Short telomeres compromise β-cell signaling and survival.
Short telomeres compromise β-cell signaling and survival.
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DOI：
10.1371/journal.pone.0017858
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发表时间：
2011-03-10
期刊：
影响因子：
3.7
通讯作者：
Armanios M
中科院分区：
文献类型：
--
作者：
Guo N;Parry EM;Li LS;Kembou F;Lauder N;Hussain MA;Berggren PO;Armanios M
导致糖尿病发病率随年龄增长的遗传因素尚不清楚。我们研究了端粒长度是否在年龄依赖性糖尿病发病率增加中起作用，端粒长度是遗传的，并且已知随着年龄的增长而缩短。我们发现，在端粒短的小鼠中，尽管存在完整的β细胞团，胰岛素分泌受损并导致葡萄糖耐受不良。在离体研究中，短端粒诱导β细胞中的细胞自主缺陷，包括减少线粒体膜超极化和限制胰岛素释放的Ca2+内流。为了检查机制，我们寻找凋亡的证据，但没有发现具有短端粒的β细胞的基线增加。然而，存在衰老的所有标志的证据，包括β细胞的较慢增殖和p16INK4a的积累。具体来说，我们确定了基因表达的变化，这是必不可少的Ca2+介导的胞吐作用的途径。我们还表明，端粒长度是添加剂的内质网应激的破坏作用，发生在2型糖尿病的晚期。这种累加效应表现为具有短端粒的秋田小鼠中更严重的高血糖症，其具有β细胞质量的严重损失和增加的β细胞凋亡。我们的数据表明，即使在完整的β细胞数量存在的情况下，短端粒也可以影响β细胞代谢，从而确定了端粒介导的疾病的新机制。他们暗示端粒长度是β细胞功能和糖尿病发病机制的决定因素。
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 Ca2+ 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 p16INK4a. Specifically, we identified gene expression changes in pathways which are essential for Ca2+-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.
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影响因子：
3.7
作者：
Marselli L;Thorne J;Dahiya S;Sgroi DC;Sharma A;Bonner-Weir S;Marchetti P;Weir GC
通讯作者：
Weir GC
DOI：
10.1073/pnas.0602956103
发表时间：
2006-06-13
影响因子：
11.1
作者：
Le May, Cedric;Chu, Khoi;Mauvais-Jarvis, Franck
通讯作者：
Mauvais-Jarvis, Franck
DOI：
10.1164/rccm.200804-550oc
发表时间：
2008-10-01
影响因子：
24.7
作者：
Cronkhite, Jennifer T.;Xing, Chao;Garcia, Christine Kim
通讯作者：
Garcia, Christine Kim
影响因子：
64.8
作者：
Dor, Y;Brown, J;Melton, DA
通讯作者：
Melton, DA
影响因子：
64.8
作者：
Lee, HW;Blasco, MA;DePinho, RA
通讯作者：
DePinho, RA