Defects in β-Cell Ca2+ Dynamics in Age-Induced Diabetes
Defects in β-Cell Ca2+ Dynamics in Age-Induced Diabetes
复制标题
DOI：
10.2337/db13-1855
复制
发表时间：
2014-12-01
期刊：
影响因子：
7.7
通讯作者：
Berggren, Per-Olof
中科院分区：
文献类型：
--
作者：
Li, Luosheng;Trifunovic, Aleksandra;Berggren, Per-Olof
对β细胞功能年龄依赖性退化的分子机制知之甚少。我们现在证明，胰岛素释放的年龄依赖性损伤，从而葡萄糖稳态，与小鼠β细胞中Ca2+动力学的微妙变化有关。我们表明，这些变化可能是由于线粒体功能受损，并涉及磷脂酶C/肌醇1,4,5-三磷酸介导的细胞内储存Ca2+动员，以及减少β细胞Ca2+在质膜上的内流。我们使用三种小鼠模型，即早衰表型，成熟衰老表型和抗衰老表型。在线粒体DNA突变的年龄依赖性积累的转基因小鼠模型中研究了过早衰老。在C57BL/6小鼠中研究了成熟衰老，而129小鼠代表了一种更能抵抗年龄引起的退化的模型。我们的数据表明，衰老与β细胞线粒体功能的逐渐下降有关，这对Ca2+动力学的微调产生了负面影响。这在概念上是重要的，因为它强调即使是相对适度的β细胞信号转导随时间的变化也会导致胰岛素释放受损和糖尿病表型。
Little is known about the molecular mechanisms underlying age-dependent deterioration in beta-cell function. We now demonstrate that age-dependent impairment in insulin release, and thereby glucose homeostasis, is associated with subtle changes in Ca2+ dynamics in mouse beta-cells. We show that these changes are likely to be accounted for by impaired mitochondrial function and to involve phospholipase C/inositol 1,4,5-trisphosphate-mediated Ca2+ mobilization from intracellular stores as well as decreased beta-cell Ca2+ influx over the plasma membrane. We use three mouse models, namely, a premature aging phenotype, a mature aging phenotype, and an aging-resistant phenotype. Premature aging is studied in a genetically modified mouse model with an age-dependent accumulation of mitochondrial DNA mutations. Mature aging is studied in the C57BL/6 mouse, whereas the 129 mouse represents a model that is more resistant to age-induced deterioration. Our data suggest that aging is associated with a progressive decline in beta-cell mitochondrial function that negatively impacts on the fine tuning of Ca2+ dynamics. This is conceptually important since it emphasizes that even relatively modest changes in beta-cell signal transduction over time lead to compromised insulin release and a diabetic phenotype.