Environmental Research 192 (2021) 110259

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Environmental Research
journal homepage: www.elsevier.com/locate/envres

Cadmium exposure, fasting blood glucose changes, and type 2 diabetes

mellitus: A longitudinal prospective study in China
Lili Xiao a, b, Wei Li a, b, Chunmei Zhu a, b, Shijie Yang a, b, Min Zhou a, b, Bin Wang a, b,
Xing Wang a, b, Dongming Wang a, b, Jixuan Ma a, b, Yun Zhou a, b, Weihong Chen a, b, *
a
Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei,
430030, China
b
Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health
(Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Cadmium is a recognized human carcinogen, raising global concern for its ubiquitously environ­
Cadmium exposure mental exposure on public health. Diabetogenic effects of cadmium have been suggested in previous studies, but
Fasting blood glucose the longitudinal associations of chronic cadmium exposure with fasting blood glucose changes and type 2 dia­
Type 2 diabetes mellitus
betes mellitus have not been fully elucidated.
Prospective study
Objective: To investigate the effects of long-term cadmium exposure on the fasting blood glucose changes and
type 2 diabetes mellitus risk in a longitudinal prospective study of China.
Methods: A total of 3521 urban adults were included as baseline study population from the Wuhan-Zhuhai cohort,
and followed up three years later. Urinary cadmium concentrations were determined repeatedly during the
follow-up of a three-year period. The within-person and between-person variability of urinary cadmium con­
centrations over three years was estimated using multilevel random-effects mixed models. Multivariate regres­
sion models were performed to evaluate the associations of cadmium exposure with fasting blood glucose
changes and type 2 diabetes mellitus risk.
Results: The geometric means of creatinine-corrected urinary cadmium concentration at baseline were 1.13 μg/g
creatinine, which were close to the levels of follow-up (1.14 μg/g creatinine). The intra-class correlation coef­
ficient of creatinine-corrected urinary cadmium concentrations was 0.71, achieving good reproducibility of
cadmium over three years. With adjustment for potential confounders, each one-unit increase in log10-
transformed cadmium was associated with a 0.11 (95%CI: 0.03 to 0.19) elevation in fasting blood glucose
concentration, and was associated with a 42% (95%CI: 1.16 to 1.73) increase in risk of prevalent type 2 diabetes
mellitus. Upward trends of fasting blood glucose changes and type 2 diabetes mellitus incidence were observed
with increasing cadmium exposure. Individuals with the highest urinary cadmium exposure had a significant
increase in fasting blood glucose change at follow-up [β (95% CI): 0.49 (0.31–0.67)]. Risk of incident type 2
diabetes mellitus were gradually elevated across increasing quartiles of cadmium exposure, though associations
did not reach statistical significance (P = 0.15).
Conclusions: Our findings suggested that relatively high chronic cadmium exposure for general population adults
might contribute to elevated changes of fasting blood glucose resulting in the development of type 2 diabetes
mellitus.

1. Introduction release large amounts of Cd into the air, water, and soil (Faroon et al.,
2012; Xu and FMMJMiils, 2013). Since Cd and its compounds are
As a recognized human carcinogen, cadmium (Cd) is ubiquitously difficult to be degraded, environmental exposure of Cd constantly
present in the environment. Both natural and anthropogenic activities accumulated in our body through the contaminated environment,

* Corresponding author. Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College Huazhong, University of Science
and Technology Wuhan, Hubei, 430030, China.
E-mail address: wchen@mails.tjmu.edu.cn (W. Chen).

