Alan J Stewart

Title : Magnesium supplementation as potential means to reduce thrombotic risk in type 1 diabetes

Abstract:

Type 1 diabetes (T1D) is associated with vascular complications that increase mortality risk, underpinned by extensive vascular disease coupled with an enhanced thrombotic environment. Previously, we investigated potential associations between fibrin clot properties and plasma magnesium concentrations in 45 individuals with T1D and 47 age/sex-matched controls without diabetes. Fibrin clot characteristics were assessed using a validated turbidimetric assay and associations with plasma magnesium concentration were examined.

Plasma concentrations of fibrinogen, plasminogen activator inhibitor-1 (PAI-1), and lipids were measured and fibrin fibre diameters assessed using scanning electron microscopy. Fibrin clot maximum absorbance was unchanged in subjects with T1D compared with controls, while lysis time was increased. No differences in fibrin fibre diameters or in lipid profile were observed between T1D and controls. PAI-1 concentration was lower in the T1D group compared with the controls and positively correlated with lysis time. Plasma magnesium concentration was lower in the T1DM group compared with controls. Magnesium concentration negatively correlated with both clot maximum absorbance and lysis time.

A turbidimetric fibrin clot lysis assay performed in a purified system that included PAI-1 and up to 3.2 mM Mg²⁺, showed a shortening of lysis time with increasing Mg²⁺ concentrations. Our findings revealed that plasma magnesium concentration is associated with changes in fibrin clot and lysis parameters. Hypofibrinolysis predicts cardiovascular outcomes in diabetes and targeting this pathway has the potential to reduce thrombosis risk. We hypothesise that adequate plasma magnesium concentrations are important for normal haemostasis. Going forward, we propose to examine the role(s) of magnesium in regulating fibrinolysis using in vitro/in vivo approaches and employing a clinical study of magnesium supplementation in deficient T1D individuals. We will analyse the effects of magnesium on thrombotic/fibrinolytic potential, glycaemic and insulin resistance measures as well as patient well-being.

We also will determine whether magnesium deficiency (and subsequent supplementation) induces molecular changes in coagulation factors that may influence fibrinolysis. This work will provide a mechanistic understanding of how magnesium controls fibrinolysis and will determine the usefulness of monitoring plasma magnesium in T1D and correcting abnormally low levels. In turn, this will pave the way to new T1D management strategies that reduce the mortality risk using a safe and affordable supplementary therapy.

Audience Takeaway: 

• Type 1 diabetes can lead to poor health outcomes including an increased risk of vascular disease.
• We have found that low plasma magnesium is negatively associated with hyperfibrinolysis in type 1 diabetes.
• Magnesium supplements are widely available and may be of benefit to some individuals.
• To assess this, we will carry out a trial to assess the usefulness of magnesium supplements in this context.

Biography:

Dr Alan J. Stewart is a Reader in Molecular Medicine at the University of St Andrews. His research is focused on metal ion handling in the body and the roles they play in regulating medically/physiologically relevant processes. Collectively, his work provides detailed and reliable data relating to the transport and speciation of metal ions (particularly Zn²⁺) in the circulation and new insights into their cellular functions and role in disease states. He has published >80 peer-reviewed publications, many in world class and field-leading journals. He sits on the Editorial Boards of the journals, Scientific Reports, Frontiers in Endocrinology, Nutrients and BioMetals.