Association Between Body Iron Stores and Risk of Type 2 Diabetes in the Chinese Population: A Prospective Study
by Zhaopei Liu
Senior Honors Thesis Department of Nutrition
University of North Carolina at Chapel Hill 2019
Approved:
Abstraction
Aims/hypothesis
The aim of this study was to examine the association between baseline body iron stores factors and incident type 2 diabetes mellitus. We hypothesized that elevated serum ferritin levels have a positive association with the incidence of type 2 diabetes, and soluble transferrin receptor levels and the ratio of soluble transferrin receptor to ferritin have negative associations with new-onset type 2 diabetes.
Subjects and methods
A prospective cohort study explored associations between baseline iron stores factors and incident type 2 diabetes in 3198 adults who participated in both the waves of 2009 and 2015 China Health and Nutrition Survey. Three iron stores factors were categorized into quintiles, and the outcome measure was the incident cases of type 2 diabetes.
Results
The mean baseline serum ferritin level for participants who developed type 2 diabetes during follow-up 6 years was significantly higher than those who did not have the disease. (169.4 ±
1.00, 1.10 (95% 0.63-1.94), 1.12 (95% CI 0.64 1.97), 1.86 (95% CI 1.10-3.15), 1.51 (95% CI 0.93-2.78) (P-trend=0.049); there was not a significant association found between soluble transferrin receptor and new-onset type 2 diabetes.
Conclusion
Elevated ferritin levels and a lower ratio of transferrin receptor to ferritin were independently associated with increased incident type 2 diabetes in Chinese populations.
Introduction
Diabetes mellitus (DM) and its complications are major global public health problems. In 2018, over 425 million people lived with diabetes worldwide; of whom, 95 percent had type 2 diabetes mellitus (T2DM).1 In developing countries, the number of T2DM patients is rapidly increasing, and some studies suggest that the number will increase by 70% by the end of 2030 compared to the number of 2010.1 In China, the high prevalence of T2DM and its complications are considered a great health concern.2
is associated with cardiovascular diseases9, metabolic syndrome10, and chronic liver diseases11. In recent cross-sectional and case-control studies, elevated iron was positively associated with T2DM.5,7,12,13 Authors hypothesized that excessive iron causes oxidative damage to the pancreas and decreases insulin secretion, which in turn leads to T2DM.5,8 However, due to the cross-sectional nature of these studies, the temporal sequence cannot be firmly established. Serum ferritin is usually used as a biomarker of iron storage; however, serum ferritin can be elevated in the presence of inflammation. Therefore, recent studies have proposed the use of soluble transferrin receptor level and the ratio of soluble transferrin receptor to ferritin, along with serum ferritin, as biomarkers to indicate iron stores in the body.12,14,15
Methods
Subjects and Methods
The present study is based on the China Health and Nutrition Survey (CHNS), an ongoing large-scale longitudinal, household-based study that includes multiple ages and cohorts across nine diverse provinces and conducted from 1989.17 A multistage, random cluster process was used to draw the sample in each of the provinces. Individuals in the CHNS were randomly selected from 228 communities to capture a range of economic and demographic circumstances. The CHNS sample covered approximately 56% of China’s populations.18 The study did not only cover detailed health-related data but also contained many demographic, social and economic factors, in depth at the individual, household and community levels. Fasting blood samples were collected in 2009 and 2015, and there were 6052 individuals aged 7 and older included in both waves. In CHNS 2009, 204 individuals had developed definite T2DM, and they were excluded from this study. 72 individuals aged 18 and younger were excluded in this study. People who had missing data in these two years were also excluded from the study (n=2578). Therefore, the final study population included 3198 individuals.
Ascertainment of Diabetes
Cases of diabetes were defined as having at least one of following: 1) a fasting (≥8 hours) glucose level ≥ 7.0 mmol/liter; 2) Hemoglobin A1c (HbA1c) ≥ 6.5%; 3) a self-reported physician diagnosis of T2DM. The presence of diabetes was assessed at baseline year (2009) and the follow-up year (2015).
