NLRP3炎症小体调控IRS-1/Akt信号通路在砷致糖稳态失衡和胰岛素抵抗中的作用及机制

Prevention and treatment of endemic arsenic poisoning has already caused the peoples extensive concern. Coal-burning type arsenism is a unique disease type in our province and arsenic poisoning people is the key target of poverty alleviation. Insulin resistance and glucose metabolism imbalance among the non-cancer diseases caused by long-term arsenic exposure is getting attention. Insulin resistance and glucose homeostasis imbalance may be closely related to inflammation-mediated changes in IRS-1/Akt signaling pathway, and insulin resistance is one of the early characteristics of diabetes mellitus. Recent studies shows that the activation of inflammatory bodies in NLRP3 is an important molecular event triggering inflammation, Applicant and our team also demonstrate that arsenic exposure can cause definite inflammatory reactions and abnormal glucose and lipid metabolism. But is NLRP3 inflammatory body a key trigger factor? Whether the regulation of IRS-1/Akt signaling pathway affects arsenic-induced insulin resistance and glucose homeostasis is unclear. Based on the our previous research, this project aims to explore the role of NLRP3 inflammatory body targeting IRS-1/Akt in arsenic-induced insulin resistance and glucose homeostasis from in vivo of Coal-burning type arsenism and in vitro of cell two level. The result of this study can provide a new basis and direction for the overall prevention and treatment of arsenic-induced chronic health damage.

地方性砷中毒是我国我省持续高度重视的重点防治疾病，其中燃煤型砷中毒是我国我省独特病型，是当前脱贫攻坚的重点人群。长期砷暴露引起慢性非癌症疾病中，砷暴露引起的胰岛素抵抗和糖代谢失衡已成为人们关注的焦点。胰岛素抵抗是糖尿病的早期特征之一，而胰岛素抵抗及糖稳态失衡可能与炎症反应介导的IRS-1/Akt信号通路改变密切相关。新近研究发现NLRP3炎症小体活化是触发炎症反应的重要分子事件，申请人和课题组前期研究发现砷暴露可引起明确的炎症反应和一些糖脂代谢相关指标异常，但NLRP3炎症小体是否是其关键的始发因素？是否通过调控IRS-1/Akt信号通路影响砷致胰岛素抵抗和糖稳态失衡均不清楚。本项目依托课题组前期研究基础，从燃煤型砷中毒人群和体外细胞研究，探讨NLRP3炎症小体靶向调控IRS-1/Akt在砷致胰岛素抵抗和糖稳态失衡中的作用机制，为整体推进砷致慢性健康损害的针对性防治提供新的依据和方向。

地方性砷中毒是我国我省持续高度重视的重点防治疾病，其中燃煤型砷中毒是我国我省独特病型，是当前脱贫攻坚的重点人群。长期砷暴露引起慢性非癌症疾病中，砷暴露引起的胰岛素抵抗和糖代谢失衡已成为人们关注的焦点。本项目从人群和细胞两个层次侧重探讨了NLRP3炎症小体调控IRS-1/Akt信号通路在砷致糖稳态失衡和胰岛素抵抗中的作用及机制。在人群层面明确了燃煤砷暴露是病区居民糖代谢异常的独立危险因素，胰岛素抵抗与胰岛功能损伤为砷致糖稳态失衡的重要靶点，炎症反应可促进砷致高血糖的风险；在细胞层面揭示了NaAsO2可促进NLRP3炎性小体激活，NaAsO2诱导NLRP3炎性小体活化通过IRS-1/PI3K/Akt的活性衰减介导了糖稳态失衡。本研究为推进砷致糖稳态失衡的作用机制及防治提供了科学依据。