摘要
目的探讨核因子κB(NF-κB)/亲环素D(CypD)介导的线粒体应激信号通路在2型糖尿病(T2DM)小鼠胰岛β细胞功能损伤中的作用及机制。方法选取6周龄CypD基因敲除(CypD^(-/-))小鼠和同窝野生型(WT)小鼠,分别随机分为正常对照小鼠(CypD^(-/-)组和WT组)和糖尿病模型小鼠[CypD^(-/-)+高脂饮食(HFD)+链脲佐菌素(STZ)组和WT+HFD+STZ组],共4组,每组6只。测定各组小鼠的空腹血糖、血清胰岛素、胰腺组织胰岛素、葡萄糖刺激的胰岛素分泌(GSIS)、NF-κB、胰腺十二指肠同源框-1(PDX-1)水平及胰岛细胞线粒体呼吸耗氧率(OCR)。采用重组腺病毒感染技术检测过表达NF-κB的胰岛β细胞(INS-1细胞)中CypD水平。结果与WT+HFD+STZ组相比,CypD^(-/-)+HFD+STZ组小鼠空腹血糖水平降低,血清胰岛素、胰腺胰岛素水平升高,PDX-1表达水平升高,差异有统计学意义(P<0.001)。与WT+HFD+STZ组相比,CypD^(-/-)+HFD+STZ组小鼠GSIS水平升高,胰岛细胞基础呼吸、ATP生成、最大呼吸和剩余呼吸能力均提高,差异有统计学意义(P<0.001或P<0.05)。过表达NF-κB的胰岛β细胞中CypD蛋白相对表达量高于对照细胞,差异有统计学意义(P<0.05)。结论CypD^(-/-)可改善T2DM小鼠的空腹血糖和胰岛素水平,调控PDX-1表达,增强GSIS及线粒体呼吸功能,保护胰岛β细胞。NF-κB过表达可诱导CypD表达上调,在NF-κB/CypD介导的线粒体应激信号通路中发挥上游调控作用。
Objective To investigate the role and mechanism of nuclear factor-κB(NF-κB)/cyclophilin D(CypD)-mediated mitochondrial stress signaling pathway in isletβ-cell dysfunction in type 2diabetic(T2DM)mice.Methods Six-week-old CypD gene knockout(CypD^(-/-))mice and their wild-type(WT)littermates were randomly divided into normal control groups(CypD^(-/-)group and WT group)and diabetic model groups[CypD^(-/-)+high-fat diet(HFD)+streptozotocin(STZ)group and WT+HFD+STZ group],with six mice in each group.The fasting blood glucose,serum insulin,pancreatic insulin levels,glucose-stimulated insulin secretion(GSIS),NF-κB levels,pancreatic and duodenal homeobox-1(PDX-1)expression levels,and mitochondrial respiratory oxygen consumption rate(OCR)of islet cells were measured in each group.The CypD level in isletβ-cells(INS-1 cells)overexpressing NF-κB was detected using recombinant adenovirus infection technology.Results Compared with the WT+HFD+STZ group,the CypD^(-/-)+HFD+STZ group showed significant decrease in fasting blood glucose levels,significant increase in serum insulin and pancreatic insulin levels(P<0.001),and PDX-1 expression levels(P<0.001).The CypD^(-/-)+HFD+STZ group also exhibited significantly elevated GSIS levels(P<0.001),and enhanced basal respiration,ATP production,maximal respiration,and reserve respiratory capacity of islet cells compared with the WT+HFD+STZ group(P<0.001 or P<0.05).The relative expression level of CypD protein in isletβ-cells overexpressing NF-κB was significantly higher than that in control cells(P<0.05).Conclusion CypD^(-/-)can improve fasting blood glucose and insulin levels in T2DM mice,regulate the downregulation of PDX-1expression,enhance GSIS and mitochondrial respiratory function,and protect islet β-cells.Overexpression of NF-κB can induce the upregulation of CypD expression and play an upstream regulatory role in the NF-κB/CypD-mediated mitochondrial stress signaling pathway.
作者
陈小宇
张秀娟
CHEN Xiaoyu;ZHANG Xiujuan(Department of Endocrinology and Metabolism,Provincial Hospital Affiliated to Shandong First Medical University,Ji'nan,Shandong,250021)
出处
《实用临床医药杂志》
2025年第13期109-115,共7页
Journal of Clinical Medicine in Practice
基金
国家自然科学基金资助项目(81970700)。
