Transcriptomic Analysis of Insulin-Sensitive Tissues from Anti-Diabetic Drug Treated ZDF Rats, a T2DM Animal Model

Gene expression changes have been associated with type 2 diabetes mellitus (T2DM); however, the alterations are not fully understood. We investigated the effects of anti-diabetic drugs on gene expression in Zucker diabetic fatty (ZDF) rats using oligonucleotide microarray technology to identify gene expression changes occurring in T2DM. Global gene expression in the pancreas, adipose tissue, skeletal muscle, and liver was profiled from Zucker lean control (ZLC) and anti-diabetic drug treated ZDF rats compared with those in ZDF rats. We showed that anti-diabetic drugs regulate the expression of a large number of genes. We provided a more integrated view of the diabetic changes by examining the gene expression networks. The resulting sub-networks allowed us to identify several biological processes that were significantly enriched by the anti-diabetic drug treatment, including oxidative phosphorylation (OXPHOS), systemic lupus erythematous, and the chemokine signaling pathway. Among them, we found that white adipose tissue from ZDF rats showed decreased expression of a set of OXPHOS genes that were normalized by rosiglitazone treatment accompanied by rescued blood glucose levels. In conclusion, we suggest that alterations in OXPHOS gene expression in white adipose tissue may play a role in the pathogenesis and drug mediated recovery of T2DM through a comprehensive gene expression network study after multi-drug treatment of ZDF rats.

基因表达改变与2型糖尿病（type 2 diabetes mellitus, T2DM）密切相关，但此类病理改变的具体机制尚未完全阐明。本研究采用寡核苷酸微阵列技术，探究抗糖尿病药物对Zucker糖尿病肥胖大鼠（Zucker diabetic fatty, ZDF）基因表达的影响，以明确T2DM进程中发生的基因表达变化。本研究对Zucker瘦型对照大鼠（Zucker lean control, ZLC）、抗糖尿病药物处理的ZDF大鼠以及未处理的ZDF大鼠的胰腺、脂肪组织、骨骼肌与肝脏的全基因组基因表达完成了谱分析。结果显示，抗糖尿病药物可调控大量基因的表达水平。本研究通过分析基因表达网络，为糖尿病相关病理改变提供了更为整合的研究视角。所得到的基因子网络帮助我们鉴定出多个经抗糖尿病药物处理后显著富集的生物学过程，包括氧化磷酸化（oxidative phosphorylation, OXPHOS）、系统性红斑狼疮以及趋化因子信号通路。其中，我们发现ZDF大鼠的白色脂肪组织中一组氧化磷酸化相关基因的表达呈下调趋势，而罗格列酮处理可使该组基因的表达恢复至正常水平，同时伴随血糖水平的改善。综上，通过对多药物处理的ZDF大鼠开展综合基因表达网络研究，我们认为白色脂肪组织中氧化磷酸化基因表达的改变可能在T2DM的发病机制以及药物介导的病情恢复中发挥重要作用。