https://doi.org/10.1016/j.envres.2020.110259
Received 14 June 2020; Received in revised form 17 September 2020; Accepted 18 September 2020
Available online 28 September 2020
0013-9351/© 2020 Elsevier Inc. All rights reserved.
L. Xiao et al.
leading to increased toxic effects in respiratory, circulating, endocrine,
kidney and skeletal system (Faroon et al., 2012; Fowler, 2009; Young
and Cai, 2020). It has been reported that Cd can disrupt the regulation
system of the hypothalamic-pituitary axis, resulting in alterations of
hormones secretion and disorders of endocrine systems (Xu and
FMMJMiils, 2013; Buha et al., 2018). There has been more attention to
the diabetogenic effects of widely environmental Cd exposure, partly
due to the increasing prevalence of type 2 diabetes mellitus (T2DM).
With changing dietary habits and a secondary lifestyle, nowadays T2DM
has become a growing global public health problem (Hu, 2011). In
China, the number of T2DM individuals has dramatically increased,
approximately affecting 113.9 million Chinese adults in 2010 (Xu et al.,
2013).
Accumulating evidence has suggested that Cd exposure is increas­
ingly recognized as the driving force of T2DM8-10 Lei et al., 2007; Menke
et al., 2016; Son et al., 2015. Animal studies suggested that injecting a
certain dose of Cd into mice can affect the metabolic balance of carbo­
hydrates, resulting in an increase in the blood glucose concentration (Lei
et al., 2007). In humans, the relationship between Cd and T2DM has
been extensively studied among occupational workers and susceptible
populations such as pregnant women, which are limited to be general­
ized for the general population adults (Liu et al., 2016, 2018; Xing et al.,
2018). Comparatively, few studies were conducted in the general pop­
ulation to assess the association between Cd exposure and risk of T2DM,
and the results of which have not been consistent. For example, Schwarz
et al. conducted a cross-sectional study among the United States adults,
and demonstrated high urinary Cd concentration contributed to a higher
risk of T2DM14 Schwartz et al., 2003. Barregard and his colleagues
conducted a prospective study in a cohort of 244 older women and found
no significant associations between blood and urinary Cd concentration
and risk of incident T2DM15 Barregard et al., 2013. It is worthwhile to
note that internal concentrations of Cd exposure may vary between in­
dividuals because of diverse exposure levels, routes, and duration. It is
reported that blood Cd only reflects the recent exposure of Cd, while
urinary Cd is proportional to the total body burden (Faroon et al., 2012;
Åkesson et al., 2014). Possibly due to variations in research design,
study population characteristics, individual Cd exposure assessment,
previous studies do not fully address whether the body burden of Cd
contributes to the increased risk of T2DM, which is still in more
exploration.
In the present study, we conducted a longitudinal prospective study
among a community-based population in China. Urinary Cd concen­
trations were measured repeatedly over three years to test the repro­
ducibility of urinary Cd concentrations. We examined the associations
between urinary Cd, fasting blood glucose changes, and T2DM among
general population adults during a follow-up of three years.
2. Methods
2.1. Study population
The study population is derived from the Wuhan-Zhuhai cohort
study, a community-based prospective study of urban adults in China. It
has been described in detail previously (Song et al., 2014). In brief, the
cohort was established in 2011–2012 and followed-up every three years.
A total of 4812 local adults recruited from randomly selected commu­
nities in Wuhan and Zhuhai cities at baseline. For each investigation,
data on socio-demographic characteristics, health conditions, and life­
style were obtained with a standardized questionnaire interviews at
baseline, which were tracked and updated at follow-ups. Doctors con­
ducted physical examinations for each participant, and collected
morning spot urine samples and fasting blood after an overnight fast.
With an exclusion of individuals who failed to complete the required
health examination (n = 131), lacked sufficient urine for urinary bio­
markers assay (n = 761), and had the level of urinary creatinine lower
than 0.3 g/L or higher than 3.0 g/L (n = 399), we finally included 3521
2
Environmental Research 192 (2021) 110259
participants as baseline study population. For longitudinal analysis, we
further excluded participants with T2DM at baseline (n = 303), and
those who failed to be followed up (n = 901) or failed to provide enough
biological samples for biomarkers determination (n = 557), and a total
of 1760 subjects were finally included. The study procedure was
approved by the Ethics Committee of Tongji Medical College, Huazhong
University of Science and Technology. All participants gave their written
informed consent.
2.2. Ascertainment of covariates
Data on gender (male/female), age (years), body mass index (BMI),
education (primary school or below/middle school/high school and
above), smoking status (current/former/never), drinking status (cur­
rent/former/never), physical activity (yes/no) were collected through
structured questionnaire. BMI was calculated as the ratio of body weight
divided by the square of height (kg/m2). We identified current smokers
and alcohol drinkers as smoking ≥1 cigarette/day or drinking ≥1 time/
week over the last six months, respectively; former smokers and drinkers
were those who quitted smoking or drinking for more than half a year,
respectively. Regular physical activity was identified as regularly exer­
cising >20 min per day and >2 days/week for more than half a year.
2.3. Definition of prevalent T2DM and incident T2DM
According to the criteria recommended by the American Diabetes
Association, we diagnosed following participants as prevalent T2DM at
baseline: (1) individuals who reported having a history of diabetes with
regular hospital diagnosis; (2) individuals who took anti-diabetic med­
ications such as insulin and hypoglycemic drugs; (3) individuals who
had the level of FBG≥7.0 mmol/L (Assoc, 2014). In addition, plasma
hemoglobin A1c (HbA1c) ≥ 6.5% was also employed as a diagnostic
criterion of T2DM in sensitivity testing where we measured HbA1c in
subjects with a self-reported diagnosis of T2DM. For longitudinal anal­
ysis, incident cases of T2DM were identified at the follow-up of three
years with the above criteria among the participants who had not
diagnosed as T2DM at baseline.
2.4. Determination of urinary Cd levels
The concentrations of Cd in urine samples were measured using
inductively coupled plasma-mass spectrometry (ICP-MS, Agilent 7700X
series, USA), which was previously described (Heitland and Koster,
2006). A 3-mL aliquot was extracted from each urine sample and
nitrated using 65% HNO3 overnight at 4 ◦ C. The urine samples were
brought to room temperature for balance and vibrated using ultrasound
for at least half an hour. Then 1-mL of each sample was diluted with
1.2% HNO3 and injected into ICP-MS for detection. The quality control
was performed by the Standard Reference Material (SRM2670a and
SRM1640a, Gaithersburg, MD, USA) to test the method accuracy and
instrument stability. The accuracy of urinary Cd measurement was
estimated using SRM2670 at two concentrations. Determination of
SRM2670a agreed well with certified values of urinary Cd in parallel
with samples. The mean results of Cd by the assay were 0.009 μg/L
(certified: 0.01 μg/L) and 0.146 μg/L (certified: 0.15 μg/L) at low and
high concentrations of SRM2670a. The uncertainty between certified
and measured urinary Cd concentrations were above zero, indicating no
significant difference between certified and measured urinary Cd con­
centrations according to the method by Linsinger reported (Linsinger,
2005). Additionally, SRM1640a was measured and assured in agree­
ment with the certified concentration every 20–25 samples before sub­
sequent sample assay. The relative standard deviation (RSD) of
duplicated analyses for urinary Cd concentration in each sample were
calculated and the sample was re-determined if the RSD was greater
than 10%. The LOD (the limits of detection) were determined in blanks
