| Backgrounds:Abnormal glucose and lipid metabolism has become a major chronic metabolic disease threatening human health.Finding early predictive biomarkers and intervention targets can facilitate the prevention and treatment of abnormal glucose and lipid metabolism.The interactive regulatory network formed by aging,mitochondrial dysfunction,and oxidative stress is closely related to abnormal glucose and lipid metabolism.However,current population studies on the predictive effect of aging,mitochondrial dysfunction and oxidative stress on abnormal glucose and lipid metabolism are inconsistent.And research evidence from the Chinese population is lacking.In addition,abnormal glucose and lipid metabolism is highly heterogeneous,and risk stratification and individualized management are critical to the optimization of patient clinical outcomes.There is no research investigating the role of biomarkers of aging,mitochondrial dysfunction and oxidative stress in the risk stratification and individualized therapy for abnormal glucose and lipid metabolism.Objectives:We sought to explore the predictive role of biomarkers of aging,mitochondrial dysfunction and oxidative stress,including leukocyte telomere length(LTL),mitochondrial DNA copy number(mtDNAcn),8 deoxyguanosine(8-OHdG),superoxide dismutase(SOD),glutathione reductase(GR),tumor necrosis factor-?(TNF-?]),interleukin-6(IL-6)for risk of T2D in the Chinese population;idenfity the predictors for MS by investigating the cross-sectional association of the above-mentioned biomarkers with MS and its components,and identify the potential mediating factors;identify distinct metabotypes based on biomarkers of glucose and lipid metabolism in a Chinese natural population to construct a novel classification system,and evaluate its value for risk stratification and individualized therapy in abnormal glucose and lipid metabolism by comparing the clinical and biochemical characteristics,prevalence and incidence of cardiometabolic diseases,and exploring the its influence on the relationship of medication with biomarkers of aging,mitochondrial dysfunction and oxidative stress.Methods:All of the 3 parts of this study are originated from a Chinese natural population.1.In a prospective study including 193 non-diabetic individuals at baseline,the follow-up was performed 3-6 years later to evaluate the glucose tolerance.2.In this cross-sectional study(n=533),the clinical diagnosis of MS adopts the NCEP ATPIII(2004)standard which is adjusted according to the waist circumference of the Asian population.3.In this cross-sectional study(n=1083),based on BMI,WC,HC,TG,HDL-C,Glu-AUC,Matsuda insulin sensitivity index(ISIM)and insulin sensitivity-secretion index-2(ISSI-2),a total of 910 participants were included in the final analysis after data preprocessing,and K-means clustering was performed,and finally 3 metabotypes were obtained.For the participants in all 3 parts of the study,a 2-hour 75g oral glucose tolerance test(OGTT)were performed to determine blood glucose,insulin,and C-peptide at 0,30,60,and 120 minutes.ISIM and ISSI-2 were calculated based on the OGTT results.And dietary data were collected through a 24-hour diet questionnaire.LTL and mtDNAcn were measured by real-time qPCR,and serum 8-OHdG,SOD activity,GR activity,TNF-?,and IL-6 by detected by ELISA.Results:1.In the first part of study,the median follow-up time of the participantsis 6 years,during which 48 participants developed T2D(progressors),whereas 145 participants did not(non-progressors).Compared with the non-progressors,the progressors had shorter LTL(adjusted for age)(p=0.001)and increased TNF-?