Publications by authors named "Ramzi A Ajjan"

85 Publications

Current and novel biomarkers of thrombotic risk in COVID-19: a Consensus Statement from the International COVID-19 Thrombosis Biomarkers Colloquium.

Nat Rev Cardiol 2022 Jan 13. Epub 2022 Jan 13.

Heart, Lung and Vascular Institute, University of Cincinnati College of Medicine, Cincinnati, OH, USA.

Coronavirus disease 2019 (COVID-19) predisposes patients to thrombotic and thromboembolic events, owing to excessive inflammation, endothelial cell activation and injury, platelet activation and hypercoagulability. Patients with COVID-19 have a prothrombotic or thrombophilic state, with elevations in the levels of several biomarkers of thrombosis, which are associated with disease severity and prognosis. Although some biomarkers of COVID-19-associated coagulopathy, including high levels of fibrinogen and D-dimer, were recognized early during the pandemic, many new biomarkers of thrombotic risk in COVID-19 have emerged. In this Consensus Statement, we delineate the thrombotic signature of COVID-19 and present the latest biomarkers and platforms to assess the risk of thrombosis in these patients, including markers of platelet activation, platelet aggregation, endothelial cell activation or injury, coagulation and fibrinolysis as well as biomarkers of the newly recognized post-vaccine thrombosis with thrombocytopenia syndrome. We then make consensus recommendations for the clinical use of these biomarkers to inform prognosis, assess disease acuity, and predict thrombotic risk and in-hospital mortality. A thorough understanding of these biomarkers might aid risk stratification and prognostication, guide interventions and provide a platform for future research.
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http://dx.doi.org/10.1038/s41569-021-00665-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8757397PMC
January 2022

A randomised controlled trial to assess the antithrombotic effects of aspirin in type 1 diabetes: role of dosing and glycaemic control.

Cardiovasc Diabetol 2021 12 17;20(1):238. Epub 2021 Dec 17.

Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK.

Background: The enhanced thrombotic milieu in diabetes contributes to increased risk of vascular events. Aspirin, a key antiplatelet agent, has inconsistent effects on outcomes in diabetes and the best dosing regimen remains unclear. This work investigated effects of aspirin dose and interaction with glycaemia on both the cellular and protein components of thrombosis.

Methods: A total of 48 participants with type 1 diabetes and 48 healthy controls were randomised to receive aspirin 75 or 300 mg once-daily (OD) in an open-label crossover study. Light transmittance aggregometry and fibrin clot studies were performed before and at the end of each treatment period.

Results: Aspirin demonstrated reduced inhibition of collagen-induced platelet aggregation (PA) in participants with diabetes compared with controls, although the higher dose showed better efficacy. Higher aspirin dose facilitated clot lysis in controls but not individuals with diabetes. Collagen-induced PA correlated with glycaemic control, those in the top HbA1c tertile having a lesser inhibitory effect of aspirin. Threshold analysis suggested HbA1c levels of > 65 mmol/mol and > 70 mmol/mol were associated with poor aspirin response to 75 and 300 mg daily doses, respectively. Higher HbA1c was also associated with longer fibrin clot lysis time.

Conclusions: Patients with diabetes respond differently to the antiplatelet and profibrinolytic effects of aspirin compared with controls. In particular, those with elevated HbA1c have reduced inhibition of PA with aspirin. Our findings indicate that reducing glucose levels improves the anti-thrombotic action of aspirin in diabetes, which may have future clinical implications.

Trial Registration: EudraCT, 2008-007875-26, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2008-007875-26 .
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http://dx.doi.org/10.1186/s12933-021-01427-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8684134PMC
December 2021

Use of continuous glucose monitoring trend arrows in the younger population with type 1 diabetes.

Diab Vasc Dis Res 2021 Nov-Dec;18(6):14791641211062155

Paediatric Endocrinology Department, Sheikh Shakhbout Medical City and Khalifa University Abu Dhabi, Abu Dhabi, UAE.

Early control of glycaemia is key to reduce vascular complications in individuals with Type 1 diabetes. Therefore, encouraging children and adolescents with T1DM to take responsibility for controlling glucose levels is an important yet a challenging task. The rapid expansion of continuous glucose monitoring (CGM) systems has allowed for more comprehensive analysis of glycaemia in T1D. Moreover, CGM devices have the ability to calculate rate of change in glucose levels and display the information as trend arrows. In turn, this can help to take evasive actions to return glucose levels to near physiological glycaemia, which can be highly motivating for young people with T1DM. In the absence of standardised, evidence-based guidance, this consensus document, generated by experts from the Arab Society of Paediatric Endocrinology and Diabetes and international advisors, summarises recent literature on the use of trend arrows in young people with T1DM. The use of trend arrows in different CGM systems is reviewed and their clinical significance is highlighted. Adjusting insulin doses according to trend arrows is discussed while also addressing special situations, such as exercise, fasting, nocturnal hypoglycaemia and menstruation. Adequate understanding of trend arrows should facilitate optimisation of glycaemic control in the T1D population.
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http://dx.doi.org/10.1177/14791641211062155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8671682PMC
December 2021

Fibrinogen and Antifibrinolytic Proteins: Interactions and Future Therapeutics.

