Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
Diabetologia. 2010 Jun;53(6):1099-109. doi: 10.1007/s00125-010-1667-2. Epub 2010 Mar 3.
AIMS/HYPOTHESIS: MicroRNAs regulate a broad range of biological mechanisms. To investigate the relationship between microRNA expression and type 2 diabetes, we compared global microRNA expression in insulin target tissues from three inbred rat strains that differ in diabetes susceptibility.
Using microarrays, we measured the expression of 283 microRNAs in adipose, liver and muscle tissue from hyperglycaemic (Goto-Kakizaki), intermediate glycaemic (Wistar Kyoto) and normoglycaemic (Brown Norway) rats (n = 5 for each strain). Expression was compared across strains and validated using quantitative RT-PCR. Furthermore, microRNA expression variation in adipose tissue was investigated in 3T3-L1 adipocytes exposed to hyperglycaemic conditions.
We found 29 significantly differentiated microRNAs (p(adjusted) < 0.05): nine in adipose tissue, 18 in liver and two in muscle. Of these, five microRNAs had expression patterns that correlated with the strain-specific glycaemic phenotype. MiR-222 (p(adjusted) = 0.0005) and miR-27a (p(adjusted) = 0.006) were upregulated in adipose tissue; miR-195 (p(adjusted) = 0.006) and miR-103 (p(adjusted) = 0.04) were upregulated in liver; and miR-10b (p(adjusted) = 0.004) was downregulated in muscle. Exposure of 3T3-L1 adipocytes to increased glucose concentration upregulated the expression of miR-222 (p = 0.008), miR-27a (p = 0.02) and the previously reported miR-29a (p = 0.02). Predicted target genes of these differentially expressed microRNAs are involved in pathways relevant to type 2 diabetes.
The expression patterns of miR-222, miR-27a, miR-195, miR-103 and miR-10b varied with hyperglycaemia, suggesting a role for these microRNAs in the pathophysiology of type 2 diabetes, as modelled by the Gyoto-Kakizaki rat. We observed similar patterns of expression of miR-222, miR-27a and miR-29a in adipocytes as a response to increased glucose levels, which supports our hypothesis that altered expression of microRNAs accompanies primary events related to the pathogenesis of type 2 diabetes.
目的/假设：MicroRNAs 调控广泛的生物学机制。为了研究 microRNA 表达与 2 型糖尿病之间的关系，我们比较了三种不同糖尿病易感性的近交系大鼠胰岛素靶组织中的全局 microRNA 表达。
使用 microarrays，我们测量了高血糖（Goto-Kakizaki）、中间血糖（Wistar Kyoto）和正常血糖（Brown Norway）大鼠脂肪、肝脏和肌肉组织中 283 种 microRNAs 的表达（每种品系 n = 5）。我们比较了不同品系之间的表达情况，并使用定量 RT-PCR 进行了验证。此外，我们还研究了在暴露于高血糖条件下的 3T3-L1 脂肪细胞中脂肪组织中 microRNA 表达的变化。
我们发现了 29 个显著差异表达的 microRNAs（p(adjusted) < 0.05）：脂肪组织中有 9 个，肝脏中有 18 个，肌肉中有 2 个。其中，有 5 个 microRNAs 的表达模式与特定的血糖表型相关。miR-222（p(adjusted) = 0.0005）和 miR-27a（p(adjusted) = 0.006）在脂肪组织中上调；miR-195（p(adjusted) = 0.006）和 miR-103（p(adjusted) = 0.04）在肝脏中上调；miR-10b（p(adjusted) = 0.004）在肌肉中下调。3T3-L1 脂肪细胞暴露于高葡萄糖浓度下，miR-222（p = 0.008）、miR-27a（p = 0.02）和先前报道的 miR-29a（p = 0.02）的表达上调。这些差异表达的 microRNAs 的预测靶基因参与与 2 型糖尿病相关的途径。
miR-222、miR-27a、miR-195、miR-103 和 miR-10b 的表达模式随高血糖而变化，表明这些 microRNAs 在 2 型糖尿病的病理生理学中发挥作用，正如 Goto-Kakizaki 大鼠模型所表明的那样。我们在脂肪细胞中观察到 miR-222、miR-27a 和 miR-29a 的相似表达模式，作为对葡萄糖水平升高的反应，这支持了我们的假设，即 microRNAs 的表达改变伴随着与 2 型糖尿病发病机制相关的原发性事件。
