MicroRNA-7a regulates pancreatic β cell function
MicroRNA-7a regulates pancreatic β cell function
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DOI：
10.1172/jci73066
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发表时间：
2014-06-01
影响因子：
15.9
通讯作者：
Stoffel, Markus
中科院分区：
文献类型：
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作者：
Latreille, Mathieu;Hausser, Jean;Stoffel, Markus
功能失调的microRNA（miRNA）网络有助于病理应激后的不适当反应，是几种疾病的根本原因。在胰腺β细胞中，miRNAs在很大程度上未被研究，并且关于特异性miRNAs如何调节葡萄糖刺激的胰岛素分泌（GSIS）或影响β细胞功能对代谢应激的适应知之甚少。在这项研究中，我们确定miR-7是β细胞中GSIS的负调节因子。使用Mir 7a 2缺陷小鼠，我们揭示了miR-7a 2通过直接调节控制胰岛素颗粒与质膜融合的晚期阶段和三元SNARE复合物活性的基因来调节β细胞功能。在β细胞中过表达miR-7a的转基因小鼠由于胰岛素分泌受损和β细胞去分化而患上糖尿病。有趣的是，β细胞中miR-7a表达的扰动并不影响增殖和凋亡，表明miR-7对于维持内分泌β细胞群是不可或缺的。此外，我们发现miR-7a水平在肥胖/糖尿病小鼠模型和来自具有代偿性β细胞功能的肥胖和中度糖尿病个体的人胰岛中降低。我们的研究结果揭示了一个相互关联的miR-7基因组电路，调节胰腺β细胞中的胰岛素颗粒胞吐作用，并支持miR-7在肥胖和2型糖尿病中胰腺β细胞功能适应中的作用。
Dysfunctional microRNA (miRNA) networks contribute to inappropriate responses following pathological stress and are the underlying cause of several disease conditions. In pancreatic beta cells, miRNAs have been largely unstudied and little is known about how specific miRNAs regulate glucose-stimulated insulin secretion (GSIS) or impact the adaptation of beta cell function to metabolic stress. In this study, we determined that miR-7 is a negative regulator of GSIS in beta cells. Using Mir7a2 deficient mice, we revealed that miR-7a2 regulates beta cell function by directly regulating genes that control late stages of insulin granule fusion with the plasma membrane and ternary SNARE complex activity. Transgenic mice overexpressing miR-7a in beta cells developed diabetes due to impaired insulin secretion and beta cell dedifferentiation. Interestingly, perturbation of miR-7a expression in beta cells did not affect proliferation and apoptosis, indicating that miR-7 is dispensable for the maintenance of endocrine beta cell mass. Furthermore, we found that miR-7a levels are decreased in obese/ diabetic mouse models and human islets from obese and moderately diabetic individuals with compensated beta cell function. Our results reveal an interconnecting miR-7 genomic circuit that regulates insulin granule exocytosis in pancreatic beta cells and support a role for miR-7 in the adaptation of pancreatic p cell function in obesity and type 2 diabetes.