Int J Mol Sci 2021 Nov 21;22(22). Epub 2021 Nov 21.

Division of Cardiovascular & Diabetes Research, Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM), University of Leeds, Leeds LS2 9JT, UK.

Thrombus formation remains a major cause of morbidity and mortality worldwide. Current antiplatelet and anticoagulant therapies have been effective at reducing vascular events, but at the expense of increased bleeding risk. Targeting proteins that interact with fibrinogen and which are involved in hypofibrinolysis represents a more specific approach for the development of effective and safe therapeutic agents. The antifibrinolytic proteins alpha-2 antiplasmin (α2AP), thrombin activatable fibrinolysis inhibitor (TAFI), complement C3 and plasminogen activator inhibitor-2 (PAI-2), can be incorporated into the fibrin clot by FXIIIa and affect fibrinolysis by different mechanisms. Therefore, these antifibrinolytic proteins are attractive targets for the development of novel therapeutics, both for the modulation of thrombosis risk, but also for potentially improving clot instability in bleeding disorders. This review summarises the main properties of fibrinogen-bound antifibrinolytic proteins, their effect on clot lysis and association with thrombotic or bleeding conditions. The role of these proteins in therapeutic strategies targeting the fibrinolytic system for thrombotic diseases or bleeding disorders is also discussed.
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http://dx.doi.org/10.3390/ijms222212537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8625824PMC
November 2021

Fibrinogen αC-subregions critically contribute blood clot fibre growth, mechanical stability, and resistance to fibrinolysis.

Elife 2021 10 11;10. Epub 2021 Oct 11.

Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom.

Fibrinogen is essential for blood coagulation. The C-terminus of the fibrinogen α-chain (αC-region) is composed of an αC-domain and αC-connector. Two recombinant fibrinogen variants (α390 and α220) were produced to investigate the role of subregions in modulating clot stability and resistance to lysis. The α390 variant, truncated before the αC-domain, produced clots with a denser structure and thinner fibres. In contrast, the α220 variant, truncated at the start of the αC-connector, produced clots that were porous with short, stunted fibres and visible fibre ends. These clots were mechanically weak and susceptible to lysis. Our data demonstrate differential effects for the αC-subregions in fibrin polymerisation, clot mechanical strength, and fibrinolytic susceptibility. Furthermore, we demonstrate that the αC-subregions are key for promoting longitudinal fibre growth. Together, these findings highlight critical functions of the αC-subregions in relation to clot structure and stability, with future implications for development of novel therapeutics for thrombosis.
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http://dx.doi.org/10.7554/eLife.68761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8553339PMC
October 2021

Addressing shortfalls of laboratory HbA using a model that incorporates red cell lifespan.

Elife 2021 09 13;10. Epub 2021 Sep 13.

Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom.

Laboratory HbA does not always predict diabetes complications and our aim was to establish a glycaemic measure that better reflects intracellular glucose exposure in organs susceptible to complications. Six months of continuous glucose monitoring data and concurrent laboratory HbA were evaluated from 51 type 1 diabetes (T1D) and 80 type 2 diabetes (T2D) patients. Red blood cell (RBC) lifespan was estimated using a kinetic model of glucose and HbA, allowing the calculation of person-specific adjusted HbA (aHbA). Median (IQR) RBC lifespan was 100 (86-102) and 100 (83-101) days in T1D and T2D, respectively. The median (IQR) absolute difference between aHbA and laboratory HbA was 3.9 (3.0-14.3) mmol/mol [0.4 (0.3-1.3%)] in T1D and 5.3 (4.1-22.5) mmol/mol [0.5 (0.4-2.0%)] in T2D. aHbA and laboratory HbA showed clinically relevant differences. This suggests that the widely used measurement of HbA can underestimate or overestimate diabetes complication risks, which may have future clinical implications.
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http://dx.doi.org/10.7554/eLife.69456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437432PMC
September 2021

Associations Between Erythrocyte Membrane Fatty Acid Compositions and Biomarkers of Vascular Health in Adults With Type 1 Diabetes With and Without Insulin Resistance: A Cross-Sectional Analysis.

Can J Diabetes 2021 Jun 26. Epub 2021 Jun 26.

Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom; School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China; Institute of Health Sciences and Wellbeing, University of Sunderland, Sunderland, United Kingdom.

Objectives: The aim of this study was to assess the relationship between specific erythrocyte fatty acid levels and vascular health in type 1 diabetes (T1D) with and without insulin resistance (IR).

Methods: We analyzed baseline pretreatment data in a subset of 23 patients with T1D from a previously published randomized controlled trial consisting of comprehensive erythrocyte-derived fatty acid profiles and a panel of inflammation-associated endothelial markers. Estimated glucose disposal rate was used to identify and categorize patients with IR. We utilized principal component analysis (PCA) to cluster vascular biomarkers to compute a single "vascular signal" and utilized univariate linear regression models to investigate the association with IR and fatty acid profiles.