(p=0.004).After adjusting for confounders,per 1SD decrease of LTL at baseline is associated with 67.8%increase of the risk of T2D(OR for per+1SD of LTL=0.313,p=0.008).Interaction between dietary intake of riboflavin/thiamine at baseline and LTL on the risk of T2D is significant.Per 1SD decrease in LTL at baseline is associated with 71.8%increase of the risk of T2D(OR[+1SD][95%CI]=0.282[0.073,0.871],p=0.041)in the high riboflavin intake group(>0.398mg/day),whereas the association between LTL at baseline and the risk of T2D is statistically non-significance(p=0.225)in the low riboflavin intake group.The association between LTL at baseline and the risk of T2D was not statistically significant(p=0.503)in the high thiamine intake group(>0.705 mg/d),whereas per 1SD decrease in LTL at baseline is associated with 45.9%increase of the risk of T2Din the low thiamine intake group(OR[+1SD][95%CI]=0.282[0.012,0.595],p=0.046).2.In the second part of the study,286(53.7%)participants were diagnosed as MS(MS group),and 247(46.3%)participants were in non-MS group.The serum SOD activity of the MS group was significantly lower than that of the non-MS group(p=0.001).And with the increase in the number of MS components,the serum SOD activity showed a linear downward trend(p=0.031).After adjusting for the potential confounders,serum SOD activity was still independently correlated with MS(OR[95CI%]0.750[0.576-0.978],p=0.034).Mediating effect analysis showed that the both indirect effect and direct effect was significant in the association between SOD activity and MS.3.In the third part of this study,the sample sizes of Cluster 1,2 and 3 are 257(28.2%),300(33.0%)and 353(38.8%),respectively.Cluster 1 is characterized with abnormal glucose metabolism combined with decreased ?-cell function;Cluster 2 is characterized with obesity,abnormal lipid metabolism and insulin resistance;Cluster 3 is characterized as the "healthiest" metabotype.Cluster 3 has the lowest prevalence and incidence of metabolic diseases;Cluster 1 has the highest prevalence of T2D(p<0.001),whereas the prevalence of HTN and dyslipidemia in Cluster 1 and 2 were higher than that in Cluster 3(both p<0.001).Cluster 2 had the highest prevalence of prevalence of hyperuricemia(p=0.014)and the highest prevalence of NAFLD(p<0.001).The incidence of T2D and HTN in Cluster 1 and 2 was significantly higher than that in Cluster 3(p<0.001;p=0.004).After adjusting for age,BMI,and HbAlc,the serum IL-6 levels of T2D patients who did not use metformin or ?-glycosidase inhibitors in Cluster 2 were significantly higher than T2D patients under the treatment of metformin(Adjusted p=0.001)or ?-glycosidase inhibitors(Adjusted p=0.004),whereas the difference was abolished in Cluster 1.After adjusting for gender,age,BMI and HbAlc,mtDNAcn and ISIM in Cluster 2 and Cluster 3 were significantly,positively correlated(Cluster 2:R=0.24,p=0.003;Cluster 3:R=0.19,p=0.003),whereas the association between mtDNAcn and ISIM was abolished in Cluster 1(R=-0.01,p=0.94).Conclusions:1.LTL shortening could independently predict increased 6-year risk of T2D.Increased dietary riboflavin intake or decreased dietary thiamine intake might amplify the promoting effect of LTL shortening on the development of T2D.2.Decreased serum SOD activity can independently predict an increase in TG and the existence of MS.Decreased insulin sensitivity and ?-cell dysfunction may jointly and partially mediate the development of MS caused by decreased SOD activity.3.Based on 8 glucose and lipid metabolism variables,we constructed a novel classification system for abnormal glucose and lipid metabolism by identifying 3 metabotypes in the Chinese population,and found significantly different clinical features,prevalence and incidence of various metabolic diseases among metabotypes.Furthermore,we observed that metformin or ?-glucosidase inhibition exerted significantly different inhibitory effect on IL-6 in T2D patients in different metabotypes.Additionally,metabotypes significantly influenced the association between mtDNAcn and insulin sensitivity.These findings suggest that metabotypes could provide novel insight in the risk stratification of metabolic diseases and individualized therapy in the Chinese population.Backgrounds:Finding early predictive biomarkers and prevention targets for T2D can facilitate the prevention for T2D.The biomarkers of aging,mitochondrial dysfunction and oxidative stress closely related to aging may provide early predictive biomarkers and early prevention targets