Talchai Shivatra Chutima, Accili Domenico
Department of Medicine and Naomi Berrie Diabetes Center, Columbia University, New York, NY Faculty of Science, King Mongkut's University of Technology Thonburi, Bangkok, Thailand.
Department of Medicine and Naomi Berrie Diabetes Center, Columbia University, New York, NY
Diabetes. 2015 Aug;64(8):2868-79. doi: 10.2337/db14-1696. Epub 2015 Mar 17.
β-Cell dysfunction in diabetes results from abnormalities of insulin production, secretion, and cell number. These abnormalities may partly arise from altered developmental programming of β-cells. Foxo1 is important to maintain adult β-cells, but little is known about its role in pancreatic progenitor cells as determinants of future β-cell function. We addressed this question by generating an allelic series of somatic Foxo1 knockouts at different stages of pancreatic development in mice. Surprisingly, ablation of Foxo1 in pancreatic progenitors resulted in delayed appearance of Neurogenin3(+) progenitors and their persistence into adulthood as a self-replicating pool, causing a fourfold increase of β-cell mass. Similarly, Foxo1 ablation in endocrine progenitors increased their numbers, extended their survival, and expanded β-cell mass. In contrast, ablation of Foxo1 in terminally differentiated β-cells did not increase β-cell mass nor did it affect Neurogenin3 expression. Despite the increased β-cell mass, islets from mice lacking Foxo1 in pancreatic or endocrine progenitors responded poorly to glucose, resulting in glucose intolerance. We conclude that Foxo1 integrates cues that determine developmental timing, pool size, and functional features of endocrine progenitor cells, resulting in a legacy effect on adult β-cell mass and function. Our results illustrate how developmental programming predisposes to β-cell dysfunction in adults and raise questions on the desirability of increasing β-cell mass for therapeutic purposes in type 2 diabetes.
糖尿病中的β细胞功能障碍源于胰岛素生成、分泌及细胞数量的异常。这些异常可能部分源于β细胞发育程序的改变。Foxo1对维持成年β细胞很重要，但关于其在胰腺祖细胞中作为未来β细胞功能决定因素的作用却知之甚少。我们通过在小鼠胰腺发育的不同阶段生成一系列体细胞Foxo1基因敲除等位基因来解决这个问题。令人惊讶的是，胰腺祖细胞中Foxo1的缺失导致神经生成素3（Neurogenin3）阳性祖细胞出现延迟，并作为一个自我复制池持续存在至成年，导致β细胞量增加四倍。同样，内分泌祖细胞中Foxo1的缺失增加了它们的数量，延长了它们的存活时间，并扩大了β细胞量。相反，终末分化的β细胞中Foxo1的缺失既没有增加β细胞量，也没有影响神经生成素3的表达。尽管β细胞量增加，但胰腺或内分泌祖细胞中缺乏Foxo1的小鼠的胰岛对葡萄糖反应不佳，导致葡萄糖不耐受。我们得出结论，Foxo1整合了决定内分泌祖细胞发育时间、池大小和功能特征的信号，从而对成年β细胞量和功能产生遗留效应。我们的结果说明了发育程序如何使成年人易患β细胞功能障碍，并引发了关于在2型糖尿病治疗中增加β细胞量是否可取的问题。
