NFAT蛋白复合体的核重新定位，刺激β细胞分化和胰岛素分泌。
哺乳动物胰腺β细胞是胰岛素的唯一来源，它们按照特定方式生长，生长速度反映了怀孕、衰老、肥胖等生理变化导致的机体对胰岛素需求情况的改变。尽管研究人员对transcription factor calcineurin/nuclear factor of activated T-cells (NFAT)信号传递途径确切的分子机制还不是很清楚，但是有研究显示此途径传递的信号与胰岛素调节有关。伦敦大学国王学院（King's College London）MRC Centre for Developmental Neurobiology研究人员Jeremy J. Heit等发现calcineurin介导的NFAT核定位调节β细胞分化。文章发表于9月21日NATURE，标题为“Calcineurin/NFAT signalling regulates pancreatic β-cell growth and function”。
淋巴细胞、肌细胞和神经元细胞发生的生理学变化刺激了Ca2+入胞，导致丝氨酸/苏氨酸的钙调神经磷酸酶（calcineurin）被激活。Calcineurin诱导NFAT转录复合物的快速核定位。以前一直认为，胰岛素和葡萄糖能够提高胞内Ca2+的浓度，激活β细胞内NFAT蛋白符合体，因此研究人员一直希望能够弄清NFAT在β细胞分化中的特殊角色。研究人员利用基因工程手段得到calcineurin磷酸酶调节亚基缺陷小鼠模型——calcineurin b1 (Cnb1)。
结果发现Cnb1KO小鼠β细胞中几乎没有NFATc1聚集，胰岛素分泌减少了85％，β细胞数量减少到原来的50％，小鼠伴随有严重的高血糖症并在10周后糖尿病加重。胰岛β细胞的葡萄糖转运蛋白2(Glucose Transporter 2,GluT2)是β细胞特异转录因子受体，并且有调节细胞周期的作用。Cnb1KO小鼠β细胞中GluT2的mRNA数量下降、蛋白表达量下降。综合这些实验结果，似乎提示我们Cnb1的缺失导致胰岛素合成量下降，是因为β细胞的分化能力下降。
染色质免疫沉淀(chromatin immunoprecipitation, ChIP)实验发现Ins1, Hnf4a, Gck, Glut2 和Cdk.等基因的启动子区都含有NFATc1的结合位点。用环孢霉素A（cyclosporine A，一种calcineurin的抑制剂）处理后，结合作用消失。一种calcineurin依赖型的结构性核NFAT突变能够使小鼠β细胞Ins1等特异基因的mRNA水平、血清中胰岛素的水平和胰腺大小恢复正常。
研究人员认为，NFAT蛋白复合体的核定位对刺激调节β细胞分化和功能的基因的表达是充分必要条件。因此NFAT不仅是治疗糖尿病的候选靶标，而且是治疗β细胞生长紊乱引发的疾病，如胰岛瘤和胰岛母细胞瘤（nesidioblastosis）的候选靶标。
部分英文原文：
Calcineurin/NFAT signalling regulates pancreatic β-cell growth and function
The growth and function of organs such as pancreatic islets adapt to meet physiological challenges and maintain metabolic balance, but the mechanisms controlling these facultative responses are unclear. Diabetes in patients treated with calcineurin inhibitors such as cyclosporin A indicates that calcineurin/nuclear factor of activated T-cells (NFAT) signalling might control adaptive islet responses, but the roles of this pathway in β-cells in vivo are not understood. Here we show that mice with a β-cell-specific deletion of the calcineurin phosphatase regulatory subunit, calcineurin b1 (Cnb1), develop age-dependent diabetes characterized by decreased β-cell proliferation and mass, reduced pancreatic insulin content and hypoinsulinaemia. Moreover, β-cells lacking Cnb1 have a reduced expression of established regulators of β-cell proliferation. Conditional expression of active NFATc1 in Cnb1-deficient β-cells rescues these defects and prevents diabetes. In normal adult β-cells, conditional NFAT activation promotes the expression of cell-cycle regulators and increases β-cell proliferation and mass, resulting in hyperinsulinaemia. Conditional NFAT activation also induces the expression of genes critical for β-cell endocrine function, including all six genes mutated in hereditary forms of monogenic type 2 diabetes. Thus, calcineurin/NFAT signalling regulates multiple factors that control growth and hallmark β-cell functions, revealing unique models for the pathogenesis and therapy of diabetes.
