challenging SC-β cells with intermediate metabolites from the TCA cycle and late but not early glycolysis, downstream of the enzymes glyceraldehyde 3-phosphate dehydrogenase and phosphoglycerate kinase. Bypassing this metabolic bottleneck results in a robust, bi-phasic insulin release in vitro that is identical in magnitude to functionally mature human islets.
干细胞衍生的β（SC-β）细胞可为治愈性糖尿病治疗提供无限的人类β细胞。SC-β细胞的分化产生可移植的胰岛，这些胰岛在受到葡萄糖刺激时会分泌胰岛素。将其移植到小鼠体内后，SC-β细胞的功能与人类胰岛相当，但体外反应的强度和一致性不如尸体胰岛。在这里，我们分析了SC-β细胞和胰岛的代谢情况，以量化它们感知葡萄糖的能力，并确定线粒体中回补反应循环减少是SC-β细胞中葡萄糖刺激的胰岛素分泌减少的原因。通过用三羧酸循环的中间代谢物以及糖酵解后期而非早期（在甘油醛3-磷酸脱氢酶和磷酸甘油酸激酶下游）的代谢物刺激SC-β细胞，可以挽救这种活性。绕过这一代谢瓶颈会导致体外强大的双相胰岛素释放，其强度与功能成熟的人类胰岛相同。
