Glucose Response by Stem Cell-Derived β Cells In Vitro Is Inhibited by a Bottleneck in Glycolysis
Glucose Response by Stem Cell-Derived β Cells In Vitro Is Inhibited by a Bottleneck in Glycolysis
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DOI：
10.1016/j.celrep.2020.107623
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发表时间：
2020-05-12
期刊：
影响因子：
8.8
通讯作者：
Melton, Douglas A.
中科院分区：
文献类型：
--
作者：
Davis, Jeffrey C.;Alves, Tiago C.;Melton, Douglas A.
干细胞衍生的β（Sc-beta）细胞可以为治愈糖尿病提供无限的人类β细胞。SC-β细胞的分化产生可移植的胰岛，其响应于葡萄糖挑战而分泌胰岛素。移植到小鼠体内后，SC-β细胞的功能与人胰岛相当，但体外反应的幅度和一致性不如尸体胰岛中观察到的那么稳健。在这里，我们分析了SC-β细胞和胰岛的代谢，以量化它们感知葡萄糖的能力，并将线粒体中的回补循环减少确定为SC-β细胞中葡萄糖刺激的胰岛素分泌减少的原因。这种活性可以通过用来自TCA循环的中间代谢物和晚期而非早期糖酵解（位于甘油醛3-磷酸脱氢酶和磷酸甘油酸激酶的下游）挑战SC-β细胞来挽救。克服这一代谢瓶颈导致体外稳健的双相胰岛素释放，其在幅度上与功能成熟的人胰岛相同。
Stem cell-derived beta (Sc-beta) cells could provide unlimited human beta cells toward a curative diabetes treatment. Differentiation of SC-beta cells yields transplantable islets that secrete insulin in response to glucose challenges. Following transplantation into mice, SC-beta 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-beta 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-beta cells. This activity can be rescued by challenging SC-beta 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.