Tugay Ksenia, Guay Claudiane, Marques Ana C, Allagnat Florent, Locke Jonathan M, Harries Lorna W, Rutter Guy A, Regazzi Romano
Department of Fundamental Neurosciences, University of Lausanne, Rue du Bugnon 9, CH-1005, Lausanne, Switzerland.
Department of Physiology, University of Lausanne, Lausanne, Switzerland.
Diabetologia. 2016 Jan;59(1):161-169. doi: 10.1007/s00125-015-3783-5.
AIMS/HYPOTHESIS: Ageing can lead to reduced insulin sensitivity and loss of pancreatic beta cell function, predisposing individuals to the development of diabetes. The aim of this study was to assess the contribution of microRNAs (miRNAs) to age-associated beta cell dysfunction.
The global mRNA and miRNA profiles of 3- and 12-month-old rat islets were collected by microarray. The functional impact of age-associated differences in miRNA expression was investigated by mimicking the observed changes in primary beta cells from young animals.
Beta cells from 12-month-old rats retained normal insulin content and secretion, but failed to proliferate in response to mitotic stimuli. The islets of these animals displayed modifications at the level of several miRNAs, including upregulation of miR-34a, miR-124a and miR-383, and downregulation of miR-130b and miR-181a. Computational analysis of the transcriptomic modifications observed in the islets of 12-month-old rats revealed that the differentially expressed genes were enriched for miR-34a and miR-181a targets. Indeed, the induction of miR-34a and reduction of miR-181a in the islets of young animals mimicked the impaired beta cell proliferation observed in old animals. mRNA coding for alpha-type platelet-derived growth factor receptor, which is critical for compensatory beta cell mass expansion, is directly inhibited by miR34a and is likely to be at least partly responsible for the effects of this miRNA.
CONCLUSIONS/INTERPRETATION: Changes in the level of specific miRNAs that occur during ageing affect the proliferative capacity of beta cells. This might reduce their ability to expand under conditions of increased insulin demand, favouring the development of type 2 diabetes.
目的/假设：衰老可导致胰岛素敏感性降低和胰腺β细胞功能丧失，使个体易患糖尿病。本研究的目的是评估微小RNA（miRNA）在与年龄相关的β细胞功能障碍中的作用。
通过微阵列收集3月龄和12月龄大鼠胰岛的整体mRNA和miRNA谱。通过模拟年轻动物原代β细胞中观察到的变化，研究了与年龄相关的miRNA表达差异的功能影响。
12月龄大鼠的β细胞保留了正常的胰岛素含量和分泌，但对有丝分裂刺激无增殖反应。这些动物的胰岛在几种miRNA水平上出现了改变，包括miR-34a、miR-124a和miR-383上调，以及miR-130b和miR-181a下调。对12月龄大鼠胰岛中观察到的转录组修饰进行的计算分析表明，差异表达基因富含miR-34a和miR-181a的靶标。事实上，在年轻动物的胰岛中诱导miR-34a并降低miR-181a可模拟老年动物中观察到的β细胞增殖受损。编码α型血小板衍生生长因子受体的mRNA对代偿性β细胞质量扩张至关重要，它直接受到miR-34a的抑制，可能至少部分负责这种miRNA的作用。
结论/解读：衰老过程中发生的特定miRNA水平变化影响β细胞的增殖能力。这可能会降低它们在胰岛素需求增加的情况下扩张的能力，从而促进2型糖尿病的发展。
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