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Dietary calcium intake and risk of type 2 diabetes: possible confounding by magnesium

Abstract

This study examined the association of dietary calcium intake with incident type 2 diabetes by a meta-analysis and explored the potential confounding by magnesium. Potential studies were identified by searching the PubMed database in September 2011. Prospective cohort studies that reported relative risks (RR) with 95% confidence intervals (CI) of type 2 diabetes for dietary calcium intake were selected. Results were combined using either a fixed- or random-effects model. Six prospective cohort studies comprising 264 268 participants and 11 225 reported cases were included. All combined random-effects meta-analysis yielded a significant pooled RR of 0.85 (95% CI 0.75–0.97). However, a sensitivity analysis limited to four studies with control for magnesium yielded an attenuated, nonsignificant pooled RR of 0.94 (95% CI 0.85–1.05). In conclusion, dietary calcium intake was not independently associated with risk of type 2 diabetes. The inverse association in prior observational studies may be partially confounded by magnesium intake.

Introduction

Calcium has been suggested to have a role in the development of type 2 diabetes for its potential in improving pancreatic beta cell function and insulin sensitivity.1 However, prospective studies linking calcium and diabetes have produced mixed results.2, 3, 4, 5, 6, 7 Potential confounding factors were not controlled in a consistent way, which may account for the differing results in prior reports. Among them, magnesium is of special concern, as dietary calcium and magnesium intakes are moderately/highly correlated in diverse populations.3, 4, 5 Magnesium is an essential cofactor for enzymes involved in glucose metabolism, and considerable evidence from cohort studies suggests that magnesium is significantly associated with a reduced risk of diabetes.8 In this meta-analysis, we examined the association of dietary calcium intake with a risk of type 2 diabetes, with emphasis on the possible confounding by magnesium.

Materials and methods

We searched published studies in the PubMed database from 1966 to September 2011, using the search term calcium in combination with diabetes. In addition, we reviewed the reference lists of obtained articles. Studies were selected for analysis if they met the following criteria: the study had a prospective design; the exposure was intake of dietary calcium; the outcome was type 2 diabetes; risk estimates with 95% confidence intervals (CI) or data to calculate them were reported.

The following information was extracted: study characteristics (first author’s name, publication year, study location, follow-up length, cohort size and incident case number), population characteristics (age and sex), exposure and outcome assessments, maximally adjusted risk estimates with 95% CI, and covariates in the multivariable models.

Heterogeneity of study-specific relative risks (RR) was examined by the Q and I2 statistics. Either a fixed- or, in the presence of heterogeneity, random-effects model was used to compute the pooled RR for type 2 diabetes comparing the highest intake of dietary calcium with the lowest. To explore the potential confounding by magnesium, we further conducted a sensitivity analysis restricted to studies that adjusted for this factor. Publication bias was assessed by Egger test. All analyses were performed using STATA version 11.0 (StataCorp., College Station, TX, USA).

Results

We identified six prospective cohort studies2, 3, 4, 5, 6, 7 for meta-analysis, comprising 264 268 participants and 11 225 reported cases. Characteristics of these six studies are presented in Table 1. Among them, three studies were conducted in the United States, and one each in Australia, China and Japan. The number of cases ranged from 199 to 4843, and the cohort sizes ranged from 5200 to 83 779. Four studies included women only, whereas two studies enrolled both men and women, of which one5 reported separate results by sex. The length of follow-up ranged from 5 to 20 years. All studies used validated food-frequency questionnaires in dietary assessment. All studies but one7 used self-report of diagnosis in diabetes ascertainment. Most adjusted covariates included age, education, total energy intake, smoking, body mass index, alcohol consumption, family history, hypertension and dietary magnesium intake.

