Ghrelin cells replace insulin-producing β cells in two mouse models of pancreas development
Ghrelin cells replace insulin-producing β cells in two mouse models of pancreas development
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DOI：
10.1073/pnas.0308604100
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发表时间：
2004-03-02
影响因子：
11.1
通讯作者：
Sussel, L
中科院分区：
文献类型：
--
作者：
Prado, CL;Pugh-Bernard, AE;Sussel, L
胰岛是维持葡萄糖稳态所必需的。在胰岛内，同源结构域蛋白Nkx2.2对于所有产生胰岛素的β细胞和产生胰高血糖素的α细胞的亚群的分化是必需的（1）。缺乏Nkx2.2的小鼠具有相对正常大小的胰岛，但突变胰岛内的大量细胞不能产生四种主要胰岛激素中的任何一种。在这项研究中，我们证明了Nkx2.2突变的内分泌细胞已被产生ghrelin的细胞所取代，ghrelin是一种主要在胃中发现的促进食欲的肽。有趣的是，正常小鼠胰腺也含有少量生长激素释放肽产生细胞，定义了一个新的胰岛“胰岛”细胞群。生长素释放素产生细胞的扩张以β细胞为代价可能是一种普遍现象，因为我们证明Pax4突变小鼠表现出类似的表型。我们提出胰岛素和生长激素释放肽细胞共享一个共同的祖细胞，Nkx2.2和Pax4是指定或维持13细胞命运分化所必需的。这一发现也表明，在调节葡萄糖代谢中，胰岛素和生长激素释放肽之间的平衡存在遗传成分。
The pancreatic islet is necessary for maintaining glucose homeostasis. Within the pancreatic islet, the homeodomain protein Nkx2.2 is essential for the differentiation of all insulin-producing beta cells and a subset of glucagon-producing a cells (1). Mice lacking Nkx2.2 have relatively normal sized islets, but a large number of cells within the mutant islet fail to produce any of the four major islet hormones. In this study we demonstrate that Nkx2.2 mutant endocrine cells have been replaced by cells that produce ghrelin, an appetite-promoting peptide predominantly found in the stomach. Intriguingly, normal mouse pancreas also contains a small population of ghrelin-producing cells, defining a new islet "epsilon" cell population. The expansion of ghrelin-producing cells at the expense of beta cells may be a general phenomenon, because we demonstrate that Pax4 mutant mice display a similar phenotype. We propose that insulin and ghrelin cells share a common progenitor and that Nkx2.2 and Pax4 are required to specify or maintain differentiation of the 13 cell fate. This finding also suggests that there is a genetic component underlying the balance between insulin and ghrelin in regulating glucose metabolism.