| As a major threat for public health,type 2 diabetes has brought serious economic burden to the development of the society.Recently,type 2 diabetes has gradually developed from a rare disease to an epidemic in China.There are now approximately 110 million adults with type 2 diabetes in China.Therefore,it is important to prevent and control the increased incidence of type 2 diabetes in China.Although there are several well-established risk factors(e.g.,central obesity,high intake of refined carbohydrates,or less physical activity),an increasing number of reports suggest that chronic exposure to environmental pollutants might be associated with diabetogenesisAs a common environmental pollutant,cadmium ranks first among 12 hazardous chemicals with global significance proposed by UNEP.Because cadmium and its compounds are difficult to degrade,the level of cadmium in the environment can increase steadily.Cadmium in the environment can enter the human body through respiratory tract,digestive tract,skin contact and other ways,causing damage to different systems and organs of the body.Studies have shown that cadmium exposure can disrupt the hypothalamic-pituitary axis regulation system,cause changes in secretion patterns and levels of various hormones such as growth hormone and adrenocorticotropic hormone,and lead to disorders in the body's endocrine and metabolic system.Previous studies for associations between cadmium exposure and type 2 diabetes were mostly confined to animal experiments or occupational workers.However,cadmium exposure in the environment is more likely to affect the health of general population in a low concentration and long-term repeated manner.Therefore,it is necessary to explore the relationship between chronic cadmium exposure and incidence of type 2 diabetes in general population.The mechanism of cadmium exposure on the development of type 2 diabetes in community population is not completely clear.Studies have shown that oxidative damage and inflammation may play important roles in the pathology.Cadmium can indirectly reduce the ability of scavenging free radicals and cause oxidative damage by binding or substituting with enzymatic sulfhydryl groups.Urinary 8-hydroxydeoxyguanosine(8-OHd G)and 8-Isoprostaglandin F2?(8-iso-PGF2?)are commonly recognized as biomarkers for assessing oxidative DNA damage and lipid oxidative damage in many studies.In addition,cadmium can also induce the aggregation of neutrophils,thereby promoting macrophages to release a large number of pro-inflammatory factors,leading to inflammatory responses in the body.C-reactive protein(CRP)is often used as a sensitive marker of systemic inflammation.However,the specific biological role of oxidative damage and inflammatory response in the association between cadmium exposure and type 2 diabetes in the general population remains unclear.Based on research background,this paper aims to study the causal associations between urinary cadmium concentration and type 2 diabetes in a community population and further to explore its related mechanism.We used prospective cohort study design to establish Wuhan-Zhuhai community population cohort,collect health examination information and biological samples of population at baseline and follow-ups,measure urinary cadmium concentration,analyze the level and time variation of urinary cadmium in community population at baseline and follow-ups,and assess the sources of cadmium exposure in a community population.Based on the study population,fasting blood glucose concentration(FPG)and questionnaire data were measured to analyze the cross-sectional relationship between urinary cadmium concentration and the risk of type 2 diabetes in a community population.Longitudinal study was conducted to analyze their follow-up relationships by excluding those with baseline type 2 diabetes.Finally,the mediating mechanism of the association between urinary cadmium concentration and type 2 diabetes in a community population was further explored from oxidative damage and inflammatory reaction,by measuring the level of urinary 8-OHd G and 8-iso-PGF2?,and plasma CRP,respectively.This paper mainly includes the following three parts:Part ?.Analysis of Chronic Exposure Level and Time Variation of Cadmium and Possible Sources in A Community PopulationObjective: To study the levels and time variations of urinary cadmium in a cohort of Chinese community population,and to further explore the possible sources of cadmium exposure in a community population,thereby providing some clues for the chronic exposure of cadmium in Chinese community population.Methods: A prospective cohort(Wuhan-Zhuhai)was established in 2011-2012 and recruited local residents from communities of Wuhan and Zhuhai city by stratified cluster random sampling methods.At baseline,we collect questionnaires,health examinations and biological samples of residents.For those who have participated at baseline,we further conducted follow-up investigations every three year.Inductively coupled plasma mass spectrometry(ICPMS)was used to determine the concentration of cadmium in urine.The time variations of uncorrected cadmium concentration,creatinine-corrected cadmium concentration and specific gravity-corrected cadmium concentration were assessed by reliability model and mixed linear model.The associations of urinary cadmium concentration with smoking and dietary cadmium intake estimates were analyzed by using the mixed linear model.Results: At baseline,4055 subjects were finally incuded in the present study.The proportion of women in the total