Hypomagnesemia in diabetes patients: comparison of serum and intracellular measurement of responses to magnesium supplementation and its role in inflammation.

PURPOSE: In this clinical trial, we assessed the efficacy of magnesium (Mg) supplementation in hypomagnesemic type 2 diabetes patients in restoring serum and intracellular Mg levels. The study had two coprimary end points: the change in serum and intracellular Mg level between baseline and after 3 months of supplementation. We compared the efficacy with regard to lowering hemoglobin A1c (HbA1c), C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and 8-isoprostane as secondary end points. PATIENTS AND METHODS: In an open-label trial, 47 hypomagnesemic type 2 diabetes patients were administered 336 mg Mg daily. At baseline and after 3 months, serum, cellular Mg, and inflammation biomarkers were measured. For intracellular Mg levels, sublingual epithelial cells were analyzed by analytical scanning electron microscopy using computerized elemental X-ray analysis. Blood samples were analyzed for Mg, creatinine, HbA1c, and CRP. Systemic inflammatory markers including TNF-α and the oxidative stress marker 8-isoprostane were determined using enzyme-linked immunosorbent assay. RESULTS: Mg supplementation significantly increased the intracellular and serum levels. Statistically clinical improvement in HbA1c and CRP levels was not observed, but significant decreases in TNF-α as well as in 8-isoprostane were found. CONCLUSION: A feasible clinical method for the assessment of intracellular Mg was demonstrated in tissue samples obtained noninvasively, providing evidence for potential clinical translation of this method to routinely determine intracellular Mg concentration.

Oral Magnesium Supplementation in Chronic Kidney Disease Stages 3 and 4: Efficacy, Safety, and Effect on Serum Calcification Propensity-A Prospective Randomized Double-Blinded Placebo-Controlled Clinical Trial.

INTRODUCTION: Chronic kidney disease (CKD) is associated with high cardiovascular morbidity and mortality. Recent evidence suggests that increases in both serum and intracellular magnesium (Mg) can slow or even prevent the development of vascular calcification seen in CKD. Serum calcification propensity (T50) is a novel functional test, which is associated with all-cause mortality in CKD and measures the ability of serum to delay the formation of crystalline nanoparticles. Theoretically, increasing serum Mg should improve T50 and thereby reduce the propensity towards ectopic calcification. METHODS: We conducted a randomized placebo-controlled double-blinded clinical trial to investigate the safety of 2 different doses of oral Mg supplementation in subjects with CKD stages 3 and 4 as well as their effects on intracellular Mg and T50. Thirty-six subjects with CKD stages 3 and 4 were randomized to one of 3 groups (placebo, elemental Mg 15 mmol/d or elemental Mg 30 mmol/d) given as slow-release Mg hydroxide and followed for 8 weeks. RESULTS: Thirty-four subjects completed the trial. Intracellular Mg remained stable throughout the trial despite significant increases in both serum and urine Mg. T50 increased significantly by 40 min from 256 ± 60 (mean ± SD) to 296 ± 64 minutes (95% confidence interval, 11-70, P < 0.05) in the Mg 30 mmol/d group after 8 weeks. No serious adverse events related to the study medication were reported during the study. DISCUSSION: Oral Mg supplementation was safe and well tolerated in CKD stages 3 and 4 and improved T50, but did not increase intracellular Mg. Further studies are needed to investigate the long-term effects of Mg supplementation in CKD stage 3 and 4 and whether improvement in calcification propensity is related to clinical endpoints.

Comparison of magnesium status using X-ray dispersion analysis following magnesium oxide and magnesium citrate treatment of healthy subjects.

