Introduction

Type 1 diabetes mellitus(T1DM)is an autoimmune disease caused by absolute insulin deficiency due to destruction of the pancreaticβ-cells.Type 2 diabetes mellitus(T2DM)is a metabolic disorder of non-insulin-dependent and slow in on set characterized by a progressive decline inβ-cell function and chronic insulin resistance.1，2)Both types are characterized by progressiveβ-cell failure and recent treatments are focusing on enhancing endogenousβ-cell function and/or regeneration.3)Because apoptosis is probably the main form ofβ-cell death，4)apoptosis-causedβ-cell mass decreasing and function impairing have provided a hopeful target in diabetes treatment.5)It is suggested that cytokines，lipotoxity and glucotoxity are three main stimuli forβ-cell apoptosis.4，6，7)High glucose and cytokines have been shown to induceβ-cell death via apoptosis and/or necrosis.8- 10)Chronic exposure to elevated levels of glucose causesβ-cell dysfunction and may induceβ-cell apoptosis in T2DM.Exposure to high glucose has dual effects，triggering initially“glucose hypersensitization”and later apoptosis，via different mechanisms.4)After prolonged exposure to cytokines，functional impairment results in T1DM.11)Cytokines may induce direct deleterious effects onβ-cells via generation of toxic oxygen free radicals and nitric oxide(NO)，as well as sensitizingβ-cells to T-cell mediated cytotoxicity in vivo by upand down-regulating multiple genes.12，13)

There are three key apoptosis signaling pathways inβ-cells，namely mitochondria pathway，death signal pathway and endoplasmic reticulum(ER)stress pathway.In the process of mitochondria pathway，free radicals，B-cell chronic lymphocytic leukemia(CLL)/lymphoma-2(Bcl-2)family-regulated，apoptotic protease-activating factor 1(Apaf-1)and cysteine proteases cysteine aspartase-9(Caspase-9)are required14，15)；death signal pathway involves Fas or tumor necrosis factor(TNF)-RI-activated and demanded Fas-associating protein with death domain(FADD)and Caspase-8.14，16)The ER stress pathway is mediated by transcription factor C/EBP homologous protein(CHOP)/growth arrest and DNA damage induced gene(GADD)153 and Caspase-12.17- 20)The major functional players in apoptosis are caspase，adaptor proteins，and proteins from the TNF receptor(TNF-R)family and the Bcl-2 family.14)Each of the three pathways converges to a common execution phase of apoptosis which requires proteolytic activation of Caspase-3 through both extrinsic and intrinsic signaling pathway.21- 23)Members of Bcl-2 family are pro-apoptotic or anti-apoptotic.14，24)The pro-apoptotic/anti-apoptotic balance of Bcl-2 family members，such as Bcl-2/Bcl-2-associated X protein(Bax)，25)will effect apoptosis by cytochrome c release and Caspase activation.24)Fas is a cell-surface protein mediating apoptosis.Cytokines can induce up-regulation of Fas expression inβ-cells，making them susceptible to apoptosis in the presence of agonistic anti-Fas antibodies，or interaction with Fas ligand(FasL)-expressing Tcells.26- 28)It is well known that cytokine such as interleukin(IL)-1β，TNF-αand interferon(IFN)-γ，could induce expression of inducible nitric oxide synthase(iNOS)and then lead to NO formation within pancreaticβ-cells，which contributes to a major extent toβ-cell necrosis and apoptosis.12，29 31)(https://www.daowen.com)

Ginseng，often described as the“king herb，”has been used as an anti-diabetic herb for several thousand years in Asia.The anti-diabetic actions of ginseng might mediate through a variety of mechanisms including actions on improving systemic insulin sensitivity，32)increasing the activity of a glucose transporter protein，33)and reducing glycogenolysis，thus restraining hyperglycemia.34)Moreover，ginseng treatment increased insulin release from pancreaticβ-cells，which is probably caused by increasingβ-cell stimulation and insulin synthesis.35 37)Ginseng consists of a number of active constituents，such as polysaccharides，peptides，polyacetylenic alcohols and fatty acids，38)of these，and most pharmacological properties are mainly attributed to ginsenosides.39)Ginsenosides Rb1 and Rg1 hold important positions in stimulatory and inhibitory effects on central nervous system.40，41)Rg1 also plays a role of anti-apoptosis in neonatal rats with hypoxia ischemia brain damage，and could inhibit Caspase-3 activation by strengthening and stabilizing hypoxia inducible factor-1αsignal pathway.42)Rb1 was shown to protect cells from apoptosis induced by UVB radiation through the induction of DNA repair.43)Rb1 also could repress cell death induced by 6-hydroxydopamine in SH-SY5Y neuroblastoma cells，44)and protect dopaminergic cells from oxidative stress.45，46)Within pancreatic β-cells，there is few reported result concerning the anti-apoptotic function of Rb1 and Rg1 in the treatment of diabetes.

The aim of the study was to investigate the effects of ginsenosides Rb1 and Rg1 on stimuli-induced pancreaticβ-cell apoptosis and explore its mechanisms regarding signal transduction pathway.