胰岛素受体核转位异常促糖尿病心肌缺血易损性增加及机制

糖尿病人群缺血性心脏病的发病率及心肌损伤程度显著升高，其机制尚未完全阐明。申请者前期发现糖尿病患者心血管胰岛素信号受损。新近有研究证实肿瘤细胞胰岛素受体（InsR）存在由胞膜转运至胞核并结合DNA的全新现象，即核转位，其功能具有组织特异性。然而心肌InsR是否存在核转位，其靶点和功能如何？糖尿病状态下有何变化？国内外尚未见报道。申请者新近发现心肌存在核定位InsR，ChIP-Seq显示其可结合基因启动子区，靶基因包括线粒体脂代谢关键分子Hadhb和内膜转运分子Timm22，提示其可能通过转录调节促进线粒体脂代谢过程；预实验显示糖尿病小鼠心肌核InsR水平降低，且抑制核转位可增加心肌细胞缺氧损伤。本课题拟在此基础上，明确InsR核转位异常是否加重糖尿病心肌缺血损伤，进一步研究机制是否与其所致线粒体脂代谢紊乱、脂毒性增加有关，期望为从全新角度认识InsR功能多样性和糖尿病心肌易损机制提供依据。

Patients with type 2 diabetes mellitus (T2DM) are more susceptible to acute myocardial ischemia/reperfusion (MI/R) injury. However, the mechanisms remain largely elusive. Important roles of cardiovascular sensitivity to insulin in T2DM have been showed in our previous studies. A recent publication observed insulin receptor (InsR) translocated from the cell surface to the nucleus. However, the targets and roles of the nuclear InsR particularly in the heart are poorly understood. Our preliminary data showed that InsR also located in nucleus of cardiomyocytes. Using ChIP-seq, InsR was showed bound to specific sites, most of which were located in gene promoters. Hadhb and Timm22, which had protein products involved in mitochondrial metabolic function and protein translocation, respectively, were target genes of nuclear InsR. These data suggested the novel and potential role of nuclear InsR in regulation of mitochondrial functional homeostasis via transcriptional regulation. Importantly, the translocation of InsR to nucleus was significantly reduced in diabetic hearts compared with that in control hearts and inhibiting InsR translocation augmented cardiomyocyte hypoxic injury. Based on these findings, this proposal was aimed to determine whether reduced InsR translocation promotes vulnerability of diabetic myocardium to ischemia/reperfusion and to further explore the mechanisms of reduced InsR translocation leading to mitochondrial disorders by regulating target genes. This project is supposed to reveal the novel role of InsR and the new therapeutic strategy for MI/R injury in diabetes.