| Objective:To evaluate the effect of JieduTongluoTiaogan Decoction?JTTD?in adipose tissue insulin resistance?IR?of obese type 2 diabetes mellitus?T2DM?rats,and observe its effect on endoplasmic reticulum stress?ERS?related protein expression in adipocytes,and to explore JTTD improves the function and mechanism of IR.Methods:In vivo experiments were carried out to induce obese T2DM model in ZDF rats by high-fat diet.ZL rats were used as a blank control group to maintain feeding with normal diet without drug intervention.The western medicine group was treated with metformin hydrochloride(0.5g·kg-1·d-1)as a positive drug control.JTTD group applied low,medium and high doses(1g·kg-1·d-1,3g·kg-1·d-1,5g·kg-1·d-1)to JTTD for drug administration.After 8 weeks of gavage,the effects of JTTD on glucose and lipid metabolism in the model rats were observed,and the glucose tolerance and insulin sensitivity were evaluated.The proteins of IRE1,P-IRE1,JNK and P-JNK in adipose tissue were detected.Expression and mRNA expression of IRS1.The ERS model was established in vitro by tunicamycin-induced mature 3T3-L1 adipocytes.The control group was not induced by tunicamycin and had no drug intervention.In the western medicine group,metformin hydrochloride?1mmol/L,ie,0.166?g/ml?was used as the positive drug control.JTTD group was treated with low,medium and high doses of JTTD?25?g/ml,50?g/ml,100?g/ml?.Drug intervention.To determine the effect of JTTD on glucose uptake by adipocytes,evaluate its insulin sensitivity,detect protein expression of IRE1,JNK and NF-?B in adipocytes,and adipocytokines and inflammatory factors ADPN,LP,IL-6.and protein expression changes of TNF-?.Results:After 12 weeks of high-fat feeding,the related indexes of glucose and lipid metabolism in the model group were abnormal,and the FBG,FINs,HbA1c and HOMA-IR of the rats were significantly increased?P<0.05,P<0.01?.The peak blood glucose peak was delayed in the oral glucose tolerance test,and IR was significant.After drug intervention,the abnormalities of glucose and lipid metabolism in JTTD group and the western medicine group were all improved to different degrees.The BW of each dose group of JTTD decreased,and the decrease of the high dose group was significant?P<0.05?.The HOMA-IR decreased significantly?P<0.05,P<0.01?,and the peak value of blood glucose was delayed.The oral glucose tolerance test indicated that the traditional Chinese medicine dose group could restore the glucose tolerance of ZDF rats?P<0.01?.The high-dose group of traditional Chinese medicine had better effect on the reduction of TC,HDL and FBG than the western medicine group?P<0.05?.The results of Western blot analysis of ERS-related proteins showed that compared with the model group,JTTD group inhibited the expression of IRE1?and JNK in adipose tissue and decreased the expression of phosphorylation?P<0.05,P<0.01?.The mRNA expression of IRS1 in the group was significantly increased?P<0.01?.For the inhibition of JNK,p-JNK and the up-regulation of IRS1 mRNA,the high-dose group of Chinese medicine was more significant than the western medicine group?P<0.01?.It is suggested that JTTD can significantly improve the abnormal glucose and lipid metabolism in model rats,reduces BW,restore impaired glucose tolerance,reduce insulin sensitivity index,increase insulin sensitivity,and control IR progression.After induction of mature 3T3-L1 adipocytes by tunicamycin,the expression of ERS-related proteins IRE1 and JNK was significantly up-regulated?P<0.05,P<0.01?.Glucose uptake decreased and insulin sensitivity decreased?P<0.05,P<0.01?.The expression of NF-?B protein was significantly increased?P<0.01?.The expression of TNF-?,IL-6 and LP was significantly increased?P<0.01?.ADPN decreased significantly?P<0.01?.After JTTD's drug intervention,cell inflammation and ERS were improved to varying degrees,abnormal secretion of adipocytokines was controlled,insulin sensitivity increased,and IR levels were significantly reduced.The high-dose JTTD group had better insulin sensitivity and IL-6 expression inhibition than the western medicine group?P<0.05,P<0.01?.The JTTD high-dose group had no significant difference between the JNK and TNF-?inhibition groups?P>0.05?.It suggests that the mechanism of action of JTTD on fat cell IR may inhibit the expression of IRE1?/JNK to reduce inflammation,relieve ERS,and improve insulin signaling.Conclusions:JTTD has a good therapeutic effect on abnormal glucose and lipid metabolism in obese T2DM rats,can reduce their BW,and can also act as an insulin sensitizer.Toxic damage to liver is one of the important pathogenesis of T2DM.It is feasible and unique to treat IR by JTT.The target of JTTD to improve IR may be adipose tissue ERS.Its mechanism may be to inhibit the IRE1?/JNK signaling pathway in the adipocytes,regulate the abnormal secretion of adipocytokines and inflammatory factors,alleviate ERS,and ultimately improve insulin signaling. |
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