samples and the concentrations of urinary Cd for all the participants in
L. Xiao et al.
the study were above the LOD (0.0006 μg/L). Urinary creatinine con­
centrations were determined with a commercial test kit (Mindray CREA
Kit, Shenzhen, China) and used to calibrate urinary Cd for urine di­
lutions. Creatinine levels have significant implications for urinary bio­
logical monitoring measurements, and the WHO recommends that a
sample should not be included as the calibrated unit if too diluted (<0.3
g/L) or concentrated (>3.0 g/L) (Barr et al., 2005). We excluded those
participants in the subsequent analysis and the adjusted creatinine uri­
nary Cd concentrations were expressed as μg/g creatinine.
2.5. Statistical analysis
The demographic characteristics of all participants were reported as
frequencies (percentages) and means (standard deviation) by quartiles
of urinary Cd concentration. Reproducibility of urinary Cd concentra­
tion measured repeatedly during a period of three years was estimated
using multilevel random-effect models to assess the intra-class correla­
tion coefficients (ICCs). The ICCs, the ratio of the between-person
variance divided by the total variance, were computed based on
within-person and between-person variation. The range of the ICCs is
from 0 to 1, where 0 denotes the poorest reproducibility and 1 denotes
the highest reproducibility. Due to skewed distributions of urinary Cd
concentration, we performed a logarithmic (log10) conversion of uri­
nary Cd. Due to potential correlations between covariates, we adopted
the least absolute shrinkage and selection operator (LASSO) penalized
regression model to identify important and independent predictors of
urinary Cd from gender, age, BMI, education, smoking status, drinking
status, and physical activity. In the LASSO regression model, the co­
efficients of some variables were shrinked towards exact zeros in a
sparser model with the optimal λ and the other important predictors
were selected out of these correlated variables.
For cross-sectional analysis, we assessed the regression coefficients
(β) and 95% confidence interval (CI) of FBG and odds ratio (ORs) of
T2DM across urinary Cd concentration quartiles using mixed effect
linear and logistic regression models with residence as a random effect.
To control potential confounding, models were adjusted for gender, age,
BMI, education, smoking status, drinking status, physical activity, and
family history of diabetes. To examine the dose-response trajectory for
nonlinearity or shape of urinary Cd with FBG and prevalent T2DM at
baseline, we performed restricted cubic regression models with penal­
ized spline using non-parametric smoothers, which overcomes the
inherent limitations of categorical analyses. Models were performed
with three knots set at the 5th, 50th, and 95th percentile, with the
reference value placing in the 10th percentiles of log10 transformed
urinary Cd. Stratified analysis was conducted to examine whether the
links of urinary Cd concentrations with T2DM risk is modified by po­
tential confounding factors through multiple mixed models, including
gender (male/female), age (<55 and ≥ 5 years), BMI (<24 and ≥ 24 kg/
m2), cigarette smoking (yes and no), alcohol drinking (yes and no), and
physical activity(yes and no). The test of interaction effect was calcu­
lated by modeling a multiplicative term between urinary Cd concen­
tration and the stratification factor.
For longitudinal analysis, changes of FBG at follow-up were esti­
mated as the difference between follow-up and baseline FBG (follow-up
FBG level - baseline FBG level). Regression coefficients of FBG changes
associated with baseline urinary Cd concentration were estimated using
linear mixed regression models and risk ratios (RRs) of incident T2DM
were calculated using logistic mixed regression models, with adjustment
for the above potential confounders. Restricted cubic regression models
with penalized spline were also used to assess the longitudinal dose-
response trajectory of urinary Cd with FBG changes and incident
T2DM at follow-up. We also conducted stratified analysis for the inter­
action of baseline Cd and stratification characteristics on the risk of
T2DM incidence. All data analyses were performed using Statistical
Analysis Software (SAS), version 9.1 (SAS Institute, Cary, N.C.).
3
Environmental Research 192 (2021) 110259
3. Results
3.1. General characteristics of the study population
Table 1 shows the baseline characteristics of 3521 participants by
quartiles of urinary Cd concentration. The percentage of female, less
educated, and physical activity, as well as the values of age all signifi­
cantly increased across increasing quartiles of urinary Cd (P < 0.05),
whereas BMI and number of cigarette smokers and alcohol drinkers
decreased with increasing urinary Cd concentrations(P < 0.05). No
significant difference was observed in the family history of T2DM across
quartiles of urinary Cd (P > 0.05). We performed a sensitivity analysis
by comparing the general characteristics of baseline participants with
those at follow-up and found no significant differences (shown in
appendices Table A1).
3.2. Reproducibility of urinary Cd concentrations between baseline and
follow-up
The correlations of urinary Cd concentrations between baseline and
follow-up were presented in Table 2. The geometric means of uncor­
rected and creatinine-corrected urinary Cd concentration at baseline
were 1.33 μg/L and 1.13 μg/g creatinine, which were close to the levels
of follow-up (1.31 μg/L and 1.14 μg/g creatinine). The ICCs of uncor­
rected and creatinine-corrected urinary Cd concentrations were 0.64
and 0.71, respectively, indicating good reproducibility (ICC >0.50) for
urinary Cd concentrations between baseline and follow-up. The ICCs of
creatinine-corrected urinary Cd concentrations has even surpassed 0.70,
achieving excellent reproducibility. Therefore, we adopted creatinine-
corrected urinary Cd concentrations as internal biomarkers of long-
term Cd exposure in subsequent analysis. The median value of
creatinine-corrected urinary Cd concentration at baseline was 0.91 μg/g
creatinine, ranging from 0.53 to 1.76 μg/g creatinine. Additionally, the
results of associations between urinary Cd and related covariates
showed that gender, age, BMI, education, smoking status, drinking
status, and physical activity were all selected as predictors of urinary Cd,
where gender, education, and current smoking were the three most
important predictors (shown in appendices Table A2 and Fig.A1).
3.3. Cross-sectional associations of urinary Cd and with FBG and T2DM
prevalence at baseline
A total of 303(8.6%) participants were identified with T2DM. As the
urinary Cd level gradually increased, FBG concentration and T2DM
prevalence showed upward trends. Significantly positive associations
were observed for urinary Cd level with FBG concentration, as well as for
urinary Cd level and T2DM prevalence (all P trend values < 0.05, pre­
sented in Table 3). Potential confounders were significantly associated
with urinary Cd and FBG and T2DM (shown in appendices Table A3),
and the adjusted β (95% CI) of FBG across increasing quartiles of urinary
Cd were 0.03(-0.12 to 0.18), 0.11(-0.05 to 0.26), and 0.22(0.05–0.40),
respectively. The adjusted ORs and 95% CI for prevalent T2DM were
0.86 (0.60–1.25), 1.20 (0.83–1.73), and 1.76 (1.18–2.61), respectively,
across increasing quartiles of urinary Cd. In continuous models, each
one-unit increase in log10-Cd level was related to a 0.11 (95%CI: 0.03 to
0.19) elevation in FBG concentration, and a 42% (95%CI: 1.16 to 1.73)
increase in the risk of prevalent T2DM. Additionally, upward dose-
response associations for FBG and T2DM prevalence with increasing
urinary Cd concentrations were also evident in the restricted cubic
spline (Fig. 1, P < 0.05).
Stratified analysis showed that the positive exposure-responsive as­
sociations of urinary Cd with T2DM prevalence were consistently found
in subgroups of gender, age, BMI, cigarette smoking, alcohol drinking,
and physical activity (shown in Table 4). We found that cigarette
smoking significantly modified the association of urinary Cd with T2DM
prevalence, and the increased risk of prevalent T2DM associated with
L. Xiao et al. Environmental Research 192 (2021) 110259