Results: Subjects with IR displayed significantly higher levels of linoleic acid (p=0.001), lower levels of eicosapentaenoic acid (EPA) (p<0.001), lower levels of omega-3 polyunsaturated fatty acid (n-3PUFA) (p<0.006) and an increased omega-6 (n-6)PUFA:n-3PUFA ratio (p=0.001). IR was associated with significantly higher linoleic acid levels, total n-6PUFA and an increased ratio of n-6PUFA:n-3PUFA, and negatively associated with arachidonic acid and EPA levels, total saturated fatty acid and total n-3PUFA. The PCA-derived vascular biomarker cluster was positively associated with linoleic acid and n-6PUFA:n-3PUFA ratio, and inversely associated with EPA.

Conclusions: Specific erythrocyte membrane fatty acid compositions are associated with impaired vascular health and IR in adults with T1D. These findings suggest that IR and risk of associated complications may be influenced by specific fatty acid profiles, and thus potentially modified by the selective targeting of dietary fatty acids.
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http://dx.doi.org/10.1016/j.jcjd.2021.06.005DOI Listing
June 2021

Insights Into the Results of Sotagliflozin Cardiovascular Outcome Trials: Is Dual Inhibition the Cherry on the Cake of Cardiorenal Protection?

Drugs 2021 Aug 7;81(12):1365-1371. Epub 2021 Jul 7.

Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, 1 St. Kiriakidi Street, 54636, Thessaloniki, Greece.

Sotagliflozin is a dual sodium-glucose co-transporter (SGLT) 2 inhibitor, manifesting a 20-fold higher inhibitory activity for SGLT2 than for SGLT1. Differences in SGLT2 over SGLT1 selectivity of the available agents have been proposed to relate to variability in efficacy and safety characteristics. In contrast to other SGLT2 inhibitors, the cardiorenal effects of sotagliflozin in type 2 diabetes had not been explored until recently, when the results of SOLOIST-WHF (focusing on heart failure [HF] outcomes) and SCORED (focusing on renal outcomes) were published. In SOLOIST-WHF, sotagliflozin reduced the risk of the primary composite outcome of cardiovascular (CV) death and hospitalizations and urgent visits for HF. The findings showed that the risk reduction was consistent in people with reduced but also in those with preserved ejection fraction (EF). In SCORED, sotagliflozin significantly reduced the primary end point of CV deaths, hospitalizations for HF, and urgent visits for HF. A reduction in glycated hemoglobin was evident even in participants with estimated glomerular filtration rate values below 30 mL/min/1.73 m. SCORED is also the first trial to illustrate the benefits of the class across the full range of albuminuria. Moreover, the endpoint of stroke was significantly reduced by 34% in the sotagliflozin compared with the placebo group. The findings of the two studies provide novel insights into the clinical utility of SGLT2 inhibitors, particularly with respect to the early initiation in stable HF, the benefits in HF with preserved EF, the glucose-lowering efficacy in people with severe renal impairment and their potential to improve atherosclerotic vascular disease, including stroke, outcomes.
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http://dx.doi.org/10.1007/s40265-021-01559-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261816PMC
August 2021

Fibrin(ogen) as a Therapeutic Target: Opportunities and Challenges.

Int J Mol Sci 2021 Jun 28;22(13). Epub 2021 Jun 28.

Division of Cardiovascular & Diabetes Research, Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM), University of Leeds, Leeds LS2 9JT, UK.

Fibrinogen is one of the key molecular players in haemostasis. Thrombin-mediated release of fibrinopeptides from fibrinogen converts this soluble protein into a network of fibrin fibres that form a building block for blood clots. Thrombin-activated factor XIII further crosslinks the fibrin fibres and incorporates antifibrinolytic proteins into the network, thus stabilising the clot. The conversion of fibrinogen to fibrin also exposes binding sites for fibrinolytic proteins to limit clot formation and avoid unwanted extension of the fibrin fibres. Altered clot structure and/or incorporation of antifibrinolytic proteins into fibrin networks disturbs the delicate equilibrium between clot formation and lysis, resulting in either unstable clots (predisposing to bleeding events) or persistent clots that are resistant to lysis (increasing risk of thrombosis). In this review, we discuss the factors responsible for alterations in fibrin(ogen) that can modulate clot stability, in turn predisposing to abnormal haemostasis. We also explore the mechanistic pathways that may allow the use of fibrinogen as a potential therapeutic target to treat vascular thrombosis or bleeding disorders. Better understanding of fibrinogen function will help to devise future effective and safe therapies to modulate thrombosis and bleeding risk, while maintaining the fine balance between clot formation and lysis.
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http://dx.doi.org/10.3390/ijms22136916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268464PMC
June 2021

Elimination of fibrin γ-chain cross-linking by FXIIIa increases pulmonary embolism arising from murine inferior vena cava thrombi.

