Effect And Mechanism Of Diphenyl Diselenide On Type 2 Diabetes Mellitus And Two Complications Of Type 1 Diabetes Mellitus

Type 2 diabetes mellitus(T2DM),diabetic peripheral neuropathy(DPN)and diabetic nephropathy(DN)have developed into important health problems of worldwide concern.Although there are many drugs that can be used for treatment,there is an urgent need to find new and more effective drugs and further elucidation of these disease's pathogenesis because of their low curative effect and great side effects.Diphenyl diselenide(DPDS)is a simple,stable and low toxic organic selenium compound,which has many pharmacological effects,such as glutathione peroxidase-like activity,insulin-mimetic properties,anti-inflammatory,neuroprotection,hepatocyte protection and anti-hyperglycemic,nevertheless,the effects of DPDS on T2 DM and the diabetic complications in type 1 diabetes are still unclear.Therefore,in the present study,the corresponding models were used to explore the effects of DPDS on T2 DM,DPN and DN,and to study the possible mechanism.The main results are as follows:(1)To study whether DPDS can improve the metabolic disorder of T2 DM and its possible mechanism,the spontaneous type 2 diabetes db/db mice were used as the model.Our results showed that DPDS significantly reduced body weight,water intake,food intake,blood glucose,improved abnormal glucose tolerance,insulin resistance,pyruvate tolerance and dyslipidemia in db/db mice.DPDS reduced the proinflammatory factors and maintained the redox balance in serum of the db/db mice.For the pancreas,DPDS supplementation reversed the pancreas islets dysfunctions by reducing oxidative stress,inflammatory reaction,regulatory the expression of protein tyrosine phosphatase non-receptor 2(PTPN2)and phosphorylated signal transducer and activator of transcription 1(STAT1)in pancreas.In addition,DPDS protected the liver from hyperglycemia by alleviating liver steatosis,improving liver oxidative stress injury and regulating liver insulin resistance in db/db mice,thus improving diabetic symptoms in db/db mice.(2)The rats with streptozotocin(STZ)-induced type 1 diabetes were used as the model to study the effects and mechanisms of DPDS on DPN.The results showed that DPDS significantly increased the motor nerve conduction velocity,improved thermal and mechanical hyperalgesia and the abnormal sciatic nerve morphology,and ameliorated oxidative stress in serum and the sciatic nerve in rats with STZ-induced diabetes.Mechanistically,DPDS reduced the levels of kelch like epichlorohydrin associated protein-1(Keap1)and stimulated the expression of nuclear factor E2 associated factor 2(Nrf2)signaling pathway related protein in sciatic nerve.The results of this study indicated that DPDS ameliorates DPN as an antioxidant by activating the Nrf2/Keap1 signaling pathway.(3)Based on the results of the effects of DPDS on DPN in vivo,the effects of DPDS on the toxicity and oxidative stress induced by high concentration of glucose were studied in rat RSC96 schwann cells.The results showed that DPDS markedly suppressed high glucoseinduced cytotoxicity and oxidative stress in RSC96 schwann cells by decreasing reactive oxygen species(ROS)and malondialdehyde(MDA)levels.Furthermore,the DPDS treatment effectively activated Nrf2 signaling and inhibited Keap1 expression in RSC96 cells.(4)The rats with STZ-induced type 1 diabetes were used as the model to study the effects and mechanisms of DPDS on DN.The results indicated that treatment with DPDS significantly improved hyperglycemia,glucose intolerance,dyslipidemia,and the renal pathological abnormalities,concurrent with significantly reduced levels of serum creatinine,urea nitrogen,urine micro-albumin and ?2-microglobulin.DPDS effectively reduced oxidative stress and inflammation in serum and kidney of the diabetic rats.Furthermore,DPDS supplementation activated the renal Nrf2/Keap1 signaling pathway,reduced the phosphorylation levels of nuclear factor kappa-light-chainenhancer of activated B cells(NF-?B)and mitogen-activated protein kinase(MAPK)signal pathway related proteins in kidney of the diabetic rats.(5)Based on the results of the effect of DPDS on DN in vivo,the mechanism of DPDS in improving DN was further explored in HBZY-1 cells(rat glomerular mesangial cells).The results showed that DPDS improved tert butyl hydrogen peroxide(t-BHP)-induced oxidative stress by activating the Nrf2/Keap1 pathway,and attenuated lipopolysaccharide(LPS)-induced inflammation via the inhibition of the MAPK/NF-?B pathways in HBZY-1 cells.