Hypomagnesemia in Type 2 Diabetes is Correlated with Insulin Resistance and Changes in Lipid Metabolism in Patients and Mice

Background Hypomagnesemia (plasma magnesium (Mg 2+ ) concentration <0.7 mmol/L) is a common phenomenon in patients with type 2 diabetes. Hypomagnesemia is of significant clinical importance as it results in a faster renal decline and is associated with a worse disease progression and outcome. In this study, we aimed to identify determinants of plasma Mg 2+ levels in a cohort of type 2 diabetes patients and to investigate the effect of hypomagnesemia on glucose and lipid metabolism in mice. Methods Patient data and samples of 395 type 2 diabetes patients were investigated. Plasma Mg 2+ concentrations were measured using a spectrophotometric assay. Using Pearson correlation analyses, variables were correlated to plasma Mg 2+ levels. After excluding confounding variables, all parameters correlating ( P <0.1) with plasma Mg 2+ were included in a stepwise backward regression model. Mice (n=12/group) were fed either a normal or high fat diet (HFD) (10 or 60 kCal %) in combination with a normal or low Mg 2+ content (0.03 or 0.21 w/w %) for 17 weeks. Serum Mg 2+ levels and body weight were followed for the entire duration of the study. Serum Mg 2+ , triglyceride and free fatty acid concentrations were measured using spectrophotometric assays. An intraperitoneal insulin tolerance test, reflecting insulin sensitivity, was performed at 14 weeks of the study. Results The mean plasma Mg 2+ concentration in this patient cohort was 0.74 ± 0.10 mmol/L. In total, 121 type 2 diabetes patients (30.6%) suffered from hypomagnesemia. Both plasma triglyceride (r=−0.273, P <0.001) and actual glucose levels (r=−0.231, P <0.001) negatively correlated with the plasma Mg 2+ concentration. Patients using metformin (n=251, 62%), proton pump inhibitors (n=179, 45%) or β‐adrenergic receptor agonists (n=31, 8%) displayed reduced plasma Mg 2+ levels. The model predicted (R 2 ) 20% of all variance in the plasma Mg 2+ concentration. In mice receiving low dietary Mg 2+ , the HFD induced severe hypomagnesemia (serum Mg 2+ 0.97 ± 0.05 vs. 0.48 ± 0.01 mmol/L, P <0.001). On the other hand, low dietary Mg 2+ concentration abrogated the HFD induced weight gain (bodyweight 47.00 ± 1.53 vs. 38.51 ± 1.51 gr, P <0.001). Despite the decreased weight gain, hypomagnesemic HFD mice showed equal serum triglyceride and free fatty acid levels compared to HFD mice (triglyceride 1.07 ± 0.10 vs. 1.32 ± 0.14 mmol/L; free fatty acid 1.62 ± 0.08 vs. 1.81 ± 0.09 mmol/L). Moreover, hypomagnesemic HFD mice also showed reduced blood glucose clearance 20 minutes post insulin‐injection (relative blood glucose −0.41 ± 0.03 vs. −0.24 ± 0.07 compared to ‘0 min’, P <0.05). Conclusions Hypomagnesemia is highly prevalent in type 2 diabetes patients. Plasma triglycerides and glucose levels are major determinants of the plasma Mg 2+ concentration in these patients. In mice, HFD induces hypomagnesemia. Moreover, reduced dietary Mg 2+ content attenuates fat‐induced weight gain, but increases insulin resistance and serum lipid concentrations. Thus, Mg 2+ levels affect both lipid metabolism and insulin sensitivity. Support or Funding Information This study was supported by funding from the Radboud Institute for Molecular Life Science and by grants from the Netherlands Organization for Scientific Research (NWO VICI 016.130.668) and the EURenOmics project from the European Union seventh Framework Programme (FP7/2007–2013, agreement no. 305608) to Joost Hoenderop. Jeroen H.F. de Baaij is supported by grants from NWO (Rubicon 825.14.021) and the Dutch Kidney Foundation (Kolff grant 14OKG17).