Proc Natl Acad Sci U S A 2021 07;118(27)

Leeds Thrombosis Collective, Discovery & Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 9NL, United Kingdom;

The onset of venous thromboembolism, including pulmonary embolism, represents a significant health burden affecting more than 1 million people annually worldwide. Current treatment options are based on anticoagulation, which is suboptimal for preventing further embolic events. In order to develop better treatments for thromboembolism, we sought to understand the structural and mechanical properties of blood clots and how this influences embolism in vivo. We developed a murine model in which fibrin γ-chain cross-linking by activated Factor XIII is eliminated (FGG3X) and applied methods to study thromboembolism at whole-body and organ levels. We show that FGG3X mice have a normal phenotype, with overall coagulation parameters and platelet aggregation and function largely unaffected, except for total inhibition of fibrin γ-chain cross-linking. Elimination of fibrin γ-chain cross-linking resulted in thrombi with reduced strength that were prone to fragmentation. Analysis of embolism in vivo using Xtreme optical imaging and light sheet microscopy demonstrated that the elimination of fibrin γ-chain cross-linking resulted in increased embolization without affecting clot size or lysis. Our findings point to a central previously unrecognized role for fibrin γ-chain cross-linking in clot stability. They also indirectly indicate mechanistic targets for the prevention of thrombosis through selective modulation of fibrin α-chain but not γ-chain cross-linking by activated Factor XIII to reduce thrombus size and burden, while maintaining clot stability and preventing embolism.
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http://dx.doi.org/10.1073/pnas.2103226118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271579PMC
July 2021

Albumin-mediated alteration of plasma zinc speciation by fatty acids modulates blood clotting in type-2 diabetes.

Chem Sci 2021 Feb 1;12(11):4079-4093. Epub 2021 Feb 1.

School of Medicine, University of St Andrews Fife KY16 9TF St Andrews UK +44 (0)1334 463482 +44 (0)1334 463546.

Zn is an essential regulator of coagulation and is released from activated platelets. In plasma, the free Zn concentration is fine-tuned through buffering by human serum albumin (HSA). Importantly, the ability of HSA to bind/buffer Zn is compromised by co-transported non-esterified fatty acids (NEFAs). Given the role of Zn in blood clot formation, we hypothesise that Zn displacement from HSA by NEFAs in certain conditions (such as type 2 diabetes mellitus, T2DM) impacts on the cellular and protein arms of coagulation. To test this hypothesis, we assessed the extent to which increasing concentrations of a range of medium- and long-chain NEFAs reduced Zn-binding ability of HSA. Amongst the NEFAs tested, palmitate (16 : 0) and stearate (18 : 0) were the most effective at suppressing zinc-binding, whilst the mono-unsaturated palmitoleate (16 : 1c9) was markedly less effective. Assessment of platelet aggregation and fibrin clotting parameters in purified systems and in pooled plasma suggested that the HSA-mediated impact of the model NEFA myristate on zinc speciation intensified the effects of Zn alone. The effects of elevated Zn alone on fibrin clot density and fibre thickness in a purified protein system were mirrored in samples from T2DM patients, who have derranged NEFA metabolism. Crucially, T2DM individuals had increased total plasma NEFAs compared to controls, with the concentrations of key saturated (myristate, palmitate, stearate) and mono-unsaturated (oleate, -vaccenate) NEFAs positively correlating with clot density. Collectively, these data strongly support the concept that elevated NEFA levels contribute to altered coagulation in T2DM through dysregulation of plasma zinc speciation.
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http://dx.doi.org/10.1039/d0sc06605bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179462PMC
February 2021

Accurate prediction of HbA1c by continuous glucose monitoring using a kinetic model with patient-specific parameters for red blood cell lifespan and glucose uptake.

Diab Vasc Dis Res 2021 May-Jun;18(3):14791641211013734

Abbott Diabetes Care, Alameda, CA, USA.

Background: A recent kinetic model proposed a new individualized glycaemic marker, calculated HbA1c (cHbA1c), based on kinetic parameters and glucose levels that are specific to each person. The aims of the current work were to validate the accuracy of this glucose metric for clinical use and evaluate data requirements for the estimation of personal kinetic factors.

Methods: We retrieved HbA1c and glucose data from a group of 51 Japanese T1D patients under sensor-augmented pump (SAP) therapy. Two patient-specific kinetic parameters were identified by data sections, defined as continuous glucose data between two laboratory HbA1c measurements. The cHbA1c was prospectively validated employing subsequent HbA1c data that were not originally used to determine personal kinetic parameters.

Results: Compared to estimated HbA1c (eHbA1c) and glucose management indicator (GMI), cHbA1c showed clinically relevant accuracy improvement, with 20% or more within ±0.5% (±5.5 mmol/mol) of laboratory HbA1c. The mean absolute deviation of the cHbA1c calculation was 0.11% (1.2 mmol/mol), substantially less than for eHbA1c and GMI at 0.54% (5.9 mmol/mol) and 0.47% (5.1 mmol/mol), respectively.

Conclusion: Our study shows superior performance of cHbA1c compared with eHbA1c and GMI at reflecting laboratory HbA1c, making it a credible glucose metric for routine clinical use.
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http://dx.doi.org/10.1177/14791641211013734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8481730PMC
October 2021

Fibrinolysis in Acute and Chronic Cardiovascular Disease.

