Low serum magnesium partly mediated through insulin resistance.
Magnesium (Mg) is one of the important cations in the human body. It plays a critical role in the actions of enzymes and it is a co-factor in several pathways, including glucose transport, insulin sensitivity, and insulin secretion. Studies have found an inverse relationship between serum Mg levels and the incidence of diabetes. Although it is believed that there is an increased risk of acquiring diabetes with low serum Mg levels, it is a modifiable risk factor.
Contrarily, the association between Mg levels and diabetes risk might be due to reverse causation, where diabetes may cause urinary magnesium loss. Since, in patients with prediabetes, serum glucose levels are below the threshold for urinary Mg wasting, it is unlikely to influence serum Mg levels. Therefore, the purpose of this study is to analyze the association between serum Mg levels in patients with diabetes and with prediabetes. Also, Mg-regulating genes were examined to inspect their influence on the risk of acquiring diabetes through serum Mg levels. Moreover, the effect of insulin resistance was quantified in association between serum Mg levels and diabetes risk.
From 14,926 participants age 45 years old and above, a total of 8,555 participants (mean age, 64.7 years) with normal glucose levels (mean ± SD: 5.46 ± 0.58 mmol/l) at baseline were selected from the three prospective population-based cohort studies. They were followed up every 4-5 years (median follow-up, 5.7 years). Within the population-based Rotterdam Study, Cox models was used to adjust for age, sex, lifestyle factors, comorbidities, kidney function, serum levels of electrolytes and diuretic use. It was also used to study the association between serum Mg and prediabetes or diabetes participants. Moreover, two mediation analyses were performed in order to understand if common genetic variation in eight Mg-regulating genes influenced diabetes risk through serum Mg levels and to quantify the proportion of the effect of serum Mg levels by HOMA-IR on diabetes, which is mediated through insulin resistance.
Association between serum Mg levels and incident diabetes were identified in 806 cases out of 8,555 participants without diabetes at baseline over a median follow-up of 6.7 years. A decrease in serum Mg by 0.1mmol/l was associated with an increase in diabetes risk (HR 1.18 [95% CI 1.04, 1.33]), confirming findings from previous studies. On the other hand, association between serum Mg levels and incident prediabetes yield similar results (HR 1.12 [95% CI 1.01, 1.25]). Genetic risk factors that significantly influenced diabetes incident (p<0.05) were associated with gene variation in CLDN19, CNNM2, FXYD2, SLC41A2, and TRPM6. However, gene variation in CNNM2, FXYD2, SLC41A2 and TRPM6 were completely mediated by serum Mg levels. Overall, 29.1% of the serum Mg level’s effects on diabetes were mediated through insulin resistance, whereas for prediabetes, 13.4% was mediated through insulin resistance.
The study lacked unmeasured confounding factors between the mediator and the outcome, making it difficult to check unmeasured confounding factors, but the analyses were adjusted for many potential confounders to avoid unlikely association between serum Mg and diabetes risk due to residual confounding. Also, the study was unable to stratify based on ethnicity as the population was mainly of European descent, whereas previous studies showed lack of association between serum Mg and diabetes incidence in black subjects. Overall, the comprehensive assessment of this study reduces potential bias resulting from misclassifications and the mediation analysis allowed for a causal interpretation of data.
Serum Mg had already been associated with diabetes, but increase in renal Mg wasting could also lead to low serum Mg levels. Thus, if low Mg levels were the result of uncontrolled diabetes instead of a cause, then the effect of Mg supplement on diabetes risk would not be expected. This study provides evidence that Mg does influence diabetes and prediabetes risk, but the association with prediabetes is unlikely to be caused by reversed causation as glucose levels are not high to cause increased urinary Mg wasting.
In conclusion, low serum Mg levels were associated with an increased risk of prediabetes, as well as to increased risk of diabetes. The specific variations in Mg-regulating genes can change diabetes risk through serum Mg levels. The study concludes that the findings support a potential role of Mg levels in the development of diabetes, however the theory is partly mediated through insulin resistance.
The effect of serum magnesium on prediabetes and diabetes risk is partly mediated through insulin resistance.
Serum magnesium and incident diabetes may be due to reverse causation in diabetes due to induced urinary magnesium loss. However, it is unlikely in prediabetes due to low serum glucose levels below the threshold for urinary magnesium wasting.
Common genetic variation in magnesium regulating genes TRPM6, CLDN19, SLC41A2, CNNM2 and FXYD2 can significantly modify the risk of diabetes through serum magnesium levels.
1. Arpaci D, Tocoglu AG, Ergenc H, Korkmaz S, Ucar A, and Tamer A. Associations of serum Magnesium levels with diabetes mellitus and diabetic complications. Hippokratia. 2015 Apr-Jun;19(2):153-157.
2. Kieboom BCT, Ligthart S, Dehghan A, Kurstjens S, de Baaij JHF, Franco OH, et al. Serum magnesium and the risk of prediabetes: A Population-Based Cohort Study. Diabetologia. 2017 Feb 21.
3. Xu J, Xu W, Yao H, Sun W, Zhou Q, and Cai L. Associations of serum and urinary magnesium with the pre-diabetes, diabetes and diabetic complications in the Chinese Northeast population. PLoS One. 2013;8:e56750.