Table 1
General characteristics of study population at baseline (N = 3521).
Characteristics All participants Quartiles of urinary Cd concentration (μg/g creatinine) P for trenda

Q1(<0.53) Q2 (0.53–0.85) Q3 (0.85–1.42) Q4 (≥1.42)

No. 3521 880 880 880 881

Female, n (%) 2435(69.2) 465(52.8) 602(68.4) 629(71.5) 739(83.9) <0.01
Age (years) 52.2 ± 12.8 49.6 ± 15.1 52.2 ± 12.7 53.1 ± 12.2 54.2 ± 10.2 <0.01
BMI (kg/m2) 24.0 ± 3.5 24.4 ± 3.7 24.1 ± 3.3 23.9 ± 3.4 23.7 ± 3.4 <0.01
Education, n (%)
Primary school or below 893(25.4) 133(15.1) 196(22.3) 243(27.6) 321(36.4) <0.01
Middle school 2192(62.3) 579(65.8) 560(63.6) 553(62.8) 500(56.8)
High school or beyond 436(12.4) 168(19.1) 124(14.1) 84(9.5) 60(6.8)
Cigarette Smoking category, n (%)
Current 548(15.6) 139(15.8) 152(17.3) 157(17.8) 100(11.4)
Former 177(5) 70(8) 47(5.3) 35(4) 25(2.8) <0.01
Never 2796(79.4) 671(76.2) 681(77.4) 688(78.2) 756(85.8)
Alcohol drinking category, n (%)
Current 489(13.9) 181(20.6) 134(15.2) 115(13.1) 59(6.7)
Former 101(2.9) 31(3.5) 35(4) 19(2.2) 16(1.8) <0.01
Never 2931(83.2) 668(75.9) 711(80.8) 746(84.8) 806(91.5)
Regular physical activity, yes, n (%) 1062(30.2) 242(27.5) 248(28.2) 258(29.3) 314(35.6) <0.01
Family history of T2DM, yes, n (%) 226(6.4) 70(8) 63(7.2) 45(5.1) 48(5.4) 0.09

Abbreviations: T2DM, type 2 diabetes mellitus; BMI, body mass index; Cd, cadmium; Q, quartile. Data were presented as the frequency (percentage) for categorical
variables, and mean ± SD for continuous variables.
a
P for trend was conducted by assigning the median value to each quartile of urinary Cd concentration and treated as a continuous variable.