Semin Thromb Hemost 2021 Jul 20;47(5):490-505. Epub 2021 Apr 20.

Department of Metabolic Medicine, Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom.

The formation of an obstructive thrombus within an artery remains a major cause of mortality and morbidity worldwide. Despite effective inhibition of platelet function by modern antiplatelet therapies, these agents fail to fully eliminate atherothrombotic risk. This may well be related to extensive vascular disease, beyond the protective abilities of the treatment agents used. However, recent evidence suggests that residual vascular risk in those treated with modern antiplatelet therapies is related, at least in part, to impaired fibrin clot lysis. In this review, we attempt to shed more light on the role of hypofibrinolysis in predisposition to arterial vascular events. We provide a brief overview of the coagulation system followed by addressing the role of impaired fibrin clot lysis in acute and chronic vascular conditions, including coronary artery, cerebrovascular, and peripheral vascular disease. We also discuss the role of combined anticoagulant and antiplatelet therapies to reduce the risk of arterial thrombotic events, addressing both efficacy and safety of such an approach. We conclude that impaired fibrin clot lysis appears to contribute to residual thrombosis risk in individuals with arterial disease on antiplatelet therapy, and targeting proteins in the fibrinolytic system represents a viable strategy to improve outcome in this population. Future work is required to refine the antithrombotic approach by modulating pathological abnormalities in the fibrinolytic system and tailoring therapy according to the need of each individual.
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http://dx.doi.org/10.1055/s-0040-1718923DOI Listing
July 2021

PAI-1 in Diabetes: Pathophysiology and Role as a Therapeutic Target.

Int J Mol Sci 2021 Mar 20;22(6). Epub 2021 Mar 20.

Division of Cardiovascular & Diabetes Research, Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM), University of Leeds, Leeds LS2 9JT, UK.

Hypofibrinolysis is a key abnormality in diabetes and contributes to the adverse vascular outcome in this population. Plasminogen activator inhibitor (PAI)-1 is an important regulator of the fibrinolytic process and levels of this antifibrinolytic protein are elevated in diabetes and insulin resistant states. This review describes both the physiological and pathological role of PAI-1 in health and disease, focusing on the mechanism of action as well as protein abnormalities in vascular disease with special focus on diabetes. Attempts at inhibiting protein function, using different techniques, are also discussed including direct and indirect interference with production as well as inhibition of protein function. Developing PAI-1 inhibitors represents an alternative approach to managing hypofibrinolysis by targeting the pathological abnormality rather than current practice that relies on profound inhibition of the cellular and/or acellular arms of coagulation, and which can be associated with increased bleeding events. The review offers up-to-date knowledge on the mechanisms of action of PAI-1 together with the role of altering protein function to improve hypofirbinolysis. Developing PAI-1 inhibitors may form for the basis of future new class of antithrombotic agents that reduce vascular complications in diabetes.
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http://dx.doi.org/10.3390/ijms22063170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003717PMC
March 2021

Antithrombotic therapy in diabetes: which, when, and for how long?

Eur Heart J 2021 06;42(23):2235-2259

Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK.

Cardiovascular disease remains the main cause of mortality in individuals with diabetes mellitus (DM) and also results in significant morbidity. Premature and more aggressive atherosclerotic disease, coupled with an enhanced thrombotic environment, contributes to the high vascular risk in individuals with DM. This prothrombotic milieu is due to increased platelet activity together with impaired fibrinolysis secondary to quantitative and qualitative changes in coagulation factors. However, management strategies to reduce thrombosis risk remain largely similar in individuals with and without DM. The current review covers the latest in the field of antithrombotic management in DM. The role of primary vascular prevention is discussed together with options for secondary prevention following an ischaemic event in different clinical scenarios including coronary, cerebrovascular, and peripheral artery diseases. Antiplatelet therapy combinations as well as combination of antiplatelet and anticoagulant agents are examined in both the acute phase and long term, including management of individuals with sinus rhythm and those with atrial fibrillation. The difficulties in tailoring therapy according to the variable atherothrombotic risk in different individuals are emphasized, in addition to the varying risk within an individual secondary to DM duration, presence of complications and predisposition to bleeding events. This review provides the reader with an up-to-date guide for antithrombotic management of individuals with DM and highlights gaps in knowledge that represent areas for future research, aiming to improve clinical outcome in this high-risk population.
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http://dx.doi.org/10.1093/eurheartj/ehab128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203081PMC
June 2021

Interventions for preventing type 2 diabetes in adults with mental disorders in low- and middle-income countries.

Cochrane Database Syst Rev 2021 02 16;2:CD013281. Epub 2021 Feb 16.

Department of Health Sciences, University of York, York, UK.

Background: The prevalence of type 2 diabetes is increased in individuals with mental disorders. Much of the burden of disease falls on the populations of low- and middle-income countries (LMICs).

Objectives: To assess the effects of pharmacological, behaviour change, and organisational interventions versus active and non-active comparators in the prevention or delay of type 2 diabetes among people with mental illness in LMICs.

