Laboratoire de Pharmacodynamie et de Thérapeutique, Université Libre de Bruxelles, Faculté de Médicine, B-1070, Brussels, Belgium.
Diabetes Obes Metab. 2012 Oct;14 Suppl 3:136-42. doi: 10.1111/j.1463-1326.2012.01649.x.
Ca(2+) extrusion from the β-cell is mediated by two processes the Na/Ca exchanger (NCX) and the plasma membrane Ca(2+) -ATPase (PMCA). Gain of function studies show that overexpression of NCX or PMCA leads to endoplasmic reticulum (ER) Ca(2+) depletion with subsequent ER stress, decrease in β-cell proliferation and β-cell death by apoptosis. Interestingly, chronic exposure to cytokines or high free fatty acid concentrations also induce ER Ca(2+) depletion and β-cell death in diabetes. Loss of function studies show, on the contrary, that heterozygous inactivation of NCX1 (Ncx1(+/-)) leads to an increase in β-cell function (insulin production and release), and a fivefold increase in both β-cell mass and proliferation. The mutation also increases β-cell resistance to hypoxia, and Ncx1(+/-) islets show a two to four times higher rate of diabetes cure than Ncx1(+/+) islets when transplanted in diabetic animals. Thus, down-regulation of the Na/Ca exchanger leads to various changes in β-cell function that are opposite to the major abnormalities seen in diabetes. This provides a unique model for the prevention and treatment of β-cell dysfunction in diabetes and following islet transplantation.
β细胞中的 Ca(2+) 外排由两种过程介导：钠钙交换体（NCX）和质膜 Ca(2+) -ATP 酶（PMCA）。功能获得研究表明，NCX 或 PMCA 的过表达导致内质网（ER）Ca(2+)耗竭，随后 ER 应激、β细胞增殖减少和细胞凋亡导致β细胞死亡。有趣的是，慢性暴露于细胞因子或高游离脂肪酸浓度也会在糖尿病中诱导 ER Ca(2+)耗竭和β细胞死亡。相反，功能丧失研究表明，NCX1 的杂合失活（Ncx1(+/-)）导致β细胞功能（胰岛素产生和释放）增加，β细胞质量和增殖增加五倍。该突变还增加了β细胞对缺氧的抵抗力，并且 Ncx1(+/-)胰岛在移植到糖尿病动物中时，其糖尿病治愈的速度比 Ncx1(+/+)胰岛快 2 到 4 倍。因此，钠钙交换体的下调导致β细胞功能的各种变化，与糖尿病中观察到的主要异常相反。这为预防和治疗糖尿病和胰岛移植后的β细胞功能障碍提供了一个独特的模型。