Measurement of diabetes risk factors
Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured on the right arm via mercury sphygmomanometers with appropriate cuff sizes. Experienced physicians who attended a 7-d data-collection training and passed a comprehensive reliability test measured blood pressure. Measures were collected in triplicate after a 10-min seated rest and the mean of the three measurements was used in analyses. Hypertension status was defined as ≥140 mmHg for mean SBP and ≥90 mmHg for mean DBP. Height was measured without shoes to the nearest 0.1 cm via a portable SECA stadiometer (Seca North America East, Hanover, MD, USA); weight was measured without shoes and light clothing to nearest 0.1 using a calibrated beam balance. In this study, height and weight were presented using body mass index (BMI), which is calculated by the formula BMI=kg/m2, and it was used as a categorical variable in general characteristics analyses: BMI≥25 kg/m2 is defined as overweight. Waist circumference (cm) was measured via a non-elastic tape at a point midway between the lowest rib margin and the iliac crest in a horizontal plane.19
Other variables
non-educated/primary school, middle/high school, and college or higher. Dietary data were collected via 3 consecutive 24-h dietary recalls.
Statistical analyses
We categorized the study population in two groups based on the incidence of T2DM in 2015. We calculated the mean (SD) or proportion of baseline clinical and metabolic factors and diabetes risk factors among participants. The differences of means and proportions between these two groups were tested using t or Wilcoxon test for continuous variables and χ2 test for categorical variables. We divided the distributions of the markers of iron stores (ferritin, soluble transferrin receptor and the ratio of soluble transferrin receptor to ferritin) among participants into quintiles. Quintile-specific risk ratios (RRs) of T2DM were estimated from logistic regression models. In multivariate models, we adjusted for conventional diabetes risk factors including age, gender, blood pressure, BMI, waist circumference, smoking status and physical activity. Since ferritin concentration could be elevated by inflammation, high-sensitivity CRP was also used for further adjusted models to reduce potential confounding by inflammation. To reduce the possibility of undiagnosed hemochromatosis, these analyses were repeated after excluding individuals (n=25) whose serum ferritin level were greater than 1000 ng/mL.20 Tests for trend were conducted using the median value for each quintile of ferritin, soluble transferrin receptor or the ratio of soluble transferrin receptor to ferritin as a continuous variable in the regression model. All P-values were 2-side, and P ≤ 0.05 was considered as statistically significant. All analyses were performed using SAS statistical software (version 9.4, SAS Institute Inc, Cary, NC).
Furthermore, several correlations between baseline iron stores biomarkers and conditions of inflammation and insulin secretion in the follow-up year were determined. The correlation between serum ferritin level and high-sensitivity CRP was 0.2 (P<0.001), and the correlation between the soluble transferrin receptors to ferritin ratio and high-sensitivity CRP was -0.2 (P<0.001), but there is no correlation between serum soluble transferrin receptors and high-sensitivity CRP. The correlation between serum ferritin and HOMA IR was 0.1 (P<0.001), and the correlation between the ratio of soluble transferrin receptor to ferritin and HOMA IR was -0.1 (p<0.001). Moreover, there were also a positive correlation between serum ferritin level and insulin level (0.1; p<0.001), and a negative correlation between the ratio of soluble transferrin receptor to ferritin and insulin (-0.1; p=0.002).