Search Methods: We searched the Cochrane Common Mental Disorders Controlled Trials Register, CENTRAL, MEDLINE, Embase and six other databases, as well as three international trials registries. We also searched conference proceedings and checked the reference lists of relevant systematic reviews. Searches are current up to 20 February 2020.

Selection Criteria: Randomized controlled trials (RCTs) of pharmacological, behavioural or organisational interventions targeting the prevention or delay of type 2 diabetes in adults with mental disorders in LMICs.

Data Collection And Analysis: Pairs of review authors working independently performed data extraction and risk of bias assessments. We conducted meta-analyses using random-effects models.

Main Results: One hospital-based RCT with 150 participants (99 participants with schizophrenia) addressed our review's primary outcome of prevention or delay of type 2 diabetes onset. Low-certainty evidence from this study did not show a difference between atypical and typical antipsychotics in the development of diabetes at six weeks (risk ratio (RR) 0.46, 95% confidence interval (CI) 0.03 to 7.05) (among a total 99 participants with schizophrenia, 68 were in atypical and 31 were in typical antipsychotic groups; 55 participants without mental illness were not considered in the analysis). An additional 29 RCTs with 2481 participants assessed one or more of the review's secondary outcomes. All studies were conducted in hospital settings and reported on pharmacological interventions. One study, which we could not include in our meta-analysis, included an intervention with pharmacological and behaviour change components. We identified no studies of organisational interventions. Low- to moderate-certainty evidence suggests there may be no difference between the use of atypical and typical antipsychotics for the outcomes of drop-outs from care (RR 1.31, 95% CI 0.63 to 2.69; two studies with 144 participants), and fasting blood glucose levels (mean difference (MD) 0.05 lower, 95% CI 0.10 to 0.00; two studies with 211 participants). Participants who receive typical antipsychotics may have a lower body mass index (BMI) at follow-up than participants who receive atypical antipsychotics (MD 0.57, 95% CI 0.33 to 0.81; two studies with 141 participants; moderate certainty of evidence), and may have lower total cholesterol levels eight weeks after starting treatment (MD 0.35, 95% CI 0.27 to 0.43; one study with 112 participants). There was moderate certainty evidence suggesting no difference between the use of metformin and placebo for the outcomes of drop-outs from care (RR 1.22, 95% CI 0.09 to 16.35; three studies with 158 participants). There was moderate-to-high certainty evidence of no difference between metformin and placebo for fasting blood glucose levels (endpoint data: MD -0.35, 95% CI -0.60 to -0.11; change from baseline data: MD 0.01, 95% CI -0.21 to 0.22; five studies with 264 participants). There was high certainty evidence that BMI was lower for participants receiving metformin compared with those receiving a placebo (MD -1.37, 95% CI -2.04 to -0.70; five studies with 264 participants; high certainty of evidence). There was no difference between metformin and placebo for the outcomes of waist circumference, blood pressure and cholesterol levels. Low-certainty evidence from one study (48 participants) suggests there may be no difference between the use of melatonin and placebo for the outcome of drop-outs from care (RR 1.00, 95% CI 0.38 to 2.66). Fasting blood glucose is probably reduced more in participants treated with melatonin compared with placebo (endpoint data: MD -0.17, 95% CI -0.35 to 0.01; change from baseline data: MD -0.24, 95% CI -0.39 to -0.09; three studies with 202 participants, moderate-certainty evidence). There was no difference between melatonin and placebo for the outcomes of waist circumference, blood pressure and cholesterol levels. Very low-certainty evidence from one study (25 participants) suggests that drop-outs may be higher in participants treated with a tricyclic antidepressant (TCA) compared with those receiving a selective serotonin reuptake inhibitor (SSRI) (RR 0.34, 95% CI 0.11 to 1.01). It is uncertain if there is no difference in fasting blood glucose levels between these groups (MD -0.39, 95% CI -0.88 to 0.10; three studies with 141 participants, moderate-certainty evidence). It is uncertain if there is no difference in BMI and depression between the TCA and SSRI antidepressant groups.

Authors' Conclusions: Only one study reported data on our primary outcome of interest, providing low-certainty evidence that there may be no difference in risk between atypical and typical antipsychotics for the outcome of developing type 2 diabetes. We are therefore not able to draw conclusions on the prevention of type 2 diabetes in people with mental disorders in LMICs. For studies reporting on secondary outcomes, there was evidence of risk of bias in the results. There is a need for further studies with participants from LMICs with mental disorders, particularly on behaviour change and on organisational interventions targeting prevention of type 2 diabetes in these populations.
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http://dx.doi.org/10.1002/14651858.CD013281.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092639PMC
February 2021

Body mass index, estimated glucose disposal rate and vascular complications in type 1 diabetes: Beyond glycated haemoglobin.

Diabet Med 2021 05 19;38(5):e14529. Epub 2021 Feb 19.

Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, UK.

Aims: To understand the relationship between insulin resistance (IR), assessed as estimated glucose disposal rate (eGDR), and microvascular/macrovascular complications in people with type 1 diabetes.

