Ciliary dysfunction impairs beta-cell insulin secretion and promotes development of type 2 diabetes in rodents
Ciliary dysfunction impairs beta-cell insulin secretion and promotes development of type 2 diabetes in rodents
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DOI：
10.1038/ncomms6308
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发表时间：
2014-11-01
影响因子：
16.6
通讯作者：
Berggren, Per-Olof
中科院分区：
文献类型：
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作者：
Gerdes, Jantje M.;Christou-Savina, Sonia;Berggren, Per-Olof
2型糖尿病影响着全世界超过3.82亿人。虽然已经取得了很大的进展，但仍然缺乏对潜在疾病机制的全面了解。在这里，我们报告了β细胞初级纤毛在2型糖尿病易感性中的作用。我们发现在肥胖症发作之前，年轻的Bbs 4（-/-）小鼠的葡萄糖处理受损。小鼠胰岛中的基底体/纤毛扰动导致体外和体内第一时相胰岛素释放受损。胰岛素受体被募集至受刺激的β细胞的纤毛，并且纤毛/基体完整性是激活胰岛素信号传导的下游靶标所需的。我们还观察到糖尿病大鼠模型中胰岛中纤毛β细胞沿着纤毛/基体基因表达失调的数量减少。我们认为纤毛功能与β细胞中的胰岛素分泌和胰岛素信号传导有关，纤毛功能障碍可能导致2型糖尿病易感性。
Type 2 diabetes mellitus is affecting more than 382 million people worldwide. Although much progress has been made, a comprehensive understanding of the underlying disease mechanism is still lacking. Here we report a role for the beta-cell primary cilium in type 2 diabetes susceptibility. We find impaired glucose handling in young Bbs4(-/-) mice before the onset of obesity. Basal body/ciliary perturbation in murine pancreatic islets leads to impaired first phase insulin release ex and in vivo. Insulin receptor is recruited to the cilium of stimulated beta-cells and ciliary/basal body integrity is required for activation of downstream targets of insulin signalling. We also observe a reduction in the number of ciliated beta-cells along with misregulated ciliary/basal body gene expression in pancreatic islets in a diabetic rat model. We suggest that ciliary function is implicated in insulin secretion and insulin signalling in the beta-cell and that ciliary dysfunction could contribute to type 2 diabetes susceptibility.