Table 1. General Characteristics of Study Participants, CHNS (N=3198)
Characteristics Type 2 Diabetes a, b No Type 2 Diabetes b P Value
N 204 (6.4%) 2994 (93.6%)
Age (years) 55.6±11.5 51.2±13.2 <0.001
Gender
Men 112 (54.9%) 1297 (43.3%)
Women 92 (45.1%) 1697 (56.7%) 0.002
BMI (kg/m2)
Âż25 111 (54.4%) 2135 (71.3%)
≥25 93 (45.6%) 859 (28.7%) <0.001
Systolic Blood Pressure (mmHg)
129.7±17.7 123.9±18.4 <0.001
Diastolic Blood Pressure (mmHg)
82.8±11.1 80.1±11.0 <0.001
Waist Circumference
(cm) 87.0±10.5 82.3±10.0 <0.001
Triglyceride
(mmol/L) 2.0±1.6 1.5±1.1 <0.001
High-sensitivity CRP (mg/L)
3.1±5.7 1.9±4.2 <0.001
Insulin (μIU/mL) 15.7±20.4 12.3±10.0 <0.001
Hemoglobin A1c (%) 5.9±0.8 5.5±0.7 <0.001
HOMA-IR 4.1±5.9 2.9±2.7 <0.001
Serum Ferritin (ng/mL)
169.4±205.3 124.6±170.0 <0.001
Receptor (mg/L) Soluble Transferrin Receptor to Ferritin Ratio
48.0±256.6 96.8±1169.4 <0.001
Physical Activity (METs/week)
184.9±155.3 225.6±188.9 0.005
Education (%) None/primary school
84 (41.2%) 1368 (45.7%) Middle/High school 112 (54.9%) 1543 (51.5%)
College or Higher 8 (3.9%) 83 (2.8%) 0.339
Ever Smoked (%)
Smoked 77 (37.8%) 859 (28.7%)
Non-Smoked 127 (62.2%) 2135 (71.3%) 0.006
Alcohol
Consumption (%) Consumed Last Year
81 (39.7%) 964 (32.2%)
Not Consumed Last
Year 123 (60.3%) 2030 (67.8%) 0.027
Dietary Intake Total Energy (Kcal/day)
2260.3±714.8 2243.2±697.5 0.885
Meat Intake (g) 136.5±114.1 135.7±106.4 0.880
a Type 2 diabetes defined as fasting blood-glucose≥7.0 mmol/L. b Data are presented as Mean ± Standard erroror n (%)
Chi-square tests were used for categorical variables and unpaired t-tests or Wilcoxon test were used for continuous variables.
after adjusted by age, gender, hypertension status, and central obesity condition, the RR decreased to 2.10 (95% CI 1.19-3.70; P-trend=0.011). Since central obesity was proposed as a new risk factors of T2DM and other cardiometabolic diseases, we firstly included central obesity (waist circumference) and hypertension status in our models, and then we also added classic obesity indicator BMI in our multivariate models, but there was no difference after included BMI, so our final models were only controlled by central obesity conditions and blood pressure. In model 3, we further adjusted model 2 by lifestyle factors including smoking status and physical activity level, and after adjustment, the RR slightly decreased to 2.05 (95% CI 1.16-3.62; P-trend=0.015). There was no significant difference as the model further adjusted by education level and dietary intake (not shown). There was an association between serum ferritin level and high-sensitivity CRP, so to reduce the potential confounding effect of inflammation, the model was further adjusted by high-sensitivity CRP. The RR only slightly attenuated to 2.03 (95% CI 1.15-3.58; P-trend=0.018). Thus, there was a positive association between the ferritin level and the risk of T2DM even after adjusted by other risk factors of T2DM. This positive association remained after excluding 25 individuals whose serum ferritin levels were greater than 1000 ng/mL, and RR comparing extreme quintiles ferritin levels was not significantly changed (RR 1.99; 95% CI 1.13-3.51; P-trend=0.023).
