Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
PLoS One. 2011 Mar 10;6(3):e17858. doi: 10.1371/journal.pone.0017858.
The genetic factors that underlie the increasing incidence of diabetes with age are poorly understood. We examined whether telomere length, which is inherited and known to shorten with age, plays a role in the age-dependent increased incidence of diabetes. We show that in mice with short telomeres, insulin secretion is impaired and leads to glucose intolerance despite the presence of an intact β-cell mass. In ex vivo studies, short telomeres induced cell-autonomous defects in β-cells including reduced mitochondrial membrane hyperpolarization and Ca(2+) influx which limited insulin release. To examine the mechanism, we looked for evidence of apoptosis but found no baseline increase in β-cells with short telomeres. However, there was evidence of all the hallmarks of senescence including slower proliferation of β-cells and accumulation of p16(INK4a). Specifically, we identified gene expression changes in pathways which are essential for Ca(2+)-mediated exocytosis. We also show that telomere length is additive to the damaging effect of endoplasmic reticulum stress which occurs in the late stages of type 2 diabetes. This additive effect manifests as more severe hyperglycemia in Akita mice with short telomeres which had a profound loss of β-cell mass and increased β-cell apoptosis. Our data indicate that short telomeres can affect β-cell metabolism even in the presence of intact β-cell number, thus identifying a novel mechanism of telomere-mediated disease. They implicate telomere length as a determinant of β-cell function and diabetes pathogenesis.
导致糖尿病发病率随年龄增长而上升的遗传因素尚未完全明了。我们研究了端粒长度是否在年龄相关的糖尿病发病率上升中发挥作用，端粒长度是一种可遗传的物质，已知其会随着年龄的增长而缩短。我们发现，端粒较短的小鼠胰岛素分泌受损，导致葡萄糖耐量降低，尽管β细胞数量完整。在离体研究中，端粒较短会导致β细胞发生自主缺陷，包括减少线粒体膜超极化和 Ca(2+)内流，从而限制胰岛素释放。为了研究其机制，我们寻找了β细胞凋亡的证据，但在端粒较短的β细胞中未发现基础水平的增加。然而，β细胞衰老的所有特征都有证据，包括增殖速度较慢和 p16(INK4a)的积累。具体来说，我们发现了参与 Ca(2+)介导的胞吐作用的途径中的基因表达变化。我们还表明，端粒长度与内质网应激的破坏效应呈累加性，内质网应激发生在 2 型糖尿病的晚期。这种累加效应表现为端粒较短的 Akita 小鼠的高血糖更为严重，β细胞数量明显减少，β细胞凋亡增加。我们的数据表明，即使β细胞数量完整，端粒较短也会影响β细胞代谢，从而确定了端粒介导疾病的新机制。它们表明端粒长度是β细胞功能和糖尿病发病机制的决定因素。
