title: Serum magnesium and the risk of prediabetes: a population-based cohort study.
abstract: 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.
  
  
  
  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).
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, the Netherlands.|Department of Internal Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.|Inspectorate for Health Care, Utrecht, the Netherlands.
authors.forename: Brenda C T
authors.initials: BCT
authors.lastname: Kieboom
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, the Netherlands.
authors.forename: Symen
authors.initials: S
authors.lastname: Ligthart
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, the Netherlands.
authors.forename: Abbas
authors.initials: A
authors.lastname: Dehghan
authors.affiliation: Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Steef
authors.initials: S
authors.lastname: Kurstjens
authors.affiliation: Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.|Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: Jeroen H F
authors.initials: JHF
authors.lastname: de Baaij
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, the Netherlands.
authors.forename: Oscar H
authors.initials: OH
authors.lastname: Franco
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, the Netherlands.|Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Robert
authors.initials: R
authors.lastname: Zietse
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, the Netherlands. b.stricker@erasmusmc.nl.|Department of Internal Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands. b.stricker@erasmusmc.nl.|Inspectorate for Health Care, Utrecht, the Netherlands. b.stricker@erasmusmc.nl.
authors.forename: Bruno H
authors.initials: BH
authors.lastname: Stricker
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Ewout J
authors.initials: EJ
authors.lastname: Hoorn
mesh_terms: D000368:Aged; D027682:Cation Transport Proteins; D057167:Claudins / Q000235:genetics; D015331:Cohort Studies; D016213:Cyclins / Q000235:genetics; D005260:Female; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D008274:Magnesium / Q000097:blood*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011236:Prediabetic State / Q000097:blood* / Q000453:epidemiology* / Q000235:genetics; D012307:Risk Factors; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics; D050053:TRPM Cation Channels / Q000235:genetics
chemical_list: C508912:CLDN19 protein, human; C558175:CNNM2 protein, human; D027682:Cation Transport Proteins; D057167:Claudins; D016213:Cyclins; D050053:TRPM Cation Channels; C459082:TRPM6 protein, human; C416502:FXYD2 protein, human; D000254:Sodium-Potassium-Exchanging ATPase; D008274:Magnesium
keywords: Diabetes; Epidemiology; Insulin resistance; Magnesium; Magnesium regulating genes; Mediation; Population-based cohort; Prediabetes; Single nucleotide polymorphism