Materials And Methods: Individuals with a confirmed diagnosis of type 1 diabetes were included in this cross-sectional study. BMI was categorised into normal weight (18.0-24.9 kg m ), overweight (25.0-29.9 kg m ) and obese groups (≥30.0 kg m ). We categorised eGDR into four groups: eGDR >8, 6-7.9, 4-5.9 and <4 mg kg  min . Multiple logistic regression was used to identify associations with vascular complications, after adjusting for relevant confounders.

Results: A total of 2151 individuals with type 1 diabetes were studied. Median [interquartile range (IQR)] age was 41.0 [29.0, 55.0] with diabetes duration of 20.0 [11, 31] years. Odds ratio (OR) for retinopathy and nephropathy in obese compared with normal weight individuals was 1.64 (95% CI: 1.24-2.19; p = 0.001) and 1.62 (95% CI: 1.10-2.39; p = 0.015), while the association with cardiovascular disease just failed to reach statistical significance (OR 1.66 [95% CI: 0.97-2.86; p = 0.066]). Comparing individuals with eGDR ≥8 mg kg  min and <4 mg kg  min showed OR for retinopathy, nephropathy and macrovascular disease of 4.84 (95% CI: 3.36-6.97; p < 0.001), 8.35 (95% CI: 4.86-14.34; p < 0.001) and 13.22 (95% CI: 3.10-56.38; p < 0.001), respectively. Individuals with the highest eGDR category (≥8 mg kg  min ) had the lowest complication rates irrespective of HbA levels.

Conclusions: Obesity is prevalent in type 1 diabetes and diabetes complications are not only related to glucose control. IR, assessed as eGDR, is strongly associated with both microvascular and macrovascular complications, regardless of HbA levels.
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http://dx.doi.org/10.1111/dme.14529DOI Listing
May 2021

Reduction in cardiovascular mortality following severe hypoglycemia in individuals with type 2 diabetes: the role of a pragmatic and structured intervention : Structured intervention for community hypoglycemia.

Cardiovasc Diabetol 2021 01 12;20(1):18. Epub 2021 Jan 12.

Leeds Institute of Cardiovascular and Diabetes Research, University of Leeds, Leeds, UK.

Background: Mortality in individuals with diabetes with severe hypoglycemia requiring ambulance services intervention is high and it is unclear whether this is modifiable. Our aim was to characterise this high-risk group and assess the impact of nurse-led intervention on mortality.

Methods: In this single centre study, patients with diabetes and hypoglycemia requiring ambulance call out were randomized to nurse led support (intensive arm) or managed using existing pathways (standard arm). A third group agreed to have their data collected longitudinally (observational arm). The primary outcome was all-cause mortality comparing intensive with combined standard and observational arms as well as standard arm alone.

Results: Of 828 individuals identified, 323 agreed to participate with 132 assigned to intensive, 130 to standard and 61 to observational arms. Mean follow up period was 42.6 ± 15.6 months. Mortality in type 1 diabetes (n = 158) was similar across study arms but in type 2 diabetes (n = 160) this was reduced to 33% in the intensive arm compared with 51% in the combined arm (p = 0.025) and 50% in the standard arm (p = 0.06). Cardiovascular deaths, the leading cause of mortality, was lower in the intensive arm compared with combined and standard study arms (p < 0.01).

Conclusions: Medium-term mortality following severe hypoglycemia requiring the assistance of emergency services is high in those with type 2 diabetes. In individuals with type 2 diabetes, nurse-led individualized intervention reduces cardiovascular mortality compared with standard care. Large-scale multicentre studies are warranted to further investigate this approach. Trial registration The trial was retrospectively registered on http://www.clinicaltrials.gov with reference NCT04422145.
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http://dx.doi.org/10.1186/s12933-020-01204-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802275PMC
January 2021

Personal Glycation Factors and Calculated Hemoglobin A1c for Diabetes Management: Real-World Data from the Diabetes Prospective Follow-up (DPV) Registry.

Diabetes Technol Ther 2021 Jun 26;23(6):452-459. Epub 2021 May 26.

Clinical and Computational Research, Abbott Diabetes Care, Alameda, California, USA.