3.4. Longitudinal associations of urinary Cd and with FBG changes and

Table 2
T2DM incidence at follow-up
Reproducibility of urinary Cd levels at baseline and follow-up (N = 1760).
Urinary Cd concentration Measure at baseline Measure at follow-up ICCa In the longitudinal analysis, we found that high FBG at follow-up was
Uncorrected (μg/L) significantly related to urinary Cd concentration across increasing
GM 1.33 1.31 0.64
quartiles (shown in Table 5). The adjusted β (95%CI) for FBG changes
Median 1.12 1.12 across increasing urinary Cd quartiles were 0(referent), 0.07 (− 0.11,
Interquartile (P25–P75) 0.62–2.07 0.65–2.03 0.24), 0.30 (0.12, 0.48), and 0.49 (0.31, 0.67), respectively (P trend <
Corrected (μg/g creatinine) 0.05). The results of the restricted cubic spline model confirmed that
GM 1.13 1.14 0.71
high level of urinary Cd was significantly related to an increment in
Median 0.91 0.96
Interquartile (P25–P75) 0.53–1.76 0.56–1.80 FBGF changes over a three-year of follow-up (Fig. 2, P < 0.05). Simi­
larly, an upward trend for the incidence of T2DM was reported with
Abbreviations: ICC, Intra-class correlation coefficient; GM, geometric mean; Cd,
increasing Cd exposure. Risk of incident T2DM were gradually elevated
cadmium.
a across increased Cd exposure quartiles, though associations were not
ICC is estimated by the ratio of the between person variance to the total
variance. significant (P = 0.15). The results of restricted cubic spline regression
model also visually showed that upward trends for the RRs of incident
T2DM were non-significantly associated with increasing baseline uri­
urinary Cd concentration among smokers [adjusted OR = 1.94 (95%CI:
nary Cd exposure level (Fig. 2, P > 0.05). Stratified results also showed
1.21 to 3.14)] was stronger than that in non-smokers [adjusted OR =
that the dose-response associations were not significant but showed
1.31 (95%CI: 0.66 to 2.65)].
upward trends in all subgroups (appendices Table A4).

Table 3
Associations between urinary Cd concentration and FBG and T2DM prevalence (N = 3521).
Variables All participants Quartiles of urinary Cd concentration (μg/g creatinine) P for trendc
Per unitb
Q1(<0.53) Q2 (0.53–0.85) Q3 (0.85–1.42) Q4 (≥1.42)

FBG

Mean ± SD (mmol/L) 6.3 ± 0.12 6.2 ± 0.09 6.3 ± 0.10 6.4 ± 0.10 6.5 ± 0.12
Crude β (95% CI) 0.11(0.03, 0.19) 0(referent) 0.03(-0.12, 0.18) 0.11(-0.05, 0.26) 0.24(0.07, 0.40) <0.01
Adjusted β (95% CI)a 0.11(0.03, 0.19) 0(referent) 0.03(-0.12, 0.18) 0.11(-0.05, 0.26) 0.22 (0.05, 0.40) <0.01
T2DM prevalence
Prevalent cases, n (%) 303 (8.6) 77(8.7) 64 (7.3) 75 (8.5) 87 (9.9)
Crude OR (95% CI) 1.29 (1.07, 1.54) 1(referent) 0.84 (0.59, 1.18) 1.08(0.77, 1.52) 1.55(1.08, 2.21) 0.01
Adjusted OR (95% CI)a 1.42(1.16, 1.73) 1(referent) 0.86 (0.60, 1.25) 1.20 (0.83, 1.73) 1.76 (1.18, 2.61) <0.01

Abbreviations: T2DM, type 2 diabetes mellitus; Cd, cadmium; FBG, fasting blood glucose; Q, quartile; β, regression coefficients; OR, odds ratio; CI, confidence interval.
Mixed regression models were used in both crude and adjusted models with residence as a random effect.
a
Models were adjusted for gender (male/female), age (years), BMI (kg/m2), education (primary school or below/middle school/high school and above), smoking
status (current/former/never), drinking status (current/former/never), physical activity (yes/no), and family history of diabetes (yes/no).
b
Per unit represented changes of FBG or risk of T2DM per one-unit increase of log10-transformed urinary Cd concentration.
c
P for trend was conducted by assigning the median value to each quartile of urinary Cd concentration and treated as a continuous variable.

4
L. Xiao et al. Environmental Research 192 (2021) 110259

Fig. 1. The restricted cubic spline for the associations between urinary Cd and FBG (A) and T2DM prevalence (B) at baseline (N = 3521). The lines represent adjusted
β and 95% CI (A), and OR and 95% CI (B) based on restricted cubic spline for the log-transformed urinary Cd with knots at 5th, 50th, and 95th percentiles. Models
were adjusted for gender (male/female), age (years), BMI (kg/m2), education (primary school or below/middle school/high school and above), smoking status
(current/former/never), drinking status (current/former/never), physical activity (yes/no), and family history of diabetes (yes/no). Bars represent the percentage
distribution of log (10)-transformed Cd concentrations among the study population. Abbreviations: T2DM, type 2 diabetes mellitus; Cd, cadmium; FBG, fasting blood
glucose; OR, odds ratio; CI, confidence interval.

Table 4
Stratified analysis of the association between urinary Cd and T2DM prevalence (N ¼ 3521).
Subgroups Quartiles of urinary Cd concentration (μg/g creatinine) P for interaction*