Table 2. Risk ratio (95% CI) for Type 2 diabetes according to quintiles of serum ferritin
Ferritin (ng/mL) P for trend
Q1 <28.6
Q2 28.6-58.6
Q3 58.6-95.5
Q4
95.6-162.1 Q5 >162.4 Number of
Participants
639 640 640 640 639
Number of
Diabetes 20 (3.1%) 36 (5.6%) 37 (7.1%) 49 (7.7%) 62 (9.7%) Model 1 1.00 1.84 (1.06,
Model 2 1.00 1.53 (0.87,
2.70) 1.34 (0.75, 2.40) 1.73 (0.98,3.06) 2.10 (1.19, 3.70) 0.011 Model 3 1.00 1.51 (0.86,
2.67) 1.34 (0.75, 2.40) 1.71 (0.96, 3.02) 2.05 (1.16, 3.62) 0.015 Model 4 1.00 1.51 (0.85,
2.67) 1.34 (0.75, 2.39) 1.70 (0.96, 3.00) 2.03 (1.15, 3.58) 0.018
Model 1 crude model;
Model 2 adjusted for age (continuous variable), gender (categorical variable), blood pressure (hypertension or not), central obesity (defined as WC > 90cm for men and WC > 80cm for women);
Model 3 further adjusted smoking status (coded yes/no), physical activity level (continuous variable); Model 4 further adjusted for CRP (continuous variable);
0.97-2.88; P-trend=0.039). Then the model was further adjusted by smoking status and physical activity level, and the RR only slightly decreased to 1.64 (95% CI 0.95-2.82; P-trend=0.046). Finally, we adjusted the model using high-sensitivity CRP level, the RR the lowest and the highest quintiles diminished to 1.51 (95% CI 0.93-2.78; P-trend=0.049). Therefore, the ratio of soluble transferrin receptor to ferritin was negatively associated with the risk of T2DM. The results of soluble transferrin receptor and the ratio of soluble transferrin receptor to ferritin were remained after excluding the 25 participants who has high ferritin levels (RR comparing extreme quintiles of soluble transferrin receptor 1.49, 95% CI 0.91-2.42, P-trend=0.13; RR comparing extreme quintiles of the ratio of soluble transferrin receptor to ferritin 1.73, 95% CI 1.00-3.00, P-trend=0.036).
Table 3. Risk ratio (95% CI) for Type 2 diabetes according to quintiles of soluble transferrin receptor and the ratio of soluble transferrin receptor to ferritin
Soluble Transferrin Receptor (mg/L) P for
trend
Q1
< 1.0 Q21.1-1.3 Q31.3-1.5 Q41.5-1.8 Q5>1.8 Number of
Participants
648 644 616 647 643
Number of Diabetes
46 (7.1%) 42 (6.5%) 46 (7.5%) 39 (6.0%) 31 (4.8%) Model 1 1.51 (0.95,
2.42) 1.38 (0.85, 2.22) 1.59 (1.00, 2.55) 1.27 (0.78, 2.06) 1.00 0.068
Model 2 1.44 (0.90,
2.32) 1.30 (0.80, 2.11) 1.53 (0.95, 2.45) 1.24 (0.76,2.02) 1.00 0.120 Model 3 1.41 (0.87,
2.27) 1.27 (0.78, 2.06) 1.53 (0.95, 2.45) 1.23 (0.76,2.01) 1.00 0.151 Model 4 1.41 (0.87,
2.27) 1.28 (0.79, 2.08) 1.54 (0.96, 2.48) 1.24 (0.76,2.02) 1.00 0.149
Soluble Transferrin receptor/ferritin Ratio
Number of
Participants 639 640 640 640 639
Number of
Diabetes 56 (8.8%) 59 (9.2%) 35 (5.5%) 31 (4.8%) 23 (3.6%) Model 1 2.57 (1.56,
4.24) 2.72 (1.66, 4.46) 1.55 (0.91, 2.65) 1.36 (0.79, 2.37) 1.00 <0.001 Model 2 1.68 (0.97,
2.88) 1.91 (1.13, 3.23) 1.13 (0.65, 1.98) 1.12 (0.64, 1.96) 1.00 0.039
Model 3 1.64 (0.95, 2.82) 1.86 (1.10, 3.15) 1.13 (0.64, 1.97) 1.11 (0.64, 1.95) 1.00 0.046
Model 4 1.61 (0.93, 2.78) 1.86 (1.10, 3.15) 1.12 (0.64, 1.97) 1.10 (0.63, 1.94) 1.00 0.049
Model 1 crude model;
Model 2 adjusted for age (continuous variable), gender (categorical variable), blood pressure (hypertension or not), central obesity (defined as WC > 90cm for men and WC > 80cm for women);
Model 3 further adjusted smoking status (coded yes/no), physical activity level (continuous variable); Model 4 further adjusted for CRP (continuous variable);
Discussion
The association of elevated serum ferritin concentration and incidence type 2 diabetes among Western populations has been investigated by multiple studies,5,6,12,16 but there are limited studies to investigate the association among Chinese populations,13,21,22 and one of these studies was age-specific, and the other two studies were region-specific or the population did not live in the mainland of China. To our knowledge, this is the first prospective cohort study, which includes both men and women without restrictions of age and region, to investigate the association between iron stores in body and incident type 2 diabetes among mainland Chinese populations. Although many research groups tested this association, their results were inconsistent. In this study, a significant positive association between serum ferritin levels and the incidence of type 2 diabetes was found even after adjusting by other risk factors. In the crude model of this association RRs gradually increased at each quintile of baseline serum ferritin concentration; nevertheless, after adjusted by other confounding factors, even though the P-trends were still significant, the RRs of the third quintile was smaller than the RRs of the second quintile. A possible explanation is that our study did not divide the population into groups of clinically raised ferritin and normal ferritin, and ferritin concentrations of participants in both Q2 and Q3 were in the normal range, so serum ferritin levels in this range may not have significant effects on incident T2DM.