for T2D.However,nowadays there are few prospective investigations exploring the longitudinal relationship between these biomarkers and the risk of T2D,having yielded inconsistent results.And the evidence from the Chinese population is lacking.Objectives:In this prospective investigation,we sought to explore the predictive role of biomarkers of aging,mitochondrial dysfunction and oxidative stress,including LTL,mtDNAcn,8-OHdG,SOD,GR,TNF-?,IL-6 for risk of T2D in the Chinese population,and further investigate the effects of dietary intake of nutritional components on the association between these markers and risk of T2D.Methods:A total of 193 non-diabetic individuals at baseline were included into this study and the follow-up was performed 3-6 years later.At baseline and follow-up,a 2-hour 75g OGTT were performed to determine blood glucose,insulin,and C-peptide at 0,30,60,and 120 minutes.ISIM and ISSI-2 were calculated.And dietary data were collected through a 24-hour diet questionnaire.At baseline,LTL and mtDNAcn were measured by real-time qPCR,and serum 8-OHdG,SOD,GR,TNF-?,and IL-6 by detected by ELISA.Results:1.The median follow-up time of the participants(n=193)is 6 years,during which 48 participants developed T2D(progressors),whereas 145 participants did not(non-progressors).Compared with the non-progressors,the progressors were characterized with male predominance(p=0.002),older age(p=0.003),higher proportion of obesity and overweight(p=0.011)and prediabetes(p<0.001),higher level of UA(P<0.001),lower level of HDL-C(p=0.034),higher level of HbAlc and plasma glucose at each time of OGTT(p<0.01),lower ISIM(p=0.019),ISSI-2(p<0.001),and oDI-30(p<0.001),shorter LTL(adjusted for age)(p=0.001)and increased TNF-?(p=0.004).2.After adjusting for confounders,TNF-? at baseline is independently associated with FPG(r=0.23,p<0.001),HOMA2-IR(r=0.21,p=0.003),ISIM(r=-0.23,p=0.034),ISSI-2(r=-0.26,p<0.001)and oDI-30(r=-0.33,p<0.001)at 6-year follow-up;Per 1SD decrease of LTL at baseline is associated with 67.8%increase of the risk of T2D(OR for per+1SD of LTL=0.313,p=0.008).3.The interaction between dietary intake of riboflavin/thiamine at baseline and LTL on the risk of T2D is significant.Per 1SD decrease in LTL at baseline is associated with 71.8%increase of the risk of T2D(OR[+1SD][95%CI]=0.282[0.073,0.871],p=0.041)in the high riboflavin intake group(>0.398mg/day),whereas the association between LTL at baseline and the risk of T2D is statistically non-significance(p=0.225)in the low riboflavin intake group.The association between LTL at baseline and the risk of T2D was not statistically significant(p=0.503)in the high thiamine intake group(>0.705 mg/d),whereas per 1 SD decrease in LTL at baseline is associated with 45.9%increase of the risk of T2D in the low thiamine intake group(OR[+1SD][95%CI]=0.282[0.012,0.595],p=0.046).Conclusions:TNF-? could be an independent predictor of fasting blood glucose,insulin sensitivity,and pancreatic ?-cell function 6 years later.LTL shortening could independently predict increased 6-year risk of T2D.Increased dietary riboflavin intake or decreased dietary thiamine intake might amplify the promoting effect of LTL shortening on the development of T2D.Backgrounds:Aging,mitochondrial dysfunction and oxidative stress are closely related to MS;however,the results of population studies investigating the association of aging,mitochondrial dysfunction and oxidative stress biomarkers with MS are inconsistent,most of which were conducted in Western populations.And there were few data on the Chinese population.Considering that there exist some differences in body size and glucose as well as lipid metabolism between the Chinese population and other populations,and the cut-off points used in the diagnostic criteria for MS are also different,it remains to be validated whether the results of other populations is applicable to the Chinese population.In addition,previous studies did not adjust the important potential confounders including the interaction between aging,mitochondrial dysfunction and oxidative stress