Altered gene expression profiles in the hippocampus and prefrontal cortex of type 2 diabetic rats

There has been an incresing body of epidemiologic and biochemical evidence implying the role of cerebral insulin resistance in Alzheimer-type dementia. For a better understanding of the insulin effect on the central nervous system we performed microarray-based gene expression profiling in the hippocampus, striatum and prefrontal cortex of streptozotocin-induced and spontaneously diabetic Goto-Kakizaki rats as model animals for type 1 and type 2 diabetes, respectively. Following pathway analysis and validation of gene lists by RT-PCR, 30 genes from hippocampus, such as the inhibitory neuropeptide galanin, synuclein gamma and uncoupling protein 2, and 22 genes from the prefrontal cortex, e.g. galanin receptor 2, protein kinase gamma and epsilon, ABCA1, CD47 and the RET protooncogene, were found to exhibit altered expression levels in type 2 diabetic model animals in comparison to non-diabetic control animals. These gene lists proved to be partly overlapping and encompassed genes related to neurotransmission, lipidmetabolism, neuronal development, insulin secretion, oxidative damage and DNA repair. On the other hand, no significant alterations were found in the transcriptomes of the corpus sriatum in the same animals. Changes in the cerebral gene expression profiles seemed to be specific for the type 2 diabetic model, as no such alterations were found in streptozotocin-treated animals. According to our knowledge this is the first characterization of the whole-genome expression changes of specific brain regions in a diabetic model. Our findings shed light on the complex role of insulin signaling in fine-tuning brain functions, and provide further experimental evidence in support of the recently elaborated theory of type 3diabetes.越来越多的流行病学与生化研究证据表明，大脑胰岛素抵抗（cerebral insulin resistance）在阿尔茨海默型痴呆（Alzheimer-type dementia）中发挥着重要作用。为深入解析胰岛素对中枢神经系统的调控效应，本研究以链脲佐菌素（streptozotocin）诱导的1型糖尿病模型大鼠、以及自发性糖尿病Goto-Kakizaki（GK）大鼠（分别作为1型和2型糖尿病动物模型）的海马体（hippocampus）、纹状体（striatum）与前额叶皮层（prefrontal cortex）为研究对象，开展了基于微阵列（microarray）的基因表达谱分析。经通路富集分析（pathway analysis）与逆转录聚合酶链反应（RT-PCR）验证基因集后，研究发现与非糖尿病对照大鼠相比，2型糖尿病模型大鼠的海马体中存在30个差异表达基因，包括抑制性神经肽甘丙肽（inhibitory neuropeptide galanin）、γ-突触核蛋白（synuclein gamma）与解偶联蛋白2（uncoupling protein 2）等；前额叶皮层中则存在22个差异表达基因，例如甘丙肽受体2（galanin receptor 2）、γ/ε蛋白激酶（protein kinase gamma and epsilon）、ABCA1、CD47以及RET原癌基因（RET protooncogene）。上述基因集存在部分重叠，所涵盖的基因涉及神经传递、脂质代谢、神经元发育、胰岛素分泌、氧化损伤与DNA修复等生物学过程。另一方面，同一批实验动物的纹状体转录组（transcriptomes）未检测到显著的基因表达变化。大脑基因表达谱的改变似乎仅特异性出现于2型糖尿病模型中，链脲佐菌素处理的1型糖尿病模型大鼠未出现此类表达变化。据我们所知，本研究首次在糖尿病动物模型中对特定脑区的全基因组表达变化（whole-genome expression changes）进行了系统表征。本研究结果阐明了胰岛素信号通路（insulin signaling）在微调大脑功能中的复杂调控作用，并为新近提出的3型糖尿病（type 3 diabetes）理论提供了进一步的实验证据。