Q1 Q2 Q3 Q4

Gender

Male Cases, n (%) 30(11) 26(9.6) 23(8.5) 40(14.7) 0.57

ORs (95%CI) 1(referent) 0.92(0.51, 1.65) 0.82(0.44, 1.52) 1.84(1.00, 3.44)
Female Cases, n (%) 43(7.1) 43(7.1) 43(7.1) 55(9)
ORs (95%CI) 1(referent) 1.04(0.66, 1.66) 1.08(0.67, 1.73) 1.87(1.14, 3.09)
Age (years)
<55 Cases, n (%) 24(5) 24(5) 22(4.6) 34(7.1) 0.13
ORs (95%CI) 1(referent) 1.25(0.67, 2.34) 1.3(0.67, 2.52) 3.07(1.57, 6.14)
≥55 Cases, n (%) 56(14) 42(10.5) 52(13) 49(12.2)
ORs (95%CI) 1(referent) 0.79(0.51, 1.23) 1.21(0.78, 1.87) 1.43(0.87, 2.37)
BMI (kg/m2)
<24 Cases, n (%) 25(5.4) 25(5.4) 33(7.1) 40(8.7) 0.24
ORs (95%CI) 1(referent) 0.9(0.49, 1.67) 1.48(0.82, 2.69) 2.00(1.07, 3.81)
≥24 Cases, n (%) 52(12.4) 39(9.3) 38(9.1) 51(12.2)
ORs (95%CI) 1(referent) 0.75(0.47, 1.18) 0.86(0.53, 1.39) 1.46(0.89, 2.42)
Cigarette smoking
Yes Cases, n (%) 21(11.6) 14(7.7) 20(11) 28(15.4) 0.04
ORs (95%CI) 1(referent) 0.50(0.23, 1.06) 0.76(0.38, 1.53) 1.94(1.21, 3.14)
No Cases, n (%) 53(7.6) 54(7.7) 50(7.2) 63(9)
ORs (95%CI) 1(referent) 1.16(0.76, 1.78) 1.2(0.77, 1.88) 1.31(0.66, 2.65)
Alcohol drinking
Yes Cases, n (%) 13(8.8) 11(7.5) 10(6.8) 16(10.8) 0.69
ORs (95%CI) 1(referent) 0.81(0.32, 1.97) 1.02(0.4, 2.57) 1.99(1.29, 3.11)
No Cases, n (%) 61(8.3) 57(7.8) 63(8.6) 72(9.8)
ORs (95%CI) 1(referent) 0.99(0.66,1.48) 1.28(0.86,1.94) 1.61(0.66,4.02)
Physical activity
Yes Cases, n (%) 39(14.7) 21(7.9) 38(14.3) 33(12.4) 0.47
ORs (95%CI) 1(referent) 0.52(0.28, 0.93) 1.16 (0.68, 1.98) 1.33(0.72, 2.45)
No Cases, n (%) 38(6.2) 44(7.2) 41(6.7) 49(8)
ORs (95%CI) 1(referent) 1.19(0.74, 1.94) 1.29 (0.78, 2.14) 1.98(1.15, 3.44)

Abbreviations: T2DM, type 2 diabetes mellitus; Cd, cadmium; Q, quartile; OR, odds ratio; CI, confidence interval. Mixed regression models were used with adjustment
for gender (male/female), age (years), BMI (kg/m2), education (primary school or below/middle school/high school and above), smoking status (current/former/
never), drinking status (current/former/never), physical activity (yes/no), and family history of diabetes (yes/no). We combined current and former smokers as
cigarette smoking in subgroup analysis because of small number of former smokers in each stratum, which was the same for alcohol drinking. P for interaction was
calculated by modeling a multiplicative term between urinary Cd concentration and the stratification factor.

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L. Xiao et al. Environmental Research 192 (2021) 110259

Table 5
Longitudinal associations between urinary Cd concentration and FBG changes and T2DM incidence (N = 1760).
Variables All participants Quartiles of urinary Cd concentration (μg/g creatinine) P for trendb
Per unita
Q1 (<0.53) Q2 (0.53–0.84) Q3 (0.84–1.43) Q4 (≥1.43)

Changes of FBG

Mean ± SD (mmol/L) 0.35 ± 0.03 0.16 ± 0.07 0.19 ± 0.07 0.43 ± 0.07 0.62 ± 0.07
Crude β (95% CI) 0.24(0.15, 0.32) 0(referent) 0.03(-0.14, 0.20) 0.27(0.10, 0.44) 0.46(0.29, 0.63) <0.01
Adjusted β (95% CI)# 0.25(0.16, 0.34) 0(referent) 0.07(-0.11, 0.24) 0.30(0.12, 0.48) 0.49(0.31, 0.67) <0.01
T2DM incidence
Incident cases, n (%) 82(4.7) 18(4.1) 18(4.1) 19 (4.3) 27(6.1)
Crude RR (95% CI) 1.19(0.92, 1.53) 1(referent) 1.02(0.50, 2.08) 1.04(0.49, 2.21) 1.64(0.79, 3.45) 0.27
Adjusted RR (95% CI)# 1.15(0.77, 1.72) 1(referent) 0.97(0.48, 1.94) 1.00(0.49, 2.08) 1.45(0.74, 2.92) 0.15

Abbreviations: T2DM, type 2 diabetes mellitus; Cd, cadmium; FBG, fasting blood glucose; Q, quartile; β, regression coefficients; RR, risk ratio; CI, confidence interval.
Mixed regression models were used in both crude and adjusted models with residence as a random effect. #Models were adjusted for gender (male/female), age (years),
BMI (kg/m2), education (primary school or below/middle school/high school and above), smoking status (current/former/never), drinking status (current/former/
never), physical activity (yes/no), and family history of diabetes (yes/no).
a
Per unit represented changes of FBG or risk of T2DM per one-unit increase of log10-transformed urinary Cd concentration.
b
P for trend was conducted by assigning the median value to each quartile of urinary Cd concentration and treated as a continuous variable.

Fig. 2. The restricted cubic spline for the associations between urinary Cd and FBG changes (A) and T2DM incidence (B) at follow-up (N = 1760). The lines represent
adjusted β and 95% CI (A), and RR and 95% CI (B) based on restricted cubic spline for the log-transformed urinary Cd with knots at 5th, 50th, and 95th percentiles.
Models were adjusted for gender (male/female), age (years), BMI (kg/m2), education (primary school or below/middle school/high school and above), smoking
status (current/former/never), drinking status (current/former/never), physical activity (yes/no), and family history of diabetes (yes/no). Bars represent the per­
centage distribution of log (10)-transformed Cd concentrations among the study population. Abbreviations: T2DM, type 2 diabetes mellitus; Cd, cadmium; FBG,
fasting blood glucose; RR, risk ratio; CI, confidence interval.