biomarkers and dietary intake of nutrients.Objectives:We aimed to idenfity the indepent predictors for MS by investigating the cross-sectional association of LTL,mtDNAcn,8-OHdG,SOD and GR with MS and its components,adjusting for the mutual influence of aging,mitochondrial dysfunction and oxidative stress biomarkers,and dietary intake of nutritients.Methods:In this cross-sectional study(n=533),a 2-hour 75g oral glucose tolerance test(OGTT)were performed to determine blood glucose,insulin,and C-peptide at 0,30,60,and 120 minutes.ISIM and ISSI-2 were calculated.And dietary data were collected through a 24-hour diet questionnaire.LTL and mtDNAcn were measured by real-time qPCR,and serum 8-OHdG,SOD,GR,TNF-?,and IL-6 by detected by ELISA.The clinical diagnosis of MS adopts the NCEP ATPIII(2004)standard which is adjusted according to the waist circumference of the Asian population.Results:1.Among 533 participants(34.5%males,aged 18-90 years old),286(53.7%)participants were diagnosed as MS(MS group),and 247(46.3%)participants were in non-MS group.Compared with the non-MS group,the MS group was characterized with male predominance,older age,higher BMI,WC,HC,SBP,DBP,HbAlc,plasma glucose at each time point of OGTT,UA,TG,LDL-C,HOMA-IR,and lower HDL-C,ISIM and ISSI-2(all p<0.01).The serum SOD activity of the MS group was significantly lower than that of the non-MS group(p=0.001).And with the increase in the number of MS components,the serum SOD activity showed a linear downward trend(p=0.031).2.After adjusting for the potential confounders(gender,age,BMI,WC,SBP,DBP,HbA1c,OGTT,blood glucose,UA,HDL-C,LDL-C,ISIM,ISSI-2,dietary intake of nutrients[total calories,fat,Vitamin A,vitamin C,vitamin E,zinc,selenium,manganese],and other biomarkers of aging,mitochondrial dysfunction and oxidative stress),serum SOD activity was still significantly negatively correlated with level of TG(r=-0.30,p<0.001).3.After adjusting for the above-mentioned confounders,serum SOD activity was still independently correlated with MS(OR[95CI%]0.750[0.576-0.978],p=0.034).Mediating effect analysis showed that the both indirect effect and direct effect was significant in the association between SOD activity and MS.Conclusions:Decreased serum SOD activity can indepently predict an increase in TG and the existence of MS.Decreased insulin sensitivity and ?-cell dysfunction may jointly and partially mediate the development of MS caused by decreased SOD activity.Backgrounds:For individuals with different metabolic features,risk of cardiometabolic diseases individuals and reponse to intervention measures could vary substantially.Therefore,it is important to perform risk stratification to identify high-risk groups and give targeted treatment strategies according to treatment responds in order to optimize the clinical outcome of patients.The basic definition of metabotype is to separate the population into multiple subgroups according to metabolic or phenotypic features.In recent years,studies have initially shown that metabotype has potential for the risk stratification of metabolic diseases to identify high-risk groups and those who may benefit more from interventions.However,almost all the studies are from Western populations,whereas data from Chinese populations are still lacking.Objectives:We aimed to identify distinct metabotypes based on clinical and biochemical variables closely related to the pathogenesis of cardiometabolic diseases in a Chinese natural population,and compare the lifestyle,clinical and biochemical characteristics,prevalence and incidence of cardiometabolic diseases,as well as aging,mitochondrial dysfunction and oxidative stress biomarkers among metabotypes.Furthermore,we sought to explore the influence of metabotypes on the relationship between medication and biomarkers of aging,mitochondrial dysfunction and oxidative stress.Methods:In this cross-sectional study(n=1083),a 2-hour 75g oral glucose tolerance test(OGTT)were performed to determine blood glucose,insulin,and C-peptide at 0,30,60,and 120 minutes.ISIM and ISSI-2 were calculated.And dietary data were collected through a 24-hour diet questionnaire.LTL and mtDNAcn were measured by real-time qPCR,and serum 8-OHdG,SOD,GR,TNF-?,and IL-6 by detected by ELISA among 565 participants.Based on BMI,WC,HC,TG,HDL-C,Glu-AUC,ISIM,ISSI-2,a total of 910 participants were included in the final analysis after data preprocessing,and K-means clustering was performed,and finally 3 metabotypes were obtained.Results:1.The significantly different distribution of clustering variables among metabotypes:Cluster 1 is characterized with abnormal glucose metabolism combined with decreased ?