Study On The Effect And Mechanisms Of Dendrobium Nobile Lindl. Alkaloids On Blood Glucose In KK-Ay Mice

Objective: To evaluate the efficacy of DNLA on hyperglycemia in KK-Ay T2 DM mice and explore its potential mechanism in regulation of insulin and anti-oxidation signaling pathway.Methods:Fifty KK-Ay mice(fasting blood glucose,FBG≥7.0mmol/L)were randomly divided into the following groups: Model group(solvent treatments),DNLA low-dose group(DNLA-L,10 mg/kg),DNLA medium dose group(DNLA-M,20 mg/kg),DNLA high dose group(DNLA-H,40 mg/kg),and Metformin group(Met,125 mg/kg)with twice-daily intragastrical administration for four months.Twenty non-diabetic C57BL/6J mice were used as normal control and DNLA treatment groups(20 mg/kg).The body weight,fasting blood glucose,lipid profile,Hb A1 C,oral glucose tolerance test(OGTT)and homeostasis model assessment of insulin resistance(HOMA-IR)were measured before and after DNLA treatment.H&E staining and immunohistochemical analysis were used to examine the pancreatic lesion and the expression of insulin in pancreatic islet beta cells.The serum fasting insulin(FINS)and glucacon-like peptide 1(GLP-1)were detected by ELISA in serum.The protein levels of IR,p-IR-Y1185,IRS-1,Glut4,IDE,KEAP1,Nrf2,Cat,HO-1,NQO1 and SOD1 in pancreas were determined by Western blotting.Result:The results showed a significant augment in the level of fasting blood glucose(FBG)and lipid profile in KK-Ay mice.Specifically,the OGTT,Hb A1 C and HOMA-IR were increased in model group,while the FINS and GLP-1 were decreased.H&E staining showed that pancreatic islands were atrophied and disorganized,with dyed inhomogeneity of cytoplasm in model group.IHC staining showed that the expression of insulin in pancreatic tissue was significantly reduced in the model group.In the pancreatic tissue of KK-Ay mice,the phosphorylation of IR,NQO1 and Cat decreased significantly,and the levels of IR and IRS1 were increased.After DNLA treatment,the results showed a significant decreased in the level of FBG,T-CHO,OGTT and HOMA-IR in the DNLA group compared with the model group,while serum levels of L-DLC,H-DLC and TG did not change significantly.DNLA could effectively reduce the pathological changes of islets and increase the expression of insulin in pancreatic beta cells.Moreover,the treatment of DNLA increased the protein expression levels of p-IR-Y1185,IRS-1,Glut4 and IDE.Meanwhile,the expression of Cat,HO-1,NQO1 and SOD1 proteins were increased,while the levels of KEAP1 and Nrf2 protein did not change significantly.Conclusion: Dendrobium nobile Lindl.Alkaloid decreased blood glucose levels and protected pancreas islet beta cells.The potential mechanism may be associated with improving insulin signaling and up-regulating the expression of antioxidant related proteins.