Control of Pancreatic β Cell Regeneration by Glucose Metabolism
Control of Pancreatic β Cell Regeneration by Glucose Metabolism
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DOI：
10.1016/j.cmet.2011.02.012
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发表时间：
2011-04-06
期刊：
影响因子：
29
通讯作者：
Dor, Yuval
中科院分区：
文献类型：
--
作者：
Porat, Shay;Weinberg-Corem, Noa;Dor, Yuval
最近的研究表明，小鼠体内产生胰岛素的β细胞具有惊人的再生能力，这表明原则上可以实现人类糖尿病的再生治疗。在应激条件下的生理性β细胞再生依赖于存活的β细胞的加速增殖，但触发和控制这种反应的因素尚不清楚。利用胰岛移植实验，我们证明了β细胞质量是由系统控制的，而不是由组织损伤等局部因素控制的。β细胞葡萄糖代谢的慢性变化，而不是血糖水平本身，是体内基础和代偿性β细胞增殖的主要正向调节因素。在细胞内，遗传和药物操作表明，葡萄糖通过葡萄糖激酶代谢诱导β细胞复制，这是糖酵解的第一步，随后关闭K-ATP通道和膜去极化。我们的数据为代谢需求控制β细胞质量的动态平衡提供了分子机制。
Recent studies revealed a surprising regenerative capacity of insulin-producing beta cells in mice, suggesting that regenerative therapy for human diabetes could in principle be achieved. Physiologic beta cell regeneration under stressed conditions relies on accelerated proliferation of surviving beta cells, but the factors that trigger and control this response remain unclear. Using islet transplantation experiments, we show that beta cell mass is controlled systemically rather than by local factors such as tissue damage. Chronic changes in beta cell glucose metabolism, rather than blood glucose levels per se, are the main positive regulator of basal and compensatory beta cell proliferation in vivo. Intracellularly, genetic and pharmacologic manipulations reveal that glucose induces beta cell replication via metabolism by glucokinase, the first step of glycolysis, followed by closure of K-ATP channels and membrane depolarization. Our data provide a molecular mechanism for homeostatic control of beta cell mass by metabolic demand.