ferritin concentrations and risk of T2DM. Hypertension and obesity are also important risk factors for T2DM.23,24 Finally, we also controlled lifestyle factors (smoking status, physical activity) in multivariate models. Different from previous studies, we did not include alcohol consumption in adjustments, because alcohol consumption was a binary variable in our study, which did not show the amount of alcohol intake. Some studies have shown that moderate alcohol consumption can decrease incident T2DM,25–28 so intake alcohol or not cannot be an effective confounding factor for adjustment.
T2DM has been identified as a common complication in hereditary hemochromatosis, an autosomal recessive disorder that results in the progressive accumulation of iron in the liver, heart, pancreas and other organs.3 For those patients, the initial symptoms of the disease include insulin resistance and hyperinsulinemia, and for the long term, the secretion of insulin will decrease.29 These similar phenomena were also shown in healthy participants, who do not have hemochromatosis. For participants who developed T2DM in the follow-up 6 years, their serum insulin levels were significantly higher than participants who did not have T2DM (15.7 vs 12.3 ÎĽIU/mL), and HOMA IR of the case group was also higher than the other group (5.9 vs 5.5).
understood. Iron is a transition metal that can catalyze the conversion from inactive radicals into highly reactive hydroxyl radicals. Produced hydroxyl radicals can enhance oxidative stress in human bodies and lead to systemic insulin resistance. In our study, the positive correlation between serum ferritin level and HOMA IR may support this explanation. Another mechanism has been proposed is that the effect of elevated ferritin level on T2DM is amplified by the coexistence of inflammation.21 However, this explanation was not supported by the results of the current study: before adjusted by the inflammatory factor (high-sensitivity CRP), the RR comparing the highest versus lowest quintiles of ferritin levels was 2.05, and after adjusted by the inflammatory factor, the RR only decreased to 2.03, so the effect of iron stores on incidence of T2DM is independent of inflammation conditions and not appreciably amplified by inflammation status.
only included women and participants were mostly white, but for the current study, we included both men and women, and all of them were Chinese populations. Therefore, the race and the gender of a participant may affect the effectiveness of the risk factor, and for Chinese populations, we still need more studies to confirm whether the ratio of transferrin receptor to ferritin could be an independent risk factor for T2DM.
However, there was no significant difference between participants who developed T2DM and those who did not on dietary intakes. The possible reason for this is that we did not include detailed dietary information about iron intake (red meat, processed meat, iron supplement, iron-fortified food, and plasma vitamin C), so for later studies, more detailed dietary factors should be included to examine the difference between two groups on iron intake and the association between iron intake and levels of iron stores. Lastly, although our results may support the possible mechanism that enhanced oxidative stress may lead to systemic insulin resistance and further cause the incident of T2DM. The antioxidant levels (glutathione) of participants can be used an indicator to determine whether they encounter chronic oxidative stress, but we did not have detailed data about antioxidant levels of participants (glutathione), so this possible mechanism was not fully confirmed by our study.
Conclusions
In conclusion, our results are partly consistent with previous research that elevated ferritin level and the ratio of transferrin receptor to ferritin could be used as independent risk factors to predict incident T2DM in Chinese populations, but the ratio of soluble transferrin receptor to ferritin may need more studies to confirm its prospective association with incident of T2DM among Chinese populations. These findings may have important implications to provide effective screenings and interventions to Chinese adults, who have elevated serum ferritin level, and help them effectively prevent T2DM.
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