阿托伐他汀致PAHSA下调的作用及其与新发糖尿病的相关性研究

As a first-line treatment for cardiovascular disease, statins are associated with a risk of inducing new onset diabetes in clinical use. Its mechanism has not been fully understood. Our study found that the content of a group of beneficial lipids PAHSA was decreased in serum of rat after continuous administration of atorvastatin for the first time. It has been reported that PAHSA can control blood glucose and even prevent diabetes by increasing insulin sensitivity and promoting the secretion of GLP-1 and insulin. Accordingly, it is speculated that the down-regulation of PAHSA level induced by atorvastatin may be the cause of its role in the development of diabetes, and PAHSA may play an important role in the prevention and treatment of this kind of drug-induced diabetes. In order to verify this hypothesis, 3T3L1 fat cell, obese rat, and hyperlipidemia patient were used to confirm the relationship between PAHSA level and atorvastatin induced diabetes after continuous taking of atorvastatin. Furthermore, the effect of PAHSA on prevention of drug-induced diabetes was investigated by administration of PAHSA with atorvastatin at the same time. Finally, the possible mechanism of atorvastatin to reduce PAHSA level in PAHSA synthesis and metabolism was discussed. In this study, we hope to explain the mechanism of statin induced diabetes from a new perspective, and to provide new ideas for the prevention of statin-induced diabetes.

他汀类药物作为心血管疾病治疗一线用药，临床长期使用存在致新发糖尿病的风险，机制未完全明确。我们前期研究首次发现，阿托伐他汀连续给药后大鼠血清中有益脂质PAHSA浓度降低。已有报道PAHSA可通过提高胰岛素敏感性和促进GLP-1及胰岛素的分泌起到控制血糖抗糖尿病的作用。据此猜测：阿托伐他汀致PAHSA水平下调可能是导致新发糖尿病作用的诱因之一，补充PAHSA可能对他汀类药源性糖尿病起到预防或治疗作用。为验证该假说，课题首先以3T3L1细胞、肥胖大鼠和高脂血症患者为对象，对阿托伐他汀连续给药后PAHSA水平的降低与糖尿病指征的关联性进行确认性研究；进一步，对PAHSA在阿托伐他汀致新发糖尿病中的预防性干预作用进行研究；最后，从PAHSA合成和代谢环节对阿托伐他汀降低PAHSA水平可能的机制进行探讨。本研究有望从全新角度阐释他汀类药物致新发糖尿病的机制，为他汀类药源性糖尿病的预防提供新的思路。

课题研究已经基于动物实验和小样本量临床样本的FAHFA、代谢组学和脂质组学分析以判断阿托伐他汀对FAHFA类脂质总体的干预趋势并同时获取药物对体内各代谢通路的影响情况。根据健康大鼠连续灌胃给药后血清样本分析结果，阿托伐他汀对FAHFA中的各个结构亚型未表现出显著的干预趋势。其中，对POHPO，POHPA，PAHPO，PAHPA，POHOA，PAHOA，SAHPO，OAHOA呈现轻度下调趋势（p>0.05），而对PAHSA和SAHSA呈现轻度的上调趋势（p>0.05）。临床样本监测中，对于已收集到的长期服用阿托伐他汀的患者和未服用他汀类药物的患者血样监测结果由于样本量有限、干预因素较多及未采用自身对照等原因，监测结果数据变异较大，未表现出显著差异。现对临床样本收取进行调整，正在收集基于自身对照的用药前和用药后的患者血清样本以评估阿托伐他汀对FAHFA类物质的干预趋势。同时，正在开展基于代谢流技术的细胞试验探索FAHFA类物质的合成和代谢机制。另外，动物实验部分将补充药物对肥胖动物FAHFA的干预试验。