Taylor Brandon L, Benthuysen Jacqueline, Sander Maike
Departments of Pediatrics and Cellular and Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA.
Departments of Pediatrics and Cellular and Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA
Diabetes. 2015 Mar;64(3):897-903. doi: 10.2337/db14-0684. Epub 2014 Oct 2.
All forms of diabetes are characterized by a loss of functional β-cell mass, and strategies for expanding β-cell mass could have significant therapeutic benefit. We have recently identified the transcription factor Nkx6.1 as an essential maintenance factor of the functional β-cell state. In addition, Nkx6.1 has been proposed to control β-cell proliferation, but a role for Nkx6.1 in regulating β-cell mass has not been demonstrated. Here, we show that Nkx6.1 is required for postnatal β-cell mass expansion. Genetic inactivation of Nkx6.1 in newly formed β-cells caused a drastic decrease in early postnatal β-cell proliferation, leading to reduced β-cell mass and glucose intolerance. Interestingly, Nkx6.1 was dispensable for prenatal β-cell proliferation. We found that Nkx6.1 regulates the expression of several β-cell maturation markers as well as expression of the nutrient sensors Glut2 and Glp1r. Manifestation of the β-cell mass defect at the transition to postnatal feeding suggests that Nkx6.1 could regulate β-cell growth by enabling β-cells to respond to nutrient-dependent proliferation signals, such as glucose and Glp1. Identification of β-cell-intrinsic regulators that connect nutrient-sensing and proliferation suggests new therapeutic targets for expanding functional β-cell mass.
所有形式的糖尿病都具有功能性β细胞数量减少的特征，而增加β细胞数量的策略可能具有显著的治疗益处。我们最近发现转录因子Nkx6.1是功能性β细胞状态的关键维持因子。此外，有人提出Nkx6.1可控制β细胞增殖，但Nkx6.1在调节β细胞数量方面的作用尚未得到证实。在此，我们表明Nkx6.1是出生后β细胞数量增加所必需的。新形成的β细胞中Nkx6.1的基因失活导致出生后早期β细胞增殖急剧减少，从而导致β细胞数量减少和葡萄糖不耐受。有趣的是，Nkx6.1对于产前β细胞增殖是可有可无的。我们发现Nkx6.1调节几种β细胞成熟标志物的表达以及营养传感器Glut2和Glp1r的表达。在过渡到出生后喂养时β细胞数量缺陷的表现表明，Nkx6.1可能通过使β细胞对营养依赖性增殖信号（如葡萄糖和Glp1）作出反应来调节β细胞生长。确定连接营养感知和增殖的β细胞内在调节因子为增加功能性β细胞数量提供了新的治疗靶点。
