Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
J Diabetes Res. 2020 Jan 10;2020:6542346. doi: 10.1155/2020/6542346. eCollection 2020.
Posttransplantation diabetes mellitus (PTDM) is a known complication of transplantation that affects the prognosis. Tacrolimus (Tac or FK506) is a widely used immunosuppressant that has been reported to be a risk factor for PTDM and to further induce complications in heart and skeletal muscles, but the mechanism is still largely unknown. In our preliminary experiments, we found that after Tac treatment, blood glucose increased, and the weight of skeletal muscle declined. Here, we hypothesize that tacrolimus can induce PTDM and influence the atrophy of skeletal muscle.
We designed preliminary experiments to establish a tacrolimus-induced PTDM model. Gene expression profiles in quadriceps muscle from this rat model were characterized by oligonucleotide microarrays. Then, differences in gene expression profiles in muscle from PTDM rats that received tacrolimus and control subjects were analyzed by using GeneSpring GX 11.0 software (Agilent). Functional annotation and enrichment analysis of differentially expressed genes (DEGs) helped us identify clues for the side effects of tacrolimus.
Our experiments found that the quadriceps in tacrolimus-induced PTDM group were smaller than those in the control group. The study identified 275 DEGs that may be responsible for insulin resistance and the progression of PTDM, including 86 upregulated genes and 199 downregulated genes. GO and KEGG functional analysis of the DEGs showed a significant correlation between PTDM and muscle development. PPI network analysis screened eight hub genes and found that they were related to troponin and tropomyosin.
This study explored the molecular mechanism of muscle atrophy in a tacrolimus-induced PTDM model by bioinformatics analyses. We identified 275 DEGs and identified significant biomarkers for predicting the development and progression of tacrolimus-induced PTDM.
移植后糖尿病（PTDM）是一种已知的移植并发症，会影响预后。他克莫司（Tac 或 FK506）是一种广泛使用的免疫抑制剂，据报道它是 PTDM 的一个危险因素，并进一步导致心脏和骨骼肌肉的并发症，但机制仍在很大程度上未知。在我们的初步实验中，我们发现 Tac 治疗后血糖升高，骨骼肌重量下降。在这里，我们假设他克莫司可诱导 PTDM 并影响骨骼肌萎缩。
我们设计了初步实验来建立 Tac 诱导的 PTDM 模型。使用寡核苷酸微阵列对该大鼠模型的股四头肌中的基因表达谱进行了表征。然后，使用 GeneSpring GX 11.0 软件（Agilent）分析 Tac 治疗的 PTDM 大鼠和对照组肌肉中基因表达谱的差异。差异表达基因（DEG）的功能注释和富集分析有助于我们确定 Tac 副作用的线索。
我们的实验发现 Tac 诱导的 PTDM 组的股四头肌比对照组小。该研究确定了 275 个可能导致胰岛素抵抗和 PTDM 进展的 DEG，包括 86 个上调基因和 199 个下调基因。GO 和 KEGG 功能分析显示，DEG 与 PTDM 和肌肉发育之间存在显著相关性。PPI 网络分析筛选出八个枢纽基因，发现它们与肌钙蛋白和原肌球蛋白有关。
本研究通过生物信息学分析探讨了 Tac 诱导的 PTDM 模型中肌肉萎缩的分子机制。我们确定了 275 个 DEG，并鉴定了用于预测 Tac 诱导的 PTDM 发展和进展的显著生物标志物。
