Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
Diabetes. 2022 May 1;71(5):989-1011. doi: 10.2337/db21-0581.
Finding therapies that can protect and expand functional β-cell mass is a major goal of diabetes research. Here, we generated β-cell-specific conditional knockout and gain-of-function mouse models and used human islet transplant experiments to examine how manipulating Nrf2 levels affects β-cell survival, proliferation, and mass. Depletion of Nrf2 in β-cells results in decreased glucose-stimulated β-cell proliferation ex vivo and decreased adaptive β-cell proliferation and β-cell mass expansion after a high-fat diet in vivo. Nrf2 protects β-cells from apoptosis after a high-fat diet. Nrf2 loss of function decreases Pdx1 abundance and insulin content. Activating Nrf2 in a β-cell-specific manner increases β-cell proliferation and mass and improves glucose tolerance. Human islets transplanted under the kidney capsule of immunocompromised mice and treated systemically with bardoxolone methyl, an Nrf2 activator, display increased β-cell proliferation. Thus, by managing reactive oxygen species levels, Nrf2 regulates β-cell mass and is an exciting therapeutic target for expanding and protecting β-cell mass in diabetes.
寻找能够保护和扩增功能性β细胞群体的疗法是糖尿病研究的主要目标。在这里，我们构建了β细胞特异性条件性敲除和功能获得性小鼠模型，并利用人胰岛移植实验来研究调控 Nrf2 水平如何影响β细胞的存活、增殖和数量。β细胞中 Nrf2 的耗竭导致体外葡萄糖刺激的β细胞增殖减少，以及体内高脂肪饮食后适应性β细胞增殖和β细胞数量扩增减少。Nrf2 可保护β细胞免受高脂肪饮食引起的细胞凋亡。Nrf2 功能丧失会降低 Pdx1 的丰度和胰岛素含量。以β细胞特异性方式激活 Nrf2 可增加β细胞增殖和数量，并改善葡萄糖耐量。将人胰岛移植到免疫缺陷小鼠的肾包膜下，并全身给予 Nrf2 激活剂 bardoxolone methyl 处理后，可观察到β细胞增殖增加。因此，通过调节活性氧水平，Nrf2 调节β细胞数量，是扩增和保护糖尿病中β细胞数量的一个令人兴奋的治疗靶点。
