The tacrolimus-induced glucose homeostasis imbalance in terms of the liver: From bench to bedside
The tacrolimus-induced glucose homeostasis imbalance in terms of the liver: From bench to bedside
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他克莫司引起的肝脏葡萄糖稳态失衡：从实验室到临床
DOI：
10.1111/ajt.15665
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发表时间：
2019-11-24
影响因子：
8.8
通讯作者：
Wang, Baohong
中科院分区：
文献类型：
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作者：
Ling, Qi;Huang, Haitao;Wang, Baohong
他克莫司（TAC），维持免疫抑制剂的支柱，在移植后新发糖尿病（NODAT）中起着至关重要的作用。以前研究TAC致糖尿病作用的研究集中在胰岛的β细胞上。在这项研究中，我们发现TAC通过直接影响肝脏代谢稳态而促进NODAT。在小鼠中，TAC通过抑制NODAT基因而诱导饥饿时的低血糖而不是高血糖，这表明空腹血糖在NODAT诊断中的局限性。此外，TAC分别通过胰岛素受体底物（IRS）2/AKT和固醇调节元件结合蛋白（SREBP 1）信号转导引起肝脏胰岛素抵抗和甘油三酯蓄积。此外，我们发现CREB调节的转录辅激活因子2（CRTC 2）在TAC诱导的代谢紊乱中起关键作用。肝脏CRTC 2的恢复通过其下游分子（如PCK 1、IRS 2和SREBP 1）缓解代谢紊乱。与实验室研究结果一致，移植肝细胞中CRTC 2低表达是NODAT的独立风险因素（比值比= 2.692，P = 0.023，n = 135）。将移植物的CRTC 2评分整合到临床模型中可以显著增加预测能力（受试者工作特征曲线下面积：0.71 vs 0.79，P = 0.048）。总之，除了对胰腺细胞的影响外，TAC还通过CRTC 2信号传导诱导“血源性糖尿病”。肝靶向治疗可能有助于预防或治愈TAC相关糖尿病。
Tacrolimus (TAC), the mainstay of maintenance immunosuppressive agents, plays a crucial role in new-onset diabetes after transplant (NODAT). Previous studies investigating the diabetogenic effects of TAC have focused on the beta cells of islets. In this study, we found that TAC contributed to NODAT through directly affecting hepatic metabolic homeostasis. In mice, TAC-induced hypoglycemia rather than hyperglycemia during starvation via suppressing gluconeogenetic genes, suggesting the limitation of fasting blood glucose in the diagnosis of NODAT. In addition, TAC caused hepatic insulin resistance and triglyceride accumulation through insulin receptor substrate (IRS)2/AKT and sterol regulatory element binding protein (SREBP1) signaling, respectively. Furthermore, we found a pivotal role of CREB-regulated transcription coactivator 2 (CRTC2) in TAC-induced metabolic disorders. The restoration of hepatic CRTC2 alleviated the metabolic disorders through its downstream molecules (eg, PCK1, IRS2, and SREBP1). Consistent with the findings from bench, low CRTC2 expression in graft hepatocytes was an independent risk factor for NODAT (odds ratio = 2.692, P = .023, n = 135). Integrating grafts' CRTC2 score into the clinical model could significantly increase the predictive capacity (areas under the receiver operating characteristic curve: 0.71 vs 0.79, P = .048). Taken together, in addition to its impact on pancreatic cells, TAC induces "hematogenous diabetes" via CRTC2 signaling. Liver-targeted management may be of help to prevent or heal TAC-associated diabetes.