| Objective: The purpose of this study is to explore the association of Nrf2 pathway with IRS2 and pancreatic beta cell function in people who are type 2 diabetes mellitus(T2DM), prediabetes(IGR) or normal glucose tolerance. Ultimately, it provides clinical evidence on the prevention and control of beta cell dysfunction.Methods : Based on the epidemiology of evaluation of cancers in Chinese Diabetic Individuals from April to November in 2011,we screened a random sample of 900 individuals into 3 groups: normal glucose tolerance(NGT,n=300), prediabetes(IGR, n=300) and newly diagnosed type 2 diabetes mellitus(T2DM,n=300). All the participants completed a standardized questionnaire, physical examination and biochemical tests. The contents of the laboratory examination included fasting blood glucose(FBG), 2-hours postprandial glucose(2h PBG), hemoglobin A1c(Hb A1c), fasting insulin(FINS), triglyceride(TG), total cholesterol(TC), high density lipoprotein cholesterol(HDL-C) and low density lipoprotein cholesterol(LDL-C).Enzyme-linked immunosorbent assay(ELISA) kits were used to measure serum Nrf2, insulin receptor substrate 2(IRS2), hemeoxygenase 1(HO-1) and tumour necrosis factor-?(TNF-?). Islet function characteristics of different groups were investigated and the association of Nrf2 pathway with IRS2 and pancreatic beta cell function were analyzed.Results: 1.The age,FBG,2h PBG,Hb A1 c,TG,TC,LDL-C,BMI in T2 DM group were significantly higher than those in IGR and NGT group(P<0.001).And there was an increasing tendency of these indicators from NGT,IGR to T2 DM group. The WHR in T2 DM group was significantly higher than that in NGT group(P<0.001). 2.HBCI of T2 DM group was 56.49 percent and 63.17 percent as that of NGT group and IGR group respectively(F=9.29,P<0.01).FBCI in T2 DM was significantly lower than that in NGT group(P<0.05) and ISI in T2 DM group was significantly lower than that in NGT group and IGR group(F=7.936,P<0.001).HOMA-IR of T2 DM group was 1.7 times and 1.8times higher than that of NGT group and IGR group respectively(P<0.0001).3.Nrf2,IRS2,HO-1 in T2 DM group were lower than that in NGT group and IGR group, moreover, these indicators presented a decreasing trend in the groups.Conversely, there was an increasing tendency of TNF-? from NGT, IGR to T2 DM group. Difference of HO-1, TNF-? in the groups had statistical significance(P<0.01). 4.Pearson correlation analysis : Nrf2 was positively correlated with HBCI with significance(r=0.325,P<0.05) and HO-1 was positively correlated with HBCI(r=0.299,P<0.05). Furthermore, there was negatively correlation between TNF-? and HBCI(r=-0.462,P<0.01).Conclusions:1.TNF-? increased in abnormal glucose metabolism individuals. It showed that oxidative stress and inflammation enhanced. 2.TNF-? was slightly elevated and Nrf2,HO-1,IRS2 were slightly decreased in impaired glucose metabolism(IGR) while their islet function were nearly normal. The discovery prompted that Nrf2 pathway may protect beta cell function under condition of mild oxidative stress and inflammation by inducing the expressions of anti-oxidant proteins and phase ? detoxification enzyme such as HO-1,furthermore, Nrf2 pathway may improve insulin signaling pathway mediated by IRS2 through PI3K/AKT,MAPK pathway. 3.Islet function was obviously decreased in type 2 diabetes patients. TNF-? increased and Nrf2,HO-1,IRS2 decreased significantly. It demonstrated that once oxidative stress and inflammation enhanced seriously, Nrf2 activation would be abolished.Subsequently, HO-1,IRS2 decreased and islet function impaired.Objective: The purpose of this study is to explore the association of change of pancreatic beta cell function with Nrf2 pathway and IRS2 in prediabetes.Methods : The study population was 900 permanent residents who had participated in the survey three years ago: normal glucose tolerance(NGT,n=300), prediabetes(IGR, n=300) and type 2 diabetes mellitus(T2DM, n=300).We followed them up by phone calls annually without intervention. All the participants repeatedly completed the standardized questionnaire, physical examination and biochemical tests in June 2014.Results: 1.During a follow-up period of 3 years, 78 diabetes cases were diagnosed among 600 non-diabetes. The cumulative incidence of diabetes was13.0%. And the accumulative total transformation rate to DM was IGR(17.3%) > NGT(8.70%)(P<0.001). 2. Three groups were compared with clinical features before and after the follow-up: The FBG, 2h PBG, TG, LDL-C,HDL-C, SBP in NGT group were significantly higher than three years ago(P<0.05). WHR was significantly decreased(P<0.05). The TG, LDL-C, HDL-C in IGR group and 2h PBG, TG, LDL-C, HDL-C, WHR, SBP in T2 DM group were significantly higher than baseline measurement(P<0.05). After three years,the FBG, 2h PBG, Hb A1 c, TG, LDL-C, WHR, BMI gradually increased from NGT, IGR to T2 DM group while HDL-C was decreased. The indicators in T2 DM group were significantly higher than those in NGT group except BMI(P<0.001). 3. In IGR?IGR group, HBCI and FBCI were significantly decreased to 85.3% and 80.5% of baseline state. In IGR?T2DM group, HBCI was decreased to 83.2%(P<0.05). However, in IGR?NGT group, ISI and HOMA-IR improved(P<0.05). HBCI in T2 DM group was decreased to 87.3%.4. Nrf2 in IGR?IGR group decreased significantly(P<0.05). In IGR?T2DM group, Nrf2, IRS2, HO-1 decreased but TNF-? represented an increase of20.2%(P<0.05, except Nrf2). In IGR?NGT group, Nrf2, IRS2 increased,TNF-? decreased significantly(P<0.05). Furthermore, Nrf2, IRS2, HO-1 in T2 DM group were lower and TNF-? was significantly higher than that of baseline state(P<0.05, except HO-1). 5. Logistic regression analysis showed that the risk factors of ?-cell function were age, BMI, WHR, TG and TNF-?.HO-1 was a protective factor for protecting ?-cell.Conclusions:1.As prediabetes maintained to be IGR or progressed into diabetes mellitus, islet function would aggravate due to the enhanced oxidative stress and Nrf2 pathway fail to be activated. Otherwise, when prediabetes reverted to NGT, islet function would be improved by Nrf2 pathway reducing oxidative stress and inflammation. 2. As blood lipids, BMI, WHR, TNF-?, age increased, beta cell function would aggravate. HO-1 was a protective factor for protecting ?-cell function. |
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