4. Discussion
In the present study, positive dose-response relationships between
urinary Cd and FBG and T2DM risk were observed among the general
population in China. We found that increased urinary Cd level signifi­
cantly related to elevated FBG level, and upward trends for ORs of T2DM
prevalence were also significantly related to increasing urinary Cd level.
Longitudinal analysis showed that general population adults with high
Cd exposure level had a significant increase in levels of FBG at follow-up,
and high chronic Cd exposure was associated with increased risk of
incident T2DM though without statistical significance.
Our findings have substantial implications for public health. The
prevalence of T2DM in China has risen sharply in recent years, which
has been recognized as an increased burden for individuals and society
(Murray et al., 2012). Therefore, the prevention and control of T2DM
among general population adults in China has been of great importance.
The etiology of T2DM is complex, and most previous studies have
focused on the influence of lifestyles and diet structure on T2DM.
However, environmental pollution is also inextricably linked to the
increase of T2DM prevalence (Jones et al., 2008). The diabetogenic ef­
fects from widespread Cd exposure are highlighted in the present study.
Our findings provide evidence that Cd exposure contributed to
increasing FBG level and T2DM development, emphasize the priority in
settling the Cd-associated T2DM burden. Effective strategies are ur­
gently needed to reduce Cd body burden and prevent the public from
deleterious effects of long-term Cd exposure.
Previous studies reported that women living in Cd-contaminated
areas had a high risk of deaths from T2DM24 Nakagawa et al., 1987.
Compared with the occupational population, the general population is
exposed to Cd mainly through daily consumed food and/or cigarette
smoking, which constantly affects the health of the public for a long time
(Faroon et al., 2012; Cui et al., 2006; Satarug, 2004). Slightly different
from Europe and US countries, few women smoked in China. In the
study, we found that the number of smokers decreased with increasing
urinary Cd. When we categorized the population into male and female
group, we found that the percentage of smokers (current and former
smokes) by quartiles of urinary Cd were 124(45.6), 164(60.5), 181
(66.8), and 199(73.2) in males, the percentages were 9(1.5), 16(2.6), 19

