The Mechanism Of Gegen Qinlian Decoction Reverses High-fat Diet-induced β Cell Dedifferentiation

Background:Obesity is a common chronic disease worldwide,and it has become a serious public health problem.Pancreatic β-cell dysfunction plays a key role in the pathogenesis and progression of type 2 diabetes mellitus(T2DM).Islet β-cell dedifferentiation is considered to be the main factor of β-cell dysfunction,and reversing β cell dedifferentiation can effectively alleviate the development of type 2 diabetes.Traditional Chinese medicine has a therapeutic effect on metabolic diseases such as diabetes,especially Gegen Qinlian decoction(GGQL).Therefore,the potential mechanism of GGQL in improving islet β-cell function remains to be clarified.Objective:To evaluate the effects of GGQL on islet β cell function and to analyze the mechanism of GGQL in improving pancreatic β cell function.Methods:(1)8-week-old male mice were randomly divided into 4 groups:normal control group(NC),obesity model group(HFD),Gegen Qinlian decoction low-dose group(GGQLL)and Gegen Qinlian decoction high-dose group(GGQLH)after one week of adaptive feeding.NC group was fed with standard diet,while HFD group,GGQLL group and GGQLH group were fed with high fat diet.After 13 weeks of feeding,the body weight,fasting blood glucose,fasting insulin,triglyceride,leptin,adiponectin and glucose tolerance were measured,the morphology and structure of islets were evaluated by hematoxylin-eosin staining(HE),and the pancreatic fat content was evaluated by IDEAL-IQ.The expression of specific transcription factors in mouse FoxO1,islet β cells and progenitor cells was observed by immunofluorescence co-staining.Then the mice were administered with different doses of GGQL for 8 weeks.After the administration,body weight,fasting blood glucose,fasting insulin,triglyceride,leptin,adiponectin and glucose tolerance were reassessed,the morphology and structure of pancreatic islets were evaluated,and the pancreatic fat content was evaluated again by IDEAL-IQ.The expression of specific transcription factors in mouse FoxO1,islet β cells and progenitor cells was observed.(2)MIN6 cells were treated with palmitic acid to establish the model of islet β cell dedifferentiation.The serum containing GGQL was used to intervene,and the expression of FoxO1,islet β cell and progenitor cell specific transcription factor mRNA was detected by qPCR.Results:Compared with HFD group,fasting blood glucose and area under the curve of glucose decreased significantly,HOMA-β level increased significantly in GGQLL and GGQLH groups,but there was no significant difference between the two groups.HE staining indicated that the morphology and structure of islets in GGQLL and GGQLH groups were more regular.IDEAL-IQ showed that pancreatic fat decreased significantly in GGQLL and GGQLH groups.Pancreatic immunofluorescence co-staining showed that GGQLL and GGQLH groups restored the number of β cells,increased the expression of specific β-cell transcription factors Pdx1,MafA,Nkx6.1 and FoxO1,and down-regulated the expression of progenitor transcription factors Ngn3,Oct4 and Aldh1A3.In addition,the drug-containing serum of GGQL could increase the expression of INS1,INS2,Pdx1,MafA and FoxO1 in MIN6 cells,and decrease the expression of progenitor specific transcription factor Ngn3.Conclusion:GGQL can reverse β-cell dedifferentiation,improve islet β-cell function and alleviate the progression of type 2 diabetes by reducing intrapancreatic fat deposition and up-regulating the expression of FoxO1 in islet β-cells of mice fed with high-fat diet.