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

Abstract

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.

Keywords:

• hypomagnesemia
• type 2 diabetes
• intracellular magnesium
• elemental X-ray analysis

Data availability

Data related to this clinical trial, de-identified, can be shared with interested researchers immediately after publication including a detailed clinical trial report and the study protocol. All of the individual participant data collected during the trial are stored electronically and can be made available with no end date through contacting the principal investigators of this trial (https://clinicaltrials.gov/ct2/show/NCT01980459).

Acknowledgments

This study was funded by a grant through the Kuwait Foundation for the Advancement of Science “Magnesium Treatment of Inflammation in Disorders of Glucose Homeostasis (2013-1302-01) and the DDI (RA 2012-013). The study was registered in ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT01980459).

The initial encouragement for this clinical trial was provided by late Dr Mahmoud Abdulrahim of the Kuwait Foundation for Advancement of the Sciences whose efforts in facilitating this trial are highly appreciated. The authors express their sincere appreciation to the late Dr Narayanan Nampoory, whose contribution to this work, insight, expertise, and support was of great significance. Dr Nampoory was a coprincipal investigator at study initiation and directed all patient-related aspects ensuring patient safety throughout the trial period. The authors acknowledge the efforts of Dr Osama Alsmadi for initiating and fostering the collaboration with Dr Weglicki at the beginning of the study and for obtaining initial ethical approval for conducting the study at DDI. The authors extend their thanks and appreciation to Dr Talal Muzaffar who took over the last clinics of the final visit patients and supported the study team in the screening phase. The authors thank Dr Bassam Bulbanat for conducting the ECGs ensuring patient safety. Our thanks are also extended to Mrs Asmaa Alhubail and the clinical laboratory team at DDI for their blood sample analysis and excellent technical support. The Nursing Department at the DDI is thanked for their assistance in buccal swab collection, and the Tissue Bank Department at DDI is thanked for plasma sample processing and sample storage. The authors thank pharmacists: Amina Alqassar for dispensing the Mg tablets, Naeema Qabandi for assistance in screening, and Mona Awadh for medication review. Ms Hidaya Abdalla is thanked for her assistance in patient recruitment for this study. Dr Adel Ahmed is sincerely thanked for supporting the study team and facilitating this project in the clinical research unit at DDI. Niche Pharmaceuticals Inc. is thanked for the generous donation of Mag-Tab SR (sustained release) tablets for this clinical trial. The authors thank all the patients whose participation made this study possible. Part of this study was presented in an oral presentation and poster at the 2nd World Congress for Clinical Trials in Diabetes (November 2017; Berlin, Germany). The authors would like to thank Enago (www.enago.com) for the English language review.

Author contributions

NZ coordinated with the study site in Kuwait, led the clinical experiments, and aided in designing the clinical study; obtained, analyzed, and interpreted the data; and wrote, edited, and reviewed the manuscript. NA obtained data, assisted in the clinics, and edited and reviewed the manuscript. ITM contributed to oversight of research parameters/methodology of assays of inflammation and oxidative stress, contributed to writing, interpreted data, and edited and reviewed the manuscript. WBW designed the study; contributed to oversight of patient recruitment, sampling, cellular data collection, and analysis; interpreted the clinical data; and wrote, edited, and reviewed the manuscript. BS conducted EXATEST cellular mineral testing; contributed to the interpretation and oversight of cellular mineral assays; wrote the methodology for the assay; and edited and reviewed the manuscript. All the authors gave final approval of the version to be published. NZ and WW are the guarantors of this work and take responsibility for the contents of this article. All authors contributed toward data analysis, drafting and revising the paper and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.

Supplementary materials

At study initiation, 62 patients were allocated to receive magnesium L-lactate tablets. Eight participants were excluded prior to receiving the intervention, and seven participants dropped out of the study. Reasons for exclusion were as follows: abnormal ECGs (four participants), two participants were no longer interested in participating, one participant left the country, and one participant concurrently started another magnesium supplement (magnesium oxide tablets). Seven participants dropped out of the study and discontinued taking the intervention. Reasons for dropping out were as follows: three participants could not commit to sample collection appointments, two participants travelled abroad during the study period, and two participants were doubtful of the benefit of the tablets.

Figure S1 The study flow diagram, detailing the phases of the trial including enrollment, intervention allocation, follow-up, and data analysis.

Table S1 Demographics and clinical characteristics of the study population at baseline and at the end of 3-month therapy