The magnesium content in food consumed in the Western world is steadily decreasing. Hypomagnesemia is associated with increased incidence of diabetes mellitus, metabolic syndrome, all-cause and coronary artery disease mortality. We investigated the impact of supplemental oral magnesium citrate versus magnesium oxide on intracellular magnesium levels ([Mg2+]i) and platelet function in healthy subjects with no apparent heart disease. In a randomized, prospective, double-blind, crossover study, 41 (20 women) healthy volunteers [mean age 53±8 (range 31-75) years] received either magnesium oxide monohydrate tablets (520 mg/day of elemental magnesium) or magnesium citrate tablets (295.8 mg/day of elemental magnesium) for one month (phase 1), followed by a four-week wash-out period, and then crossover treatment for one month (phase 2). [Mg2+]i was assessed from sublingual cells through x-ray dispersion (normal values 37.9±4.0 mEq/L), serum magnesium levels, platelet aggregation, and quality-of-life questionnaires were assessed before and after each phase. Oral magnesium oxide, rather than magnesium citrate, significantly increased [Mg2+]i (34.4±3 versus 36.3±2 mEq/L, p<0.001 and 34.7±2 versus 35.4±2 mEq/L, p=0.097; respectively), reduced total cholesterol (201±37 versus 186±27 mg/dL, p=0.016 and 187±28 versus 187±25 mg/dL, p=0.978; respectively) and low-density lipoprotein (LDL) cholesterol (128±22 versus 120±25 mg/dL, p=0.042 and 120±23 versus 121±22 mg/dL, p=0.622; respectively). Noteworthy is that both treatments significantly reduced epinephrine-induced platelet aggregation (78.9±16% versus 71.7±23%, p=0.013 and 81.3±15% versus 73.3±23%, p=0.036; respectively). Thus, oral magnesium oxide treatment significantly improved [Mg2+]i, total and LDL cholesterol compared with magnesium citrate, while both treatments similarly inhibited platelet aggregation in healthy subjects with no apparent heart disease.

Effect of magnesium L-lactate on blood pressure in patients with an implantable cardioverter defibrillator.

BACKGROUND: Previous studies have evaluated the impact of oral magnesium on blood pressure; however, they used magnesium salts with low bioavailability, had methodological issues, and showed differing results. OBJECTIVE: To evaluate the long-term blood pressure-lowering ability of oral magnesium L-lactate versus placebo in patients with implanted cardioverter defibrillators (ICDs). METHODS: In this double-blind, 24-week trial, 50 patients with ICDs were randomized to receive magnesium L-lactate (6 tablets daily, supplying a total of 504 mg of elemental magnesium daily) or matching placebo for at least 12 weeks. Baseline intracellular and serum magnesium concentrations were determined. The primary efficacy endpoint was the mean sitting systolic blood pressure at 24 weeks. RESULTS: In 50 patients who completed at least 12 weeks of follow-up, 86% of patients, regardless of randomization, had a baseline intracellular magnesium deficiency, but no patients had a serum magnesium deficiency. At 12 weeks, magnesium L-lactate significantly reduced systolic blood pressure compared with placebo (117.7 +/- 11.8 vs 126.3 +/- 16.7 mm Hg, respectively; p = 0.04). In the 45 patients who continued in the study through the 24-week time period, the systolic blood pressure reduction was maintained, but statistical significance was lost (118.1 +/- 14.1 vs 125.5 +/- 17.2 mm Hg, respectively; p = 0.13). Magnesium L-lactate did not impact diastolic blood pressure at either time period (p > or = 0.75 for both). Patients with a documented history of hypertension at baseline showed similar qualitative results to the primary analysis. CONCLUSIONS: A large number of subjects with ICDs have an intracellular magnesium deficiency not captured through serum magnesium determination. The use of magnesium L-lactate in patients with an ICD results in significant improvement in systolic blood pressure at 12 weeks, which may be maintained through 24 weeks.

Impact of magnesium sulfate on serum magnesium concentrations and intracellular electrolyte concentrations among patients undergoing radio frequency catheter ablation.

BACKGROUND: We evaluated the impact of intravenous magnesium on intracellular magnesium (iMg) and serum magnesium (sMg) in patients undergoing radio frequency catheter ablation (RFCA) for atrial fibrillation (AF). METHOD: Patients with AF received 4g intravenous magnesium sulfate or normal saline in a randomized, double-blinded fashion. Venous blood and buccal cells were collected for evaluation of sMg and iMg at baseline, postinfusion, at the end of ablation procedure and six-hours posttherapy. RESULTS: All subjects (n = 18) had baseline sMg within normal range but iMg concentrations below normal in 89% of subjects. Baseline sMg and iMg concentrations were similar between groups. After infusion, the magnesium group had significantly higher sMg concentration than the placebo group over the six hours. In contrast, iMg concentrations were significantly higher than placebo immediately after the infusion (P = 0.007) but not at the end of RFCA or six-hours postinfusion (P = 0.187 and P = 0.267). CONCLUSION: iMg deficiencies exist despite normal sMg concentrations in patients undergoing RFCA. Intravenous magnesium sulfate corrects iMg deficiencies immediately postinfusion.

An evaluation of the impact of oral magnesium lactate on the corrected QT interval of patients receiving sotalol or dofetilide to prevent atrial or ventricular tachyarrhythmia recurrence.

