基于"脂-胰-骨"相关性探索黄芪散治疗糖尿病性骨质疏松的机制

The correlation of "Adipose-pancreas-bone" is proposed because adipose tissue，pancreas and bone interrelate closely with each other in the maintenance of energy metabolism. In recent years the studies about "The adipoinsular axis", "the bone-pancreas loop" and adipocyte factor reveal that an interactive mechanism exists between the leptin, insulin and osteocalcin in the internal endocrine environments. And they together take a part and maintain the balance of energy metabolism. If one of them has metabolic disorder, the others will be influenced and even lead to diseases. Diabetic osteoporosis results from a metabolic disorder of adipose tissue, pancreas and bone. Our preliminary research proved that HuangQi San (HQS) had obvious effect of lowering the fat, adjusting adipocytokines and improving the insulin resistance. With definite preventive and therapeutic effect to the osteoporosis induced by diabetes. So we proposed our hypothesis: HQS can protect bone by lowering the fat, adjusting adipocytokines and improving the insulin resistance based on the correlation of "adipose-pancreas-bone". This research firstly will evaluate the influence of the HQS on the secretion and interactive function of the leptin, insulin and osteocalcin by studying animal models with various osteoporosis inducement, as well as cell and molecule levels, secondly prove the function of "adipose-bone", "pancreas-bone" to diabetic osteoporosis. And lastly illustrate the influence of lowering the fat and improving the insulin resistance on bone protection, and further elucidate the curing mechanism of HQS in the treatment of diabetic osteoporosis from a scientific perspective of the correlation of "adipose-pancreas-bone".

"脂-胰-骨"相关性的提出是基于脂肪、胰腺与骨骼三者关系密切，在维持机体代谢平衡中相互影响和制约。近年"脂-胰轴"、"骨-胰环"、脂肪因子等研究揭示了瘦素、胰岛素与骨钙素之间在机体内分泌环境下存在交互作用机制，共同参与并维持机体能量代谢平衡。一方的代谢失调将影响其它的代谢平衡并导致疾病产生，糖尿病性骨质疏松就是脂、胰、骨三者的代谢失调产物。研究证实黄芪散有降脂、调节脂肪因子和胰岛素抵抗作用，对糖尿病引发的骨质疏松有明确作用。故，我们提出假说：黄芪散是基于"脂-胰-骨"相关性，通过调节脂肪因子和胰岛素抵抗而产生骨骼保护作用。研究拟从多种骨质疏松诱因的模型动物、细胞、分子水平综合评价黄芪散对瘦素、胰岛素、骨钙素等的交互影响，验证"脂-骨"，"胰-骨"关联对糖尿病性骨质疏松的作用；阐明调节脂肪因子和胰岛素抵抗如何对骨骼产生保护，从"脂-胰-骨"相关性角度诠释黄芪散治疗糖尿病性骨质疏松的科学内涵。

本研究基于脂肪、胰腺与骨骼三者之间的密切关系，研究拟从多种骨质疏松诱因的模型动物，细胞，分子水平综合评价黄芪散对瘦素、胰岛素及骨钙素等的交互影响，验证“脂-骨”“胰-骨”关联对糖尿病性骨质疏松的作用，阐明调节脂肪因子和胰岛素抵抗如何对骨骼产生保护，从“脂-胰-骨”相关性角度诠释黄芪散治疗糖尿病性骨质疏松的科学内涵。建立STZ+高脂饮食诱导的糖尿病性骨质疏松大鼠模型，测大鼠血糖、血脂、血清钙、磷、瘦素、骨钙素水平，大鼠体重及脏器脂肪体比，测定股骨骨生物力学与胫骨骨组织形态计量学指标。其次，建立醋酸泼尼松灌胃诱导的糖皮质激素性骨质疏松，测大鼠骨形成血液指标BGP、PINP水平，骨吸收血液指标CTX-1水平，大鼠体重及脏器脂肪体比，股骨骨生物力学与胫骨骨组织形态计量学指标。进行白色脂肪组织中MCP-1基因表达和棕色脂肪组织中UCP-1、PRDM16、Cidea表达的测定。研究黄芪散含药血清对成骨细胞和骨髓间充质干细胞的作用，检测成骨细胞中胰骨代谢相关基因OPG、Twist2、FoxO1、OC、ALP、OPN的mRNA和蛋白表达，测定BMSCs细胞中成骨转化及相关功能基因ALP、OC、OPN、RUNX2和成脂转化及相关功能基因PPARγ、AP2 mRNA表达。黄芪散均能显著降低模型大鼠FPG、TC、TG，说明黄芪散可调节模型大鼠的糖脂代谢，且药效稳定。黄芪散具有显著提高2型糖尿病大鼠血中骨钙素和降低血中瘦素含量的作用。黄芪散明显改善糖尿病模型大鼠股骨骨材料力学和骨结构力学各种参数值。提示具有增强模型大鼠骨质量的作用。黄芪散高糖条件下5%~20%含药血清可显著促进成骨细胞增殖。在5%，10%，20%三个浓度血清条件下黄芪散均具有促进BMSCs向成骨细胞分化作用。“脂-胰-骨”相关性的提出是基于脂肪、胰腺与骨骼三者关系密切，在维持机体代谢平衡中相互影响和制约。本研究通过探讨黄芪散对“脂-胰-骨”相关性的作用，进一步解释了代谢失调导致疾病产生的机制，揭示疾病的交互影响与机体内分泌环境下的交互作用机制。