population was about 2/3,with an average age of about 52 years.The basic characteristics of 2238 subjects were similar to baseline.The median values of uncorrected urinary cadmium concentration,creatinine-corrected cadmium concentration and specific gravity-corrected urinary cadmium concentration at baseline were 1.155 ?g/L,0.096 ?g/mmol Cr and 1.164 ?g/L SG,respectively.The urinary cadmium concentrations wtih three corrected ways were 1.134 ?g/L,0.107 ?g/mmol Cr and 1.289 ?g/L SG at follow-up.The distribution of urinary cadmium at baseline and follow-up was also similar.The concentrations of urinary cadmium in the three corrected ways were all higher in women,or those aged over 55 years,BMI<24 kg/m2,smokers,non-drinkers and regular exercisers.Pearson correlation coefficients between baseline and follow-up concentrations of uncorrected urinary cadmium,creatinine-corrected cadmium and specific gravity-corrected urinary cadmium were 0.521,0.632 and 0.551,respectively.There were significant positive correlations between baseline and follow-up urinary cadmium concentrations(all P<0.001).The ICCs of uncorrected urinary cadmium,creatinine-corrected cadmium and specific gravity-corrected urinary cadmium betweent baseline and follow-up were 0.697,0.773 and 0.727(P<0.001),respectively.The ICC of creatinine-corrected cadmium concentrations even exceeded 0.75,which had a very good consistency.Therefore,we used urinary creatinine-corrected cadmium concentration as the internal exposure level of chronic cadmium exposure in subsequent analysis.In the analysis of possible sources of urinary cadmium exposure in a community population,we found that urinary cadmium concentration increased monotonously with the increase of smoking,and the positive asociation was more obvious in the population with age less than 55 years.In addition,positives associations between the estimated intake of cadmium and the urinary cadmium concentration were observed in the community population,and the correlation was stronger in the population with BMI more than 24 kg/m2(P<0.05).Conclusions: The baseline and follow-up urinary cadmium concentrations of community population were similar,and the chronic exposure to cadmium was basically stable.The time variability of urinary creatinine corrected cadmium was the smallest.Creatinine corrected urinary cadmium could be used as the best index for evaluating long-term cadmium exposure in community population.For the general population,smoking and dietary intake are the main sources of exposure.Part ?.Cross-sectional and follow-up associations of cadmium exposure with type 2 diabetes in a community populationObjective: To study the causal correlations between cadmium exposure and type 2 diabetes in a community population.Methods: Based on the results of first part,urinary cadmium was log-transformed because of their skewed distribution.The correlation between urinary cadmium concentration and the risk of prevalent type 2 diabetes was analyzed by logistic regression model.The restrictive cubic spline model was used to analyze the non-linear dose-response relationship between them.Stratified analysis was used to compare the impact of population characteristics on the interaction between them.In the follow-up correlation analysis,the dose-response associations of baseline urinary cadmium exposure with the risk of incident type 2 diabetes mellitus and the change of FPG was analyzed by logistic regression model,excluding baseline type 2 diabetes mellitus.Results: The urinary cadmium concentration(0.104 ?g/mmol Cr)of type 2 diabetes at baseline was significantly higher than that of non-type 2 diabetes(0.098 ?g/mmol Cr)(P<0.01).The subjects were divided into four groups according to urinary cadmium concentration.With the increase of urinary cadmium concentration,the prevalence of baseline type 2 diabetes showed an increasing trend.For each unit increase in log-transformed urinary cadmium,there was 94.0% [OR(95% CI)= 1.944(1.276-2.962)] increase in the risk of prevalent type 2 diabetes with ajusment for potential counfounders.Comparing with the lowest urinary cadmium concentration group Q1(OR=1),with the increase of urinary cadmium concentration group(Q2-Q4),the ORs of type 2 diabetes in baseline community population were 0.896(0.629-1.277),1.222(0.857-1.743)and 1.734(1.18-2.55),showing an increasing dose-response relationship(P<0.001).The results of restrictive cubic spline showed that the cross-sectional correlation between urinary cadmium concentration and the risk of prevalent type 2 diabetes at baseline also showed an increasing trend(P<0.05).The results of stratified analysis showed that the positive dose-response relationships between urinary cadmium concentration and prevalent type 2 diabetes was still significant in each subgroup.Moreover,smoking and urinary cadmium concentration had significant multiplicative and additive interactions with the risk of type 2 diabetes in a community population(P<0.05).The association between urinary cadmium and type 2 diabetes was stronger in smokers than in non-smokers.The 40% increased risk of type 2 diabetes in the community population was attributed to smoking and high urinary cadmium concentration.With the increase of baseline urinary cadmium exposure,the incidence of type 2 diabetes was 4.92%,6.23%,5.86% and 6.99% at follow-up,respectively.The incidence of type 2 diabetes showed an upward trend with increasing levels of urinary cadmium(P>0.05).After adjusted for potential confounders,with the increasing quartiles of baseline urinary cadmium