从胰岛微循环探讨“脾气散精”环节对糖尿病血糖波动的调节机制

Reducing glycemic excursion is of great importance to the successful practices of diabetes intervention and complications prevention. However, there is no effective therapies within western medicine to improve the function of islet. TCM suggests that glycemic excursion in diabetes mellitus is closely related to the incapability of “spleen qi to dispersing essence”. Thus, by supplementing the “spleen” qi and promoting the dispersion of nutrient substance (hormone) in “pancreas”, the balance between sugar-regulated hormones can be restored and therefore glycemic excursion can be reduced. Moreover, earlier studies of the previous Natural Fund projects(No.30772806；No.81273749) reveals that prescriptions of promoting “spleen qi to dispersing essence” not only can improve the function of islet, but also can promote repairs of islet microvasular endothelial cells (IMECs). Therefore, it remains great possibility that the effects of “spleen qi to dispersing essence” on the improvement of islet functionality and the regulation of glycemic excursion may be achieved by improving the structure and function of islet microcirculation, and its mechanism may be related to the activation status of local RAS in islet microcirculation. As such, this project applies the Shenqi compound, which can benefit spleen qi, nourish spleen yin and smooth spleen collaterals, to promote the function of “spleen qi to dispersing essence” in diabetic rats through glycemic excursion. Then, gene expressions of local RAS in islet microcirculation are collected using microdissection and single-cell transcriptase sequencing technology and are used to explore the molecular network mechanism of the segment of “spleen qi to dispersing essence” on regulating glycemic excursion of local RAS in islet microcirculation. Finally, the project aims to verify the important scientific value of “spleen qi to dispersing essence” theory on the treatment of diabetes mellitus.

减少血糖波动是目前干预糖尿病和预防并发症的重点，西医目前尚没有针对胰岛功能本身的治疗方法。中医学认为糖尿病血糖波动与“脾气散精”障碍密切相关，通过补益“脾”气以促进“胰”中精微物质的布散能够恢复糖调节激素间的平衡，从而减少血糖波动。申请人在之前的自然基金项目（No.30772806；No.81273749）中发现，促进“脾气散精”的方药能够改善胰岛功能并修复血管内皮损伤。由此我们推测：“脾气散精”环节通过促进机体胰岛微循环从而发挥其改善胰岛功能、调节血糖稳态的作用，其机制可能与抑制胰岛微循环局部RAS的激活状态相关。本项目应用补脾气、滋脾阴、通脾络的参芪复方促进糖尿病血糖波动大鼠“脾气散精”功能的发挥，采用显微切割、单细胞转录组测序等技术检测胰岛微循环局部RAS相关通路各基因的表达，构建“脾气散精”环节对胰岛微循环调控的分子网络机制，为中医“脾气散精”理论指导糖尿病诊疗提供科学依据。

本项目以补脾气、滋脾阴、通脾络的参芪复方促进糖尿病机体脾气散精作用的发挥，并观察散精之脏（胰）的微观变化，从整体水平、组织水平、细胞水平、分子水平多层次探索了“脾气散精”环节调节血糖波动的作用机制。结果表明：“脾气散精”障碍可引起胰岛微循环障碍以及胰岛内分泌功能紊乱，导致血糖波动；助脾散精法可在一定程度上改善糖尿病血糖波动大鼠多饮、多食、体重减轻等症状及胰岛病理形态，并且改善胰岛细胞凋亡，恢复糖调节激素水平，降低RAS激素的血管损伤，改善胰岛微血管血供，促进胰岛微循环结构的恢复以及功能的发挥，从而改善胰岛微循环；助脾散精法改善血糖波动大鼠胰岛微循环的可能机制是通过激活RAS旁路途径（ACE2/Mas轴），促进IRS-1及AKT的表达而实现的。本研究在探索中医药防治糖尿病血糖波动的疗效及机制的基础上，明确了糖尿病血糖波动“脾气散精障碍”这一重要病理环节，认为中医药防治糖尿病血糖波动应注重“补脾气、滋脾阴、通脾络”，以恢复脾气散精功能。本研究目前已发表学术论文14篇，尚有2篇SCI论文在修稿阶段。