Special issue of Frontiers in Endocrinology

A special issue of Frontiers in Endocrinology focussed on “Insulin resistance and cardiovascular disease” has been just published. The issue, which was edited by Drs Alan Stewart and Samantha Pitt and well as Dr Erkan Tuncay (Ankara University) and Dr Richard Rainbow (University of Liverpool), includes 8 new articles that successfully explore the mechanisms by which insulin resistance contributes to cardiovascular diseases including atherosclerosis, hypertensive disorders, heart disease and metabolic syndrome.

A link to the editorial summarising this special issue can be found here.

Diabetes UK Project Grant Award

A research grant of £324,643 has been awarded to Dr Alan Stewart and Prof Ramzi Ajjan (University of Leeds) from Diabetes UK to carry out a new 30-month study entitled “Magnesium deficiency as a reversible driver of vascular complications in type 1 diabetes”.

People with type 1 diabetes (T1D) are at a higher risk of developing vascular problems where blockages in the blood vessels, caused by unwanted clot formation, limit the flow of blood. This, in turn, can causes heart attacks and strokes which are serious conditions that can be fatal or impair quality of life.

We previously found that people with T1D can have lower blood magnesium levels compared to those without diabetes. Magnesium is an essential nutrient important for health and our work has also shown that the lower the level of blood magnesium, the more difficult it is for a blood clot to break down after it forms. This increases the risk of blood vessel occlusion and consequently adverse health conditions.

In this new study, we will take blood samples from people with T1D with low blood levels of magnesium to examine in detail clot formation and breakdown, which will help to understand the exact mechanism(s) involved. Importantly, we will assess whether providing magnesium supplements to people with T1D helps to normalise blood clotting profile to match, or at least come close, to people without diabetes. It is hoped that this work may provide a simple and affordable treatment to reduce the formation of dangerous blood clots in people with T1D.

BHF Studentship Award

A research grant of £117,081 has been awarded to Dr Alan Stewart and Prof Ramzi Ajjan (University of Leeds) from British Heart Foundation to carry out a new 36-month study entitled “Zinc-mediated effects on the fibrin network and its importance in thrombotic disease”.

Diabetes affects nearly half a billion people worldwide with cardiovascular disease representing the major cause of morbidity and mortality. An enhanced thrombotic environment is a key mechanism for the adverse vascular outcome in diabetes; obstructive blood clots (leading to myocardial infarction and cerebrovascular events) are formed secondary to complex interactions between platelets and coagulation proteins. Both the cellular and protein arms of coagulation are activated in diabetes leading to the formation of compact fibrin networks and impaired fibrinolysis.

We have identified a new mechanism for increased thrombosis risk in diabetes caused by the displacement of zinc from its primary circulatory buffering/transport protein, albumin through elevated levels of non-esterified fatty acid (NEFA). NEFAs are also transported by albumin and their binding causes a structural change that disrupts zinc binding allowing other molecules to bind available zinc. Raised plasma NEFAs, as observed in diabetes, are associated with zinc-dependent aberrations in fibrin clot formation and platelet functioning through zinc-dependent pathways.

In this project we will explore the mechanisms by which zinc impacts upon the fibrin network both through direct co-ordination to the fibrinogen molecule and through modulation of interactions between the fibrin network with activated platelets and other haemostatic molecules.

Cobalt-albumin manuscript accepted for publication in Chemical Science.

PhD student, Dongmei Wu (from the Stewart group) has had a joint first author paper focussed on serum albumin interaction with Co2+ , accepted for publication in the RSC journal, Chemical Science. The work was a collaboration between several groups, including that of Prof. Wladek Minor from the Univeristy of Virginia (who is joint lead author with Dr Stewart) and Prof. Claudia Blindauer from the University of Warwick.

Serum albumin-Co2+ interactions are of clinical importance. They play a role in mediating the physiological effects associated with cobalt toxicity and are central to the albumin cobalt binding (ACB) assay for diagnosis of myocardial ischemia. To further understand these processes, a deeper understanding of albumin-Co2+ interactions was required. In the paper, the first crystallographic structures of human serum albumin (HSA; three structures) and equine serum albumin (ESA; one structure) in complex with Co2+ are presented. Amongst a total of sixteen sites bearing a cobalt ion across the structures, two locations were prominent, and they relate to metal-binding sites A and B. Site-directed mutagenesis and isothermal titration calorimetry (ITC) were employed to characterise sites on HSA. The presence of bound myristate (C14:0) in the HSA crystal structures provided insight into the fatty acid-mediated structural changes that diminish the affinity of the protein toward Co2+.

