基于甜味觉受体研究参苓白术散干预糖尿病前期的作用机制

The prevention and treatment of diabetes mellitus has become a major and difficult issue in the global medical community. Effective intervention in pre-diabetes can significantly reduce the possibility of its transformation into diabetes. The concept of "pre-treatment" of traditional Chinese medicine coincides with the prevention of diabetes mellitus. Spleen deficiency runs through the occurrence and development of diabetes mellitus. The therapeutic effect of treating diabetes mellitus from spleen in traditional Chinese medicine is clear and widely recognized. Since ancient times, there has been a theory of "the spleen is sweet in taste" in traditional Chinese medicine. Recent studies have found that sweet taste receptors are closely related to the occurrence and development of diabetes mellitus, affecting the absorption of nutrients and the balance of metabolism. In view of this, this study selected Shenling Baizhu Powder, a representative prescription of spleen therapeutics, to study the effect of Shenling Baizhu Powder on sweet taste receptor in pre-diabetic rats by establishing pre-diabetic animal model and using modern molecular biology technology, and further explored the role of Gαgust and PLC-β 2 signal transduction pathway in the regulation of GLP-1 and GLUT-2 by Shenling Baizhu Powder. The aim of this study is to preliminary explore the part of the mechanism and ways of Shenling Baizhu Powder in the treatment of pre-diabetes, and to lay the foundation for further elaborating the molecular biological mechanism of traditional Chinese medicine from spleen. It has a practical guiding significance for the prevention and treatment of diabetes by traditional Chinese medicine.

糖尿病防治研究已经成为全球医学界的重大和疑难课题，有效干预糖尿病前期可明显减少其转化为糖尿病的可能性，中医的“治未病”理念与糖尿病的预防不谋而合。脾虚贯穿于糖尿病发生发展的始终，中医的从脾论治法在防治糖尿病方面疗效明确，得到广泛认可。中医自古有“脾在味为甘”的理论，近年来研究发现甜味觉受体与糖尿病发生发展密切相关，影响着人体营养物质吸收和新陈代谢平衡。鉴于此，本研究选取从脾论治法代表方剂参苓白术散，通过建立糖尿病前期动物模型，运用现代分子生物学技术研究参苓白术散对糖尿病前期模型大鼠甜味觉受体的影响，并进一步探讨Gαgust及PLC-β2信号转导通路在参苓白术散对GLP-1和GLUT-2调节中所发挥的作用，旨在初步探明参苓白术散治疗糖尿病前期的部分作用机制与途径，同时也为进一步阐述中医从脾论治的分子生物学机制奠定基础，对中医药防治糖尿病有着现实的研究指导意义。

长期过量的高糖高脂饮食、肥胖是造成糖尿病的主要危险因素之一。近年来研究发现甜味觉受体与糖尿病发生发展密切相关。本研究通过长期高脂饮食诱导糖尿病前期大鼠模型，对相关指标进行检测统计，结果显示，长期高脂饮食，大鼠体重显著高于正常饮食组，引起明显的脂代谢异常，出现糖调节在一定程度受损及胰岛素抵抗，造成胰岛萎缩、消失和十二指肠糜烂和溃疡。舌、小肠、胃等组织中甜味觉受体（T1R2、T1R3）及相关信号分子（Gαgust 、PLC-β2）的蛋白表达降低，说明甜味觉受体及其信号关键分子在肥胖型糖尿病发生机制中扮演重要角色。高脂饮食可降低大鼠的甜味觉检测阈值，使其对甜味刺激的敏感性增加，从而更易于寻找和发现高能量食物，从而导致肥胖，进而增加肥胖型2型糖尿病的发生风险。提示长期过量的高糖高脂饮食、肥胖是造成糖尿病的主要危险因素之一，合理饮食，减少高脂食物的摄入，降低肥胖发生，以逆转糖尿病前期，对防治糖尿病具有积极指导意义，体现了中医“治未病”思想“未病先防、既病防变”。. 参苓白术散作为从脾论治法代表方剂，可有效控制并改善IR，调节脂代谢，降低体质量，保护改善味觉系统及胃肠道组织，起到延缓肥胖型T2DM前期病程发展的作用，且呈剂量依赖性。可以增加糖尿病前期大鼠舌、肠道、胰组织中甜味觉受体及关键信号分子Gαgust、GLP-1、GLUT2、PLCβ2及TRPM5的蛋白和mRNA的表达，WB与qPCR实验分析结果有高度的一致性，说明参苓白术散通过增加糖尿病前期模型大鼠中舌、肠道、胰组织中甜味觉受体的表达，并通过激活并上调Gαgust蛋白的表达，幵放TRPM5通道，即甜味物质转导的经典通路（T1Rs-Gαgust/PKCβ2通路）开放，干预舌、肠道、胰甜味觉信号分子转导进而恢复脾主运化功能，调节胃肠道，诱导 GLP-1、GLUT2 分泌，进而影响胰岛素的分泌来调节糖代谢，初步揭示从脾论治糖尿病前期的科学内涵。同时也为进一步阐述中医从脾论治的分子生物学机制奠定基础，对中医药防治糖尿病有着现实的研究指导意义。