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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.

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.

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.

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.

Between the  5^th-10^th 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.