甜菊糖甙改善2型糖尿病炎症反应的作用及其机制探讨

Accumulating evidence suggests that type 2 diabetes mellitus is a systemic chronic inflammatory disease featured by extensively occurred inflammation in liver, skeletal muscle, adipose tissue and pancreatic islets. Ameliorating the inflammatory state or interfering with the relevant signaling pathways emerges as an effective approach to treat diabetes. Our previous study has revealed that the natural sweetener stevioside improves high-fat diet induced insulin resistance and beta cell dysfunction in C57BL6J mice. Furthermore, stevioside downregulates the expressions of multiple inflammatory cytokines in adipose tissue and in palmitate/high glucose treated INS1 cells. Moreover, stevioside reduces macrophage infiltration in the adipose tissue and pancreatic islets of high-fat diet fed mice. In addition, stevioside significantly suppresses the activation of the NF-κB signaling pathway in adipose tissue of high-fat diet fed mice and palmitate/high glucose treated INS1 cells. Next, we will further investigate the modulating effects of stevioside on the inflammatory state of type 2 diabetes in insulin responsive tissues and pancreatic beta cells in vivo and in vitro. We will also explore the potential molecular mechanisms, providing new evidence for treating diabetes mellitus..

研究表明2型糖尿病是一种全身慢性炎症反应性疾病，改善炎症状态或干扰炎症信号通路成为防治糖尿病的一条新途径。甜菊糖甙是从草本植物甜叶菊中提取的一种天然化合物。我们前期研究发现甜菊糖甙能改善高脂诱导的糖尿病小鼠胰岛抵抗及胰岛分泌功能损伤，进一步研究发现甜菊糖甙能减轻糖尿病小鼠脂肪组织和胰岛炎症因子表达及巨噬细胞浸润。同时，甜菊糖甙能抑制高脂诱导的脂肪组织及棕榈酸/高糖诱导的INS1胰岛细胞NF-κB炎症信号通路的激活。本课题将在前期研究基础上，通过在体内、体外建立2型糖尿病模型，进一步明确甜菊糖甙对胰岛素抵抗及胰岛B细胞分泌功能的影响，阐明其对外周组织及胰岛炎症反应的作用，并深入探讨其改善炎症的潜在分子途径，为糖尿病的防治提供新思路。

心肌细胞炎症在心肌疾病发展中起重要作用。最近研究发现Omega-3多不饱和脂肪酸具有抗炎作用。本研究采用阿霉素及脂多糖（LPS）建立心肌病模型，采用omega 3多不饱和脂肪酸的重要成份DHA(Docosahexaenoic Acid, 二十二碳烯酸)对模型进行干预，结果发现：阿霉素或LPS可诱导H9C2心室肌细胞损伤，而DHA能减轻阿霉素或LPS的心肌毒性作用。进一步机制研究发现，DHA可减轻阿霉素及LPS诱导的心肌细胞炎症反应。Real-time PCR及ELISA检测发现阿霉素/脂多糖（LPS）可促进心肌细胞炎症细胞因子表达，脂多糖（LPS）组IL-6，MCP-1, iNOS等炎症因子表达明显升高，而阿霉素组TNF-α, IL-1β, MCP-1, iNOS等炎症因子表达显著升高，而DHA干预可降低脂多糖或阿霉素诱导的炎症因子表达，且DHA可降低心肌细胞活性氧族产生，提示DHA可改善阿霉素/LPS诱导的心肌炎症及氧化应激。深入机制研究发现DHA通过抑制NF-κB/iNOS/NO炎症信号通路激活发挥抗心肌抗炎作用，我们的研究表明DHA可通过减轻心肌细胞炎症反应改善阿霉素或LPS诱导的心肌损伤。