BACKGROUND: Intravenous magnesium reduces the QTc interval of patients receiving ibutilide. Whether oral magnesium can reduce the QTc interval associated with oral sotalol and dofetilide is not known. This study was undertaken to evaluate the impact of oral magnesium on the QTc interval and whether an inherent intracellular magnesium deficiency exists among patients with arrhythmias. METHODS: Participants receiving sotalol or dofetilide for atrial or ventricular arrhythmias were randomized to receive magnesium l-lactate (504 mg elemental magnesium daily, Niche Pharmaceuticals, Roanoke, TX) or placebo for 48 hours. A 12-lead electrocardiogram (ECG) was obtained at baseline, 3 hours, and 51 hours after dosing to correspond to the Tmax after oral ingestion. The QTc interval was measured from the ECGs and compared between groups. Intracellular magnesium concentrations were determined by energy-dispersive x-ray analysis at baseline and 51 hours after dosing (Intracellular Diagnostics, Inc., Foster City, CA). RESULTS: The QTc interval reductions from baseline were greater in the magnesium group than placebo at 3 and 51 hours (P = 0.015 and P < 0.001, respectively). Sixty-three percent of patients (regardless of experimental group) had baseline intracellular magnesium concentrations below the normal reference range of 33.9-41.9 mEq/IU, with an average level of 32.6 +/- 2.2 mEq/IU. CONCLUSIONS: Oral magnesium l-lactate raises intracellular magnesium concentrations and lowers the QTc interval of patients receiving sotalol or dofetilide.

Validation of diagnostic tests for determination of magnesium status in horses with reduced magnesium intake.

OBJECTIVE: To evaluate the diagnostic value of serum concentrations of total magnesium (tMg) and ionized magnesium (iMg), concentrations of magnesium (Mg) in muscle, intracellular Mg (icMg) concentrations, urinary Mg excretion (EMg), Mg clearance (CMg), and fractional clearance of Mg (FCMg) in horses fed diets with Mg content above and below National Research Council recommendations. ANIMALS: 9 young female horses. PROCEDURES: 6 horses were fed a reduced-Mg diet for 29 days followed by an Mg-supplemented diet for 24 days. Control horses (n = 3) were fed grass hay exclusively. Blood, urine, and tissue samples were collected, and an Mg retention test was performed before and after restriction and supplementation of Mg intake. Serum tMg, serum iMg, muscle Mg, icMg, and urine Mg concentrations were measured, and 24-hour EMg, CMg, and FCMg were calculated. RESULTS: Reductions in urinary 24-hour EMg, CMg, and FCMg were evident after 13 days of feeding a reduced-Mg diet. Serum tMg and iMg concentrations, muscle Mg content, and results of the Mg retention test were not affected by feeding the Mg-deficient diet. Spot urine sample FCMg accurately reflected FCMg calculated from 6- and 24-hour pooled urine samples. Mean +/- SD FCtMg of horses eating grass hay was 29 +/- 8%, whereas mean FCtMg for horses fed a reduced-Mg diet for 29 days was 6 +/- 3%. CONCLUSIONS AND CLINICAL RELEVANCE: The 24-hour EMg was the most sensitive indicator of reduced Mg intake in horses. Spot sample FCMg can be conveniently used to identify horses consuming a diet deficient in Mg.

Development of cellular magnesium nano-analysis in treatment of clinical magnesium deficiency.

A novel technique, using energy dispersive X-ray microanalysis (EXAtm), for noninvasive intracellular (i.c.) measurement of magnesium [Mg2+]i has now been accomplished and proven to be a valuable tool in multiple aspects of normal as well as pathological magnesium metabolism. Since only 1% of total body Mg2+ is found in the intravascular space, serum levels of Mg2+ give little information about a patient's overall Mg2+ status with respect to this essential mineral. Using the EXAtm analysis it has shown been determined that Mg2+ levels are significantly reduced in many physiological states which may lead to serious pathological conditions [15]. Description of the methodology and examples of data as well as potential applications will focus on intracellular (i.c.) [Mg2+]i determinations obtained in cells from subjects with cardiovascular disease (CVD) syndromes related to Mg2+ deficiency. Examples of the application of EXAtm evaluation include examination of intracellular magnesium and other minerals in a wide spectrum of conditions which include cardiovascular conditions, arrhythmias, heart failure, myocardial infarction, and bypass surgery. Standardization of control values were performed at NASA.