姜黄素对db/db小鼠基因组DNA甲基化的影响

Effects of Curcumin on Genomic DNA Methylation in db/db Mice

目的:观察姜黄素对2型糖尿病模型db/db小鼠糖尿病症状的改善作用,并从表观遗传角度分析其对小鼠外周血DNA甲基化水平的影响。方法:2型糖尿病模型db/db小鼠随机分为糖尿病组和姜黄素干预组(给予250 mg/kg姜黄素溶液),连续灌胃8周。OGTT检测葡萄糖耐量,ELISA法测定空腹胰岛素并计算HOMA-IR和HOMA-β,RRBS技术检测外周血基因组DNA甲基化水平。结果:与糖尿病组相比,姜黄素干预小鼠的血糖、空腹胰岛素和HOMA-IR显著降低,葡萄糖耐量显著改善(P<0.05);且小鼠外周血基因组启动子区、CGI岸和5’-非编码区CpG甲基化水平显著降低(P<0.05);对两组间差异甲基化基因进行功能富集分析,筛选出前10位显著富集的可能与2型糖尿病相关的差异基因包括Hdac7、Micall1、Vangl2、Dhcr24、Kcnj8、Gnas、Tcf7l2、Dgkh、Dlgap1和Plekhg4。结论:姜黄素能够改善db/db小鼠的葡萄糖耐量及胰岛素抵抗,并且其外周血中存在显著低甲基化改变,提示姜黄素可能是通过抑制糖尿病小鼠中某些基因的异常甲基化修饰而发挥抗糖尿病作用。

Objective: To observe the effect of curcumin on diabetes symptoms and analysis of its effect on the DNA methylation levels in peripheral blood of type 2 diabetes model db/db mice from the perspective of epigenetics. Methods: Type 2 diabetes model db/db mice were randomly divided into diabetes mellitus group and curcumin intervention group(given 250 mg/kg curcumin), and followed by gavage for 8 weeks. Glucose tolerance was measured by OGTT, fasting insulin was detected by ELISA and HOMA-IR and HOMA-β indexes were calculated. The genome-wide methylation detection of peripheral blood DNA was performed using RRBS.Results: Compared with the diabetes mellitus group, curcumin significantly reduced blood glucose, fasting insulin and HOMA-IR, and improved glucose tolerance(P<0.05). CpG methylation levels in the genomic promoter, CGI-shore and 5’-non-coding region of peripheral blood was significantly lower with curcumin(P<0.05). The functional enrichment analysis were performed on the differential methylated genes, and the top 10 significantly enriched differential genes that may be associated with type 2 diabetes including Hdac7,Micall1, Vangl2, Dhcr24, Kcnj8, Gnas, Tcf712, Dgkh, Dlgap1 and Plekhg4. Conclusion: Curcumin can improve glucose tolerance and insulin resistance in db/db mice, and there is a significant difference of DNA methylation in peripheral blood, suggesting that curcumin may play an anti-diabetic role by inhibiting the abnormal DNA methylation level of certain genes in diabetic mice.