Together, these data provide further support for the idea that ischemia-modified albumin corresponds to albumin with excessive fatty-acid loading.  Collectively, our findings provide a comprehensive understanding of the molecular underpinnings governing Co2+ binding to serum albumin.


International Conference of Trace Elements and Minerals, Aachen, Germany.

Between the  5th-10th June seven members of the Metal Ions in Medicine Group were in Aachen, Germany to present their work at the International Conference of Trace Elements and Minerals. Dr Alan Stewart organised and chaired a session on Zinc in Cardiovascular Disease and gave a talk on aberrant plasma zinc handling in type 2 diabetes. Dr Samantha Pitt and Dr Amy Dorward gave Invited Talks each focussed on the role of zinc in heart failure. Jordan March gave an Oral Presentation on the role of zinc in platelets, while Stephen Hierons, Dongmei Wu and Spencer Regan-Smith gave poster presentations based on their research. The group would like to thank the organisers of the conference, particularly Prof. Lothar Rink for what was an exciting meeting held in a beautiful and historically-important city.

7th International Caparica Conference on Analytical Proteomics (ICAP)

On the 14th July Dr Alan Stewart gave an online invited talk at the 7th International Caparica Conference on Analytical Proteomics (ICAP), 2021 held in Lisbon, Portugal. The talk was entitled “Plasma fatty acid levels control circulatory zinc speciation: Relevance to pro-coagulatory disorders from speciomic and lipidomic studies”. He would like to thank the organisers, especially Prof Capelo for (as always!) a really exciting and engaging meeting.

UKRI-BBSRC/FAPESP Grant Award to Alan Stewart: A “speciomic” toolkit to investigate fatty acid-mediated changes in plasma zinc speciation and their physiological effects

Dr Alan Stewart has been awarded £783,100 from the BBSRC to fund a new bilateral project entitled “A “speciomic” toolkit to investigate fatty acid-mediated changes in plasma zinc speciation and their physiological effects”. The work will be a collaboration between researchers at the Universities of St Andrews, Warwick in the UK and Campinas in Brazil. The project, which Dr Stewart will lead, has been awarded additional funding from FAPESP (The São Paulo Research Foundation) to support the work in Brazil. As part of this study, state-of-the-art and bespoke analytical methods will be employed to understand the (re)distribution of zinc within plasma in the presence of high concentrations of fatty acids, mirroring conditions observed in disease states. The impact of this dynamic on physiological processes including insulin signalling and cellular zinc uptake will also be examined. Prof Claudia Blindauer will oversee work at the University of Warwick and Profs Marco Arruda and Carlos Ramos the research at University of Campinas.

British Heart Foundation – Lunch and Learn Talk

On the 15th June 2021, Dr Alan Stewart gave a Lunch and Learn talk for the British Heart Foundation based upon his research.

The talk was entitled “Could zinc be the key to new diabetes treatments?” and featured a small quiz. The audience was made up of fundraisers and other BHF staff based throughout the UK.

Fatty acids influence blood clotting through modulation of plasma zinc – new publication in Chemical Science

The Metal Ions in Medicine group have just published new data that may shed light on how fats in your blood could affect your health. The paper entitled “Albumin-mediated alteration of plasma zinc speciation by fatty acids modulates blood clotting in type-2 diabetes” has just been accepted for publication in the high impact journal, Chemical Science. In this study, it was found that free fatty acids  influence certain blood clotting characteristics including parameters relating to fibrin clot formation as well as platelet aggregation. It was found that the mechanism of action most likely involves reduction of zinc binding to the protein, serum albumin (the main zinc and fatty acid carrier protein in the blood) and a consequent increase in binding of zinc to proteins that regulate clot formation. The study suggests that this mechanism may contribute to pathogenic clot formation, which is more frequently observed in individuals with disease states marked by elevated plasma fatty acid levels, such as type-2 diabetes, obesity and fatty liver disease.

BioMetals 2020 Meeting

Dr Alan Stewart would like to thank Dr Isabelle Michaud-Soret and all the other organisers of the BioMetals 2020 Meeting which was held between the 6th -10th July 2020. The meeting was originally meant to take place in Grenoble, France but was switched to an online meeting due to the ongoing Covid-19 Pandemic. The meeting was well attended – with over 150 delegates from all over the world. Alan gave a talk on his group’s work entitled “Metal ion dyshomeostasis and coagulatory defects in type-1 and type-2 diabetes”.