Table 1 Characteristics of prospective cohort studies of dietary calcium intake and type 2 diabetes

Among the seven reports from six studies, six showed an inverse association between dietary calcium intake and risk of type 2 diabetes, with two reaching statistical significance. Moderate heterogeneity among studies was detected (P=0.05, I2=52.9%), and random-effects meta-analysis yielded a significant pooled RR of 0.85 (95% CI 0.75–0.97, Figure 1a). Egger test suggested no indication of publication bias (P=0.77).

Figure 1
figure1

Meta-analyses of prospective cohort studies examining dietary calcium intake and risk of type 2 diabetes. (a) all combined; (b) restricted to studies adjusting for magnesium. M, men; W, women.

We next examined the potential confounding effect of magnesium by conducting a sensitivity analysis limited to four studies3, 4, 5, 7 that adjusted for this variable. None of the five reports from these studies showed a significant association. No heterogeneity among studies was observed (P=0.52, I2=0.0%), and fixed-effects meta-analysis yielded an attenuated, nonsignificant pooled RR of 0.94 (95% CI 0.85–1.05, Figure 1b). There was little evidence of publication bias (P=0.31).

Discussion

In this meta-analysis, we examined the association of dietary calcium intake with risk type 2 diabetes. All combined, higher dietary calcium intake was associated with a significant reduced diabetes risk. However, this association did not survive in the sensitivity analysis limited to studies with control for magnesium.

Our findings are in line with the Women's Health Initiative trial that found no effect of combined supplementation with 1000 mg of calcium and 400 IU of vitamin D on incident type 2 diabetes over 7-year follow-up (RR 1.01, 95% CI 0.94–1.10).9 The null result of this trial indicates associations of calcium supplementation with reduced diabetes risk observed in nonrandomized studies3, 10 may be the result of confounding. Also, most intervention studies examining the effects of calcium supplementation (alone or as a component of dairy products) on blood glucose or insulin resistance reported no evidence of effects.1 On the other hand, our recent meta-analysis of 13 cohort studies supported a protective role of magnesium intake against diabetes.8 Intervention studies also showed benefits of magnesium supplementation on glucose control in diabetes.11 Thus, magnesium may explain the inverse relation between calcium and diabetes risk in prior reports. Nevertheless, consumption of dairy foods (especially low-fat dairy), which are good sources of both calcium and magnesium, may have a role in diabetes prevention.12

Of note, our study was not designed or powered to separate the independent effect of magnesium on the calcium-diabetes association, because the analysis was based upon published studies using various multivariable models. Moreover, the high correlation between dietary calcium and magnesium in some individual studies made it difficult to separate their independent effects.6 However, in the Black Women's Health Study that mutually adjusted for magnesium and calcium, the association between calcium intake and diabetes risk disappeared (RR 1.04, 95% CI 0.88–1.24), whereas an inverse association with magnesium intake persisted (RR 0.65, 95% CI 0.54–0.78).4 These data thus provided further evidence for a confounding effect of magnesium. Indeed, when magnesium alone or along with other dietary factors was added to the models, the calcium–diabetes association was to some extent weakened.3, 4, 7

A major strength of our study is the prospective design of included studies, which minimizes the possibility of recall bias and selection bias. Potential limitations include residual confounding due to imprecisely measured or unmeasured factors, self-reported dietary intakes and diabetes diagnoses, and lack of repeated measurements in dietary assessment. The different ranges of dietary calcium intake across studies might also have impacts on the results. In addition, although Egger test suggested no indication of publication bias, this analysis was underpowered owing to the limited number of included studies.

In conclusion, findings from this meta-analysis suggested dietary calcium intake was not independently associated with risk of type 2 diabetes. The inverse association in prior observational studies may be partially confounded by magnesium intake.

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Correspondence to L-Q Qin.

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Dong, JY., Qin, LQ. Dietary calcium intake and risk of type 2 diabetes: possible confounding by magnesium. Eur J Clin Nutr 66, 408–410 (2012). https://doi.org/10.1038/ejcn.2012.5

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Keywords

  • calcium
  • magnesium
  • type 2 diabetes
  • meta-analysis

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