6
L. Xiao et al.
(3.1), and 13(2.1) for females. Agreeing with our results that urinary
cadmium is higher among women, data from the study of NHANES re­
ported that the median values of urinary Cd concentration in female
adults of the United States was 0.20 μg/L which was slightly higher than
that in the males (0.180 μg/L) (Crinnion, 2010). The possible reason
may be that women are reported to have a low iron status which results
in the absorption rate of Cd increasing significantly (Akesson et al.,
2002).
In the present study, increased risk ofT2DM was found to be related
with high urinary Cd exposure. Contrary to our study, Nie et al. con­
ducted a cross-sectional study of Chinese adults and did not observe
significant associations of blood Cd level and T2DM prevalence (Nie
et al., 2016). It is worthy to note that much of the Cd accumulates in the
kidney and urinary Cd is commonly recognized as the biomarker of
long-term exposure, but blood Cd tends to reflect current exposure of Cd
(Vacchi-Suzzi et al., 2016). Scott et al. compared the urinary Cd and
blood Cd concentrations in 32,464 adults of longitudinal NHANES data
and reported that ten pack-years of smoking was more associated with
urinary Cd, but smoking changes in several days was more associated
with blood Cd level (Adams and Newcomb, 2014).Wang et al. deter­
mined concentrations of multiple metals and found only urinary Cd
represented a good reproducibility among adult men over a three-month
interval (Wang et al., 2016a). Several studies reported that changes in
diet, lifestyle, and excretion rates such as urine creatinine can affect the
long-term stability of urine Cd. A California study including 141 adult
women found that concentrations of urinary Cd varied within individual
characteristics (Gunier et al., 2013). In the present study, urinary Cd
concentration was measured repeatedly after 3 years among 1760
adults, and relatively high reproducibility of urinary Cd concentration at
baseline and follow-up was obtained suggesting that urinary Cd con­
centrations is considered as a more appropriate indicator to reflect
chronic exposure of Cd.
Agreeing with our results, a meta-analysis involving 28,691 subjects
found a significant linear relationship between urinary Cd and T2DM
risk, and reported that each 1-unit increase in the level of urinary Cd was
related to a 16% increase in the risk of T2DM prevalence (Li et al., 2017).
However, the studies involved in the meta-analysis were cross-sectional,
which are limited to draw causal associations of Cd with T2DM. Swad­
diwudhipong and his colleagues conducted a five-year follow-up study
in the Cd-polluted area of Northwestern Thailand, and revealed a sig­
nificant increase of incident T2DM cases among local residents with
prolonged Cd exposure (Swaddiwudhipong et al., 2012). The findings of
a 19-year follow-up study in China showed that residents in polluted
areas with high Cd exposure had higher levels of FBG than control
groups (Zhang et al., 2014). Slightly different from above two studies,
our study was conducted in a general population and showed that
chronic Cd exposure contributed to higher levels of FBG elevation at
follow-up of three years. The increased risk of incident T2DM was also
found to be related with high urinary Cd exposure although without
statistical significance. Nevertheless, we found the urinary Cd concen­
trations (1.12 μg/L) in our study were higher than those among pop­
ulations from the United States (0.23 μg/L), Canada (0.37 μg/L) and
South Korea (0.65 μg/L) (Crinnion, 2010; Haines et al., 2017; Lee et al.,
2012). Different from our results, a meta-analysis involving prospective
and cross-sectional studies suggested that high blood and urinary cad­
mium may not be risk factors for T2DM in the general population (Wu
et al., 2017). The only two prospective studies in this meta-analysis
conducted by Barregard et al. and Borné et al. reported that blood and
urinary cadmium were not associated with increased incidence of T2DM
and blood glucose at follow-up (Barregard et al., 2013; Borné et al.,
2014). The possible reason may be that the body burden of cadmium in
their studies (0.36 μg/g creatinine) were much lower than those in the
present study (1.1 μg/g creatinine), indicating that relative high cad­
mium exposure (i.e., around 1 μg/g creatinine for urinary cadmium) in
the general population adults might contributed to the increased risk of
T2DM.
7
Environmental Research 192 (2021) 110259
The biological mechanisms underlying the association between Cd
exposure and increased risk of T2DM have yet to be elucidated (Edwards
and Ackerman, 2016). It is reported that Cd can damage mitochondria,
produce oxidized free radicals during the interference of related cellular
respiration, and thereby promote the peroxidation of cellular lipids,
resulting in damage to the structure and function of cell membranes
(Singh et al., 2012; Zhang et al., 2015; Ghosh, 2018). Our previous
published paper showed that oxidative damage played important roles
in associations of urine metals and T2DM45 Xiao et al., 2018. Cd has a
high affinity to sulfhydryl groups, which can inhibit the activity of
antioxidant enzymes such as glutathione (GSH) and superoxide dis­
mutase (SOD), thus resulting in elevated generation of reactive oxygen
species (ROS) and the development of oxidative damage in target cells or
tissues (Cuypers et al., 2010; Djukić-Cosić et al., 2008; Ivanova et al.,
2013). Additionally, Cd can cause DNA single-strand breaks, damage the
DNA repair system, and lead to apoptosis (Ghosh, 2018; Wang et al.,
2016b). Experimental studies have shown that exposure of Cd can
activate specific cells causing the aggregation of neutrophils, and release
a large number of pro-inflammatory factors, such as interleukin-1,
interleukin-6, interleukin-8 and tumor necrosis factor (Ghosh, 2018;
Phuagkhaopong et al., 2017; Freitas and Fernandes, 2011). The role of
these possible specified mechanisms in the development of T2DM
associated with Cd exposure in the community population needs more
research to further explore.
Our study has several strengths. First, this longitudinal prospective
study had a relatively larger sample size of community-based adults,
enabling us to establish a powerful association between Cd exposure and
T2DM and avoiding potential confounding because of variations
between-persons of cross-sectional design. Second, determining urinary
Cd concentrations at baseline and follow-up demonstrates that urinary
Cd concentration is a reliable biomarker for chronic Cd exposure with
excellent long-term reproducibility. Finally, the robustness of findings in
the study was verified by sensitivity analysis and bias of results was
reduced by strict quality control in data collection and experimental
measurement. Several limitations should also be acknowledged in the
present study. First, almost half of individuals at baseline were not
included in the longitudinal analysis. Some were lost to follow-up
because of changed contact information, while others were not
included because of failing to provide biological samples or having
T2DM at baseline. However, there were no selection bias between
baseline and follow-up analysis, where the sensitivity analysis showed
no significant differences by comparing the general characteristics of
baseline with follow-up. Besides, the risk of incident T2DM was not
significantly related to increasing Cd exposure in our study because of
the relatively slow development of diabetes and the short duration of our
follow-ups. However, individuals with a high Cd exposure actually had a
significant increase in levels of FBG at follow-up of a three-year interval,
suggesting that further studies with a longer period of follow-up are
urgently warranted in the future.
5. Conclusions
Our community-based population study suggested that relatively
high chronic Cd exposure for general population adults might contribute
to the development of T2DM, highlighting the effective strategies such
as actions against cigarette smoking to prevent the public in China from
diabetogenic effects of long-term Cd exposure in the environment.
Funding
This study was supported by National Natural Science Foundation of
China’s Major Research Program (91843302); the Key Program of the
National Natural Science Foundation of China (91543207); the Funda­
mental Research Funds for the Central Universities (HUST
2016JCTD116).
L. Xiao et al.
CRediT authorship contribution statement
Lili Xiao: Conceptualization, Methodology, Investigation, Formal
analysis, Writing - original draft. Wei Li: Methodology, Investigation.
Chunmei Zhu: Methodology, Investigation. Shijie Yang: Methodology,
Investigation. Min Zhou: Methodology, Investigation. Bin Wang:
Investigation. Xing Wang: Investigation. Dongming Wang: Investiga­
tion, Writing - review & editing. Jixuan Ma: Investigation, Formal
analysis, Writing - review & editing. Yun Zhou: Investigation, Data
curation, Writing - review & editing. Weihong Chen: Conceptualiza­
tion, Methodology, Investigation, Resources, Writing - review & editing,
Project administration, Funding acquisition.
Declaration of competing interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgements
This study was supported by National Natural Science Foundation of
China’s Major Research Program (91843302); the Key Program of the
National Natural Science Foundation of China (91543207); the Funda­
mental Research Funds for the Central Universities (HUST
2016JCTD116). The study procedure was approved by the Ethics
Committee of Tongji Medical College, Huazhong University of Science
and Technology. All participants gave their written informed consent.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.envres.2020.110259.
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