Department of Medicine, Columbia University, New York, New York, USA.
Department of Pediatrics, University of Colorado, Denver, Colorado, USA.
J Clin Invest. 2019 Jan 2;129(1):268-280. doi: 10.1172/JCI98098. Epub 2018 Dec 3.
Notch signaling regulates differentiation of the pancreatic endocrine lineage during embryogenesis, but the role of Notch in mature β cells is unclear. We found that islets derived from lean mice show modest β cell Notch activity, which increases in obesity and in response to high glucose. This response appeared maladaptive, as mice with β cell-specific-deficient Notch transcriptional activity showed improved glucose tolerance when subjected to high-fat diet feeding. Conversely, mice with β cell-specific Notch gain of function (β-NICD) had a progressive loss of β cell maturity, due to proteasomal degradation of MafA, leading to impaired glucose-stimulated insulin secretion and glucose intolerance with aging or obesity. Surprisingly, Notch-active β cells had increased proliferative capacity, leading to increased but dysfunctional β cell mass. These studies demonstrate a dynamic role for Notch in developed β cells for simultaneously regulating β cell function and proliferation.
Notch 信号通路在胚胎发育过程中调节胰腺内分泌谱系的分化，但 Notch 在成熟β细胞中的作用尚不清楚。我们发现，来自瘦鼠的胰岛显示出适度的β细胞 Notch 活性，这种活性在肥胖和高葡萄糖刺激下增加。这种反应似乎是适应不良的，因为在高脂肪饮食喂养下，β细胞特异性 Notch 转录活性缺陷的小鼠表现出改善的葡萄糖耐量。相反，具有β细胞特异性 Notch 功能获得（β-NICD）的小鼠由于 MafA 的蛋白酶体降解而导致β细胞成熟逐渐丧失，导致葡萄糖刺激的胰岛素分泌受损和葡萄糖耐量下降，随着年龄增长或肥胖而恶化。令人惊讶的是，Notch 活性的β细胞具有增加的增殖能力，导致β细胞质量增加但功能失调。这些研究表明 Notch 在已发育的β细胞中具有动态作用，可同时调节β细胞功能和增殖。