exposure,the RRs of type 2 diabetes at follow-up were 1(reference),1.376(0.791-2.396),1.409(0.794-2.499)and 1.736(0.977-3.086),respectively,although the dose-response relationships were not significant(P>0.05).Restricted cubic spline results also showed that the association between baseline urinary cadmium exposure and RRs of type 2 diabetes was increasing(P>0.05).To further explore the effect of cadmium exposure on the development of type 2 diabetes,the results of mixed linear regression showed that,with the increase of baseline urinary cadmium exposure group,the regression coefficients(?)of FPG changes were 0(reference),0.086(-0.079-0.252),0.238(0.071-0.406)and 0.620(0.447-0.794),respectively.The dose-response relationship between them showed an increasing trend(P<0.001).Conclusions: In cross-sectional analysis,increased urinary cadmium concentration is positively associated with type 2 diabetes risk,which is more obvious in smokers.In longitudinal analysis,increased FPG changes at follow-up was induced by increasing baseline urinary cadmium exposure,but baseline urinary cadmium exposure was associated with incident type 2 diabetes risk wihout statistical significance,which may be related to the short follow-up time or limited sample sizes.Part ?.Mediating mechanism of association between cadmium exposure and type 2 diabetes in community populationObjective: This part aims to explore the mediating mechanism of association between urinary cadmium concentration and type 2 diabetes in a community population from two aspects of oxidative damage and inflammatory response.Methods: The study population was still based on the population of the cohort.Urinary 8-OHd G concentration was determined by high performance liquid chromatography-electrochemical coupling(HPLC-EDC);urinary 8-iso-PGF2?and plasma CRP concentrations were determined by enzyme-linked immunosorbent assay(ELISA).Urinary 8-OHd G and 8-iso-PGF2? and plasma CRP concentrations were log-transformed because of their skewed distribution.The relationships among urinary cadmium concentration and oxidative damage biomarkers(urinary 8-OHd G and 8-iso-PGF2?),plasma CRP content of inflammatory factors,and type 2 diabetes were studied by mixed linear regression model and logistic regression model.Mediation effect model was used to evaluate the exposure-to-outcomes,mediation-to-outcome effects and the proportion of mediation effects mediated by oxidative damage markers and inflammatory factor.Results: The concentrations of urinary 8-OHd G and 8-iso-PGF2?(median values were 74.18 nmol/mmol Cr and 0.187 ng/mmol Cr,respectively)in type 2 diabetes were higher than those in non-type 2 diabetes(median values were 60.735 nmol/mmol Cr and 60.357 ng/mmol Cr,respectively).The results of mixed linear regression showed that the correlation between urinary cadmium concentration and urinary 8-OHd G concentration in type 2 diabetic patients [?(95% CI)= 0.243(0.038-0.448)] was much higher than that in non-type 2 diabetic patients [?(95% CI)= 0.171(0.099-0.243)].Similarly,for 8-iso-PGF2?,the association between urinary cadmium concentration and urinary 8-iso-PGF2? concentration in type 2 diabetic patients [?(95% CI)= 0.322(0.183-0.461)] was higher than that in non-type 2 diabetic patients [?(95% CI)= 0.300(0.260-0.340)].Logistic regression analysis showed that the ORs(95% CI)of type 2 diabetes was 1.000(reference),1.037(0.755-1.426)and 1.039(0.760-1.421),respectively,across increasing tertiles of urinary 8-OHd G after adjusting for potential counders(P > 0.05).With the increase of urinary 8-iso-PGF2? concentration,the ORs(95% CI)of type 2 diabetes was 1.00(reference),1.123(0.809-1.56)and 1.477(1.077-2.025),respectively.The trend of dose-response relationship was significant(P<0.05).Mediation analysis showed that urinary 8-OHd G mediated 7.13% of the association between urinary cadmium and type 2 diabetes risk(P>0.05).Urinary 8-iso-PGF2? mediated 27.55% of the association between urinary cadmium and type 2 diabetes risk(P<0.05).The participants with highest urinary cadmium concentration and the highest urinary 8-OHd G concentration(or the highest urinary 8-iso-PGF2alpha concentration)had the highest risk of type 2 diabetes.The level of plasma CRP in type 2 diabetes were significantly higher than those in non-type 2 diabetes(plasma CRP: median=0.845 vs.0.334 mg/L,P<0.001).The results of mixed linear regression showed that the regression coefficients of urinary cadmium concentration and plasma CRP were 0.000(reference),0.091(0.045-0.228),0.175(0.035-0.316)and 0.174(0.019-0.328),respectively(P<0.001).For each unit increase in log-transformed plasma CRP,there was 23.3% [OR(95% CI)= 1.233(1.137-1.336)] increase in the risk of prevalent type 2 diabetes with ajusment for potential counfounders(P<0.001).Mediation effect model showed that plasma CRP mediated mediated 4.01% of the association between urinary cadmium and type 2 diabetes risk(P<0.05).The participants with highest urinary cadmium concentration and the highest plasma CRP concentration had the highest risk of type 2 diabetes.Conclusions: Lipid peroxidation damage(urine 8-iso-PGF2alpha)mediates the association between urinary cadmium concentration and the risk of type 2 diabetes;systemic inflammatory response(plasma CRP)mediates the association between urinary cadmium concentration and the risk of type 2 diabetes.Lipid peroxidation damge and inflammatory response may be involved in the risk of type 2 diabetes caused by cadmium exposure in community population. |
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