Influence Of HCV Infection On Insulin Secretion And Its Inducing Mechanism For Type 2 Diabetes

With living circumstance improving,people pay more attention to the environmental factor influencing people's health.Hepatitis C and T2DM(Ty pe 2 diabetic mellitus)are typical diseases caused by environmental facto r.Having common prevalence and serious consequence,Hepatitis C is some how affected by environmental factor.Leading to the hepatic damage,HCV may also lead to metabolic disorder including T2DM.T2DM is a disease cau sed by multiple gene and environmental factors.It is a possible etiology pa thway that HCV infection may damage the pancreatic ?-cell.In this study,t he c?ltured HCV in vitro is used to infect the insulinoma cell of mice,the tri partite pathogenesis forms:the direct and indirect mechanism of HCV induc ing pancreatic damage,the effect of insulin secretion and the change betwee n T2DM signaling pathway and insulin receptor substrate were further elu cidated.From Jun 2014 to Jan 2015,this study was conducted in Endocrinology Department in the First People's Hospital of Yunnan Province.65 cases of HCV infecting individuals with complete medical records were recruited and 70 cases of non-HCV infecting individuals were selected as a control group.There was no significant difference on age and gender between these two groups.The relative index of Type 2 diabetic mellitus were further ana lyzed.Of 65 HCV infection individuals,15 were suffered from T2DM(23.1%).Comparatively,this number in healthy individuals is 6 of 70(8.6%).HC V infected individuals have a high morbidity of T2DM with a higher level of blood triglycerides and interleukin-1? in type 2 diabetes patients with HCV infection.This small-scale clinical investigation has demonstrated that HCV infection and type 2 diabetes has a certain correlation.In terms of the pathogenesis of type 2 diabetes induced by HCV,we found that HCV infection can cause Min6 cell morPhology damage 0.5x 106IU/ml HCV was used to infect the Min6 cell with more than 106IU/ml copy in c?lture supernatant.In the contrast,HCV RNA copy number in supe rnants of J6/JFH-Rluc transfected Huh7.5.1 is 105IU/ml.It means that Min6 cell can be infected and HCV can efficiently replicate in Min6 cell.In order to determine the influence of HCV infection on insulin secretion,we use different glucose concentrations to stimulate the Min6 cells infected by HCV.It is found that the insulin concentration in Min6 cell supernatant is(0.24±0.035)?g/lwith non-HCV infection and non-glucose stimulatio n.However,its concentration is up to 0.654±0.043?g/lin non-HCV infectio n,but glucose stimulatio n group.With glucose stimulatio n and and lower dose of HCV(0.2×106IU/ml)infection,the supernatant concentration is 0.500±0.023?g/l.With glucose stimulatio n and high dose of HCV(0.8×106 IU/ml)infection,the supernatant concentration is 0.251 ±0.023?g/l.It is demo nstrated that HCV can suppress the incretin of insulin now that vari eties of the dealing supernatant has significant different insulin concentra tions which is gradually decreased with the increasing of HCV dose.For recent clinical researches has illustrated that T2DM patients with HCV-infection has a high level of blood IL-1?,we use varieties of IL-1? to intervene glucose-stim?1a tion Min6 cell.As a result,the insulin in the supernatant is 0.251 ±0.025?g/l with non-glucose stimulatio n,and it is 0.631±0.033?g/l f or glucose stimulation and without IL-1? content;IL-1?(0.25ng/ml)interv ened insulin concentration under glucose stimulation is 0.450±0.021 ?g/l;IL-1?(2.5ng/ml)intervened insulin concentration under glucose stimula tion is 0.211 ±0.032?g/l.There is statistical significance between each gro up(F=349.92,P<0.05).It is demonstrated that IL-1? has a inhibiting effect to insulin secretion.Which means human body can appears IL-1? level incre asing,has a inhibiting effect to insulin secretion after HCV infection.To testify the pattern of HCV inhibiting effect to insulin secretion,we investigated the molec?lar mechanism from cellular signaling pathway.HC V infecting key protein PhosPhorylation of Min6 cellular in MAPK signali ng pathway was tested.It was showed that glucose can stimulate the MAPK PhosPhorylation of Min6 cell,HCV infecting Min6 cell JNK PhosPhorylat ion co?ld be suppressed under the glucose stimulatio n.Under varieties of glucose dose stim?lating,HCV infection can reduce the cell JNK PhosPh orylate level,which is accounting for HCV has a suppressing effect to JNK pathway.Mean while,we used different concentration of IL-1? to interfere Min6 cell by MAPK signaling pathway.It was found that glucose stimulatio n can advance the PhosPhorylate level of Min6 cell ERK1/2,ERK1/2 PhosP ho rylate level can be suppressed significantly dependent by IL-1? dos e.When adding 2.5ng/ml IL-1?,ERK1/2 PhosPhorylate level can be lowe st.Comparing with that,IL-1? has a relatively small effect on JNK and P38 pathway.HCV infection can directly and indirectly damage islet cells throu gh comparing key protein PhosPhorylate signal level,accordingly affecting insulin secretion.Since insulin resistance is also one of the pathog enesis of T2D M.In this study,we found HCV infection can significantly suppress the IR S-1 when using immunofluorescence technique to observe distribution of IR S-1 in Min6 cell infected by HCV.This also happened in immunoblotting approach.It was deduced that HCV infection can decrease the insulin recep tor substrate,leading to insulin resistance.In conclusion,clinic investigation indicates that patients infected by HCV have a high morbidity of T2DM.HCV infection can significantly sup ress insulin secretion when using high dose of HCV to infect insulinoma.M eanwhile,IL-1? also can suppress insulin secretion.HCV can damage islet ce 11 through direct and indirect pathway and inhibit insulin secretion.Moreo ver,HCV infection can decrease the protein PhosPhorylate level of cell sig naling and insulin receptor substrate quantity,increasing insulin resistanc e.HCV infection can induce T2DM by injuring pancreatic ? cell and incre asing insulin resistance.Obtaining result demonstrates that HCV can lead to the pathogenesis of type 2 diabetes,this is meaningful for illuminating the T2DM pathogenesis,and provides a new thought for diabetes treatment strat egy and development of anti-diabetes drugs.