-cell function;Cluster 2 is characterized with obesity,abnormal lipid metabolism and insulin resistance;Cluster 3 is characterized as the "healtiest" metabotype.2.The significantly different clinical and biochemical features among metabtypes:The sample sizes of Cluster 1,2 and 3 are 257(28.2%),300(33.0%)and 353(38.8%),respectively.Cluster 1 is characterized with the highest proportion of male,the oldest age,and the highest proportion of regular exercise,the highest plasma glucose during OGTT,Glu-AUC,HbAlc,ACR,BUN,and serum ferritin,and the lowest HOMA2-beta,ISSI-2,and oDI-30;Cluster 2 is characterized with the highest BMI,proportion of obesity,WC,HC,WHR,basal metabolic rate,body age,body fat ratio,visceral index,visceral fat index,SBP,DBP,hepatic insulin resistance index,UA,TG,TG/HDL,hsCRP,the lowest ISIM,ApoA1;all the clinical and biochemical parameters of Cluster 3 are in the "healthiest".3.The significantly different prevalence and incidence of metabolic diseases among metabotypes:Cluster 3 has the lowest prevalence and incidence of metabolic diseases;Cluster 1 has the highest prevalence of T2D(p<0.001),whereas the prevalence of HTN and dyslipidemia in Cluster 1 and 2 were significantly higher than that in Cluster 3(p<0.001).The prevalence of hyperuricemia in Cluster 2 was significantly higher than that in Clusters 1 and 3(p=0.014).Cluster 2 had the highest prevalence of NAFLD,whereas Cluster 3 had the lowest(p<0.001).The incidence of T2D and HTN in Cluster 1 and 2 was significantly higher than that in Cluster 3(p<0.001;p=0.004).4.Differences in aging,oxidative stress and inflammatory biomarkers among metabotypes:Serum TNF-? and SOD were significantly different among metabotypes(p=0.029;p=0.004).The TNF-? of Cluster 1 was significantly higher than that of Cluster 3(Adjusted p=0.031),whereas the SOD activity of Cluster 2 was significantly lower than that of Cluster 3(Adjusted p=0.004).5.Different responses to oral hypoglycemic agents of T2D patients in different metabotypes:After adjusting for age,BMI,and HbA1c,the serum IL-6 levels of T2D patients who did not use metformin or a-glycosidase inhibitors in Cluster 2 were significantly higher than T2D patients under the treatment of metformin(Adjusted p=0.001)or a-glycosidase inhibitors(Adjusted p=0.004),whereas the difference was abolished in Cluster 1.6.The influence of metabotypes on the association of aging,oxidative stress and inflammatory biomarkers with clinical variables:Subgroup analysis(adjusted for gender,age,BMI,and HbA1c)stratified by metabotypes found that mtDNAcn and ISIM in Cluster 2 and Cluster 3 were significantly,positively correlated(Cluster 2:R=0.24,p=0.003;Cluster 3:R=0.19,p=0.003),whereas the association between mtDNAcn and ISIM was abolished in Cluster 1(R=-0.01,p=0.94).Conclusions:This study identified 3 metabotypes based on 8 variables in the Chinese population,and found significantly different clinical features,prevalence and incidence of various metabolic diseases among metabotypes.Furthermore,we observed that metformin or ?-glucosidase inhibition exerted significantly different inhibitory effect on IL-6 in T2D patients in different metabotypes.Additionally,metabotypes significantly influenced the association between mtDNAcn and insulin sensitivity.These findings suggest that metabotypes could provide novel insight in the risk stratification of metabolic diseases and individualized therapy in the Chinese population. |
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