干姜黄芩黄连人参汤对2型糖尿病小鼠胰岛β细胞铁死亡相关代谢途径的影响OA

Objective To investigate the effects of Ganjiang Huangqin Huanglian Renshen(JQLS)Decoction on ferroptosis-related metabolic pathways in pancreatic β-cells of a mouse model of type 2 diabetes mellitus(T2DM).Methods The components of JQLS decoction were characterized by liquid chromatography-mass spectrometry.Ten male C57BL/6J mice were randomly assigned to the Control group and fed a normal diet.The remaining mice were fed a high-fat diet and received intraperitoneal injection of streptozotocin to induce T2DM.Successfully modeled mice were randomly assigned to Model,Met(0.26 g/(kg·d)),JQLS-L(4 g/(kg·d))and JQLS-H(8 g/(kg·d))groups(n=10/group).After 12 weeks of intragastric administration,an oral glucose tolerance test was performed and fasting serum insulin levels were measured.Pancreatic islet morphology was evaluated by hematoxylin and eosin staining.The β/α cell ratio and 4-hydroxynonenal(4HNE)expression in islets were assessed by immunofluorescence co-staining.Levels of malondialdehyde(MDA),reduced glutathione(GSH),and superoxide dismutase(SOD)were measured by enzyme-linked immunosorbent assay.Fe2+content was determined using commercial kits.The mRNA expression of GSH metabolism-related molecules solute carrier family 7 member 11(SLC7A11)and glutathione peroxidase 4(GPX4),and iron metabolism-related molecules ferritin heavy chain 1(FTH1)and ferritin light chain(FTL),were quantified by reverse transcription quantitative real-time PCR.Results Compared with Control group,Model group showed:significantly increased blood glucose levels,area under the curve(AUC),4HNE expression in β-cells,MDA levels in pancreatic tissue,and Fe2+content(all P<0.001),together with significantly decreased homeostasis model assessment of β-cells function index(HOMA-β),β/α cell ratio,SOD activity,GSH levels,and downregulated mRNA expression of SLC7A11,GPX4,FTH1,and FTL(all P<0.001).Severe islet atrophy and structural deformation,and reduced,unevenly distributed nuclei were also observed.Compared with Model group,JQLS-H and Met groups significantly reduced blood glucose levels(P<0.001)and AUC(P<0.01),significantly improved HOMA-β(P<0.001),restored islet morphology and the β/α cell ratio(P<0.05),significantly decreased 4HNE expression,MDA levels,and Fe2+content(P<0.001),significantly increased SOD activity(P<0.001),GSH levels(P<0.01),and upregulated mRNA expression of SLC7A11(P<0.01),GPX4(P<0.001),FTH1(P<0.001),and FTL(P<0.01).Conclusions JQLS effectively improved glycemic control and preserved pancreatic β-cells number and function in T2DM mice,possibly by regulating GSH metabolism and iron metabolism pathways,thereby inhibiting β-cells ferroptosis.