Serum magnesium and the risk of prediabetes: a population-based cohort study

Brenda C T Kieboom, Symen Ligthart, Abbas Dehghan, Steef Kurstjens, Jeroen H F de Baaij, Oscar H Franco, Albert Hofman, Robert Zietse, Bruno H Stricker, Ewout J Hoorn, Brenda C T Kieboom, Symen Ligthart, Abbas Dehghan, Steef Kurstjens, Jeroen H F de Baaij, Oscar H Franco, Albert Hofman, Robert Zietse, Bruno H Stricker, Ewout J Hoorn

Abstract

Aims/hypothesis: Previous studies have found an association between serum magnesium and incident diabetes; however, this association may be due to reverse causation, whereby diabetes may induce urinary magnesium loss. In contrast, in prediabetes (defined as impaired fasting glucose), serum glucose levels are below the threshold for urinary magnesium wasting and, hence, unlikely to influence serum magnesium levels. Thus, to study the directionality of the association between serum magnesium levels and diabetes, we investigated its association with prediabetes. We also investigated whether magnesium-regulating genes influence diabetes risk through serum magnesium levels. Additionally, we quantified the effect of insulin resistance in the association between serum magnesium levels and diabetes risk.

Methods: Within the population-based Rotterdam Study, we used Cox models, adjusted for age, sex, lifestyle factors, comorbidities, kidney function, serum levels of electrolytes and diuretic use, to study the association between serum magnesium and prediabetes/diabetes. In addition, we performed two mediation analyses: (1) to study if common genetic variation in eight magnesium-regulating genes influence diabetes risk through serum magnesium levels; and (2) to quantify the proportion of the effect of serum magnesium levels on diabetes that is mediated through insulin resistance (quantified by HOMA-IR).

Results: A total of 8555 participants (mean age, 64.7 years; median follow-up, 5.7 years) with normal glucose levels (mean ± SD: 5.46 ± 0.58 mmol/l) at baseline were included. A 0.1 mmol/l decrease in serum magnesium level was associated with an increase in diabetes risk (HR 1.18 [95% CI 1.04, 1.33]), confirming findings from previous studies. Of interest, a similar association was found between serum magnesium levels and prediabetes risk (HR 1.12 [95% CI 1.01, 1.25]). Genetic variation in CLDN19, CNNM2, FXYD2, SLC41A2, and TRPM6 significantly influenced diabetes risk (p < 0.05), and for CNNM2, FXYD2, SLC41A2 and TRPM6 this risk was completely mediated by serum magnesium levels. We found that 29.1% of the effect of serum magnesium levels on diabetes was mediated through insulin resistance, whereas for prediabetes 13.4% was mediated through insulin resistance.

Conclusions/interpretation: Low serum magnesium levels are associated with an increased risk of prediabetes and this increased risk is similar to that of diabetes. Furthermore, common variants in magnesium-regulating genes modify diabetes risk through serum magnesium levels. Both findings support a potential causal role of magnesium in the development of diabetes, where the hypothesised pathway is partly mediated through insulin resistance.

Keywords: Diabetes; Epidemiology; Insulin resistance; Magnesium; Magnesium regulating genes; Mediation; Population-based cohort; Prediabetes; Single nucleotide polymorphism.

Conflict of interest statement

Data availability

Because of restrictions based on privacy regulations and informed consent of the participants, data cannot be made freely available in a public repository. Data can be obtained upon request. Requests should be directed towards the management team of the Rotterdam Study (secretariat.epi@erasmusmc.nl), which has a protocol for approving data requests.

Duality of interest statement

OHF works in ErasusAGE, a centre for ageing research across the life course funded by Nestlé Nutrition (Nestec Ltd.); Metagenics Inc.; and AXA. Nestlé Nutrition (Nestec Ltd.); Metagenics Inc; and AXA had no role in design and conduct of the study; collection, management, analysis and interpretation of the data; and preparation, review, and approval of the study. JHFdB receives support from the Netherlands Organisation for Scientific Research (Rubicon 825.14.021) and the Dutch Kidney Foundation (Kolff 14OKG17). All other authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

BCTK was lead author, collected the data, performed the data analyses and wrote the manuscript. SL was involved in data collection, data analysis and report writing. AD contributed to the data collection, data analysis and report writing. OHF, AH and BHS were principal investigators that designed the study, collected the data and were involved in report writing. SK and JHFdB made the figures and were involved in the data analysis and report writing. RZ took part in the study design and report writing. EJH was responsible for the overall supervision and contributed to the data analysis and report writing. All authors had access to the data, commented on the manuscript drafts and approved the final version submitted. BHS is the guarantor of this work.

Figures

Fig. 1
Fig. 1
Flowchart of the study population. Of the 11,740 eligible participants, 3185 participants were excluded because of missing data in magnesium or glucose measurements at baseline, no informed consent or prevalent diabetes mellitus. This resulted in a total study population of 8555 participants, which could be further divided into 7209 participants with normal glucose level at baseline and 1346 participants with prediabetes at baseline
Fig. 2
Fig. 2
The role of insulin sensitivity in the association between serum magnesium levels and prediabetes/diabetes. The association was modelled using a mediation analysis, with insulin resistance calculated as loge HOMA-IR levels. (a) The association with diabetes was studied in participants without diabetes at baseline. The direct effect of serum magnesium levels on incident diabetes was found not to be significant when adjusting for loge HOMA-IR levels. The indirect effect, which represents the effect of serum magnesium levels on diabetes as mediated by loge HOMA-IR levels, was found to be significant. (b) The association with prediabetes was studied in participants with normal blood glucose at baseline. The direct effect of serum magnesium levels on incident prediabetes was found not to be significant when adjusting for loge HOMA-IR levels. The indirect effect was found to be significant
Fig. 3
Fig. 3
Sensitivity analyses. For both the analysis on (a) diabetes and (b) prediabetes we performed several sensitivity analyses, using the fully adjusted model (model 3). In the first analysis, we excluded all participants with an eGFR below 60 ml min−1 [1.73 m2]−1. In the second analysis, we excluded all participants with hypomagnesaemia or hypermagnesaemia. For the analysis on prediabetes we performed an additional sensitivity analyses to study if misclassified prediabetes cases (i.e. those without a prediabetes diagnosis date) could have influenced our results

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