Glycated hemoglobin A1c (HbA1c) is a key biomarker in the glycemic management of individuals with diabetes, but the relationship with glucose levels can be variable. A recent kinetic model has described a calculated HbA1c (cHbA1c) that is individual specific. Our aim was to validate the routine clinical use of this glucose metric in younger individuals with diabetes under real-life settings. We retrieved HbA1c and glucose data from the German-Austrian-Swiss-Luxembourgian diabetes follow-up (DPV) registry, which covers pediatric individuals with type 1 diabetes (T1D). The new glycemic measure, cHbA1c, uses two individual parameters identified by data sections that contain continuous glucose data between two laboratory HbA1c measurements. The cHbA1c was prospectively validated using longitudinal HbA1c data. Continuous glucose monitoring data from 352 T1D individuals in 13 clinics were analyzed together with HbA1c that ranged between 4.9% and 10.6%. In the prospective analysis, absolute deviations of estimated HbA1c (eHbA1c), glucose management indicator (GMI), and cHbA1c compared with laboratory HbA1c were (median [interquartile range]): 1.01 (0.50, 1.75), 0.46 (0.21, 084) and 0.26 (0.12, 0.46), giving an average bias of 0.6, 0.4 and 0.0, respectively, in National Glycohemoglobin Standardization Program (NGSP) % unit. For eHbA1c and GMI only 25% and 54% of subjects were within ±0.5% of laboratory HbA1c values, whereas 82% of cHbA1c were within ±0.5% of laboratory HbA1c results. Our data show the superior performance of cHbA1c compared with eHbA1c and GMI at reflecting laboratory HbA1c. These data indicate that cHbA1c can be potentially used instead in laboratory HbA1c, at least in younger individuals with T1D.
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http://dx.doi.org/10.1089/dia.2020.0553DOI Listing
June 2021

Metformin: Is it Still the First Line in Type 2 Diabetes Management Algorithm?

Curr Pharm Des 2021 ;27(8):1061-1067

The LIGHT Laboratories, Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom.

Type 2 diabetes mellitus (T2DM) has an ever-growing prevalence worldwide, affecting 1 in 11 adults. It continues to significantly impact patients in terms of morbidity and mortality, in addition to impairing quality of life while adding to the spiralling healthcare costs. Metformin was first used over half a century ago, and for the past two decades, it has been considered first-line oral therapy to treat patients with T2DM, in whom lifestyle measures failed to improve glycaemic control. Early landmark studies supported a glycaemic benefit with metformin use with a relatively safe adverse effect profile, particularly with avoidance of hypoglycaemia. Moreover, studies have indicated other potential beneficial role for metformin on organs typically affected by diabetes complications. However, more recently, with the discovery of newer hypoglycaemic agents and the wealth of data provided by large-scale cardiovascular safety studies, algorithms for the treatment of patients with T2DM have become increasingly complex. Indeed, recent guidelines challenge current thinking and advocate the use of agents other than metformin as first-line agents in those with higher cardiovascular risk, potentially unseating metformin from its long-held throne. This narrative review aims to summarize the background and origins of metformin, assess its role in the current management of patients with T2DM, highlighting the clinical efficacy and safety profile of this agent. Also, the position of metformin in the clinical algorithms is discussed in light of the most recent evidence in the field, helping with an ever-increasing shift towards individualized patient care to maximize benefits and minimize risks.
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http://dx.doi.org/10.2174/1381612826666201222154616DOI Listing
May 2021

Improving outcome prediction in individuals with colorectal cancer and diabetes by accurate assessment of vascular complications: Implications for clinical practice.

Eur J Surg Oncol 2021 05 3;47(5):999-1004. Epub 2020 Nov 3.

Nuffield Department of Population Health, Big Data Institute, Old Road Campus, University of Oxford, Headington, Oxford, OX3 7LF, UK.

Background: Diabetes is considered a risk factor for mortality following a diagnosis of cancer. We hypothesised that the risk will vary due to the heterogeneous nature of the population and accurate classification of vascular complications will improve prediction of clinical outcomes.

Methods: The COloRECTal cancer data Repository (CORECT-R) was used to identify individuals with primary colorectal cancer, who underwent surgical resection in England (2005-2016). Diabetes was recorded using ICD10 codes (E10-E14) during inpatient hospital admission in the six years preceding cancer diagnosis, complication status was determined using the adapted Diabetes Complications Severity Index (aDCSI). Survival and post-operative outcomes were compared between groups.

Results: Of 232,367 individuals, 28,642 (12.3%) were recorded as having diabetes, 49.2% of whom had complications according to the aDCSI. Patients with diabetes complications had increased incidence of adverse post-operative outcomes (90-day post-operative mortality (6.6% versus 3.2%) and death during the surgical episode (7.9% versus 3.6%)), compared to those without diabetes. Those without complications had rates comparable to the population without diabetes. The odds of death within a year of diagnosis were higher for those with complicated diabetes compared to those without diabetes [OR 1.58 (95%CI 1.51-1.66) p < 0.01], but no difference was observed between those with uncomplicated diabetes and those without diabetes [OR 1.05 (95%CI 0.99-1.11) p = 0.10].

Conclusions: Prediction of outcome following surgery in colorectal cancer patients with diabetes relies on the accurate assessment of complications. This study suggests that the poor post-operative outcomes in diabetes patients may be associated with diabetes complication rather than diabetes itself.
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http://dx.doi.org/10.1016/j.ejso.2020.10.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117971PMC
May 2021

Rationale and design of the LIBERATES trial: Protocol for a randomised controlled trial of flash glucose monitoring for optimisation of glycaemia in individuals with type 2 diabetes and recent myocardial infarction.

Diab Vasc Dis Res 2020 May-Jun;17(5):1479164120957934

Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, West Yorkshire, UK.

Hyperglycaemia in individuals with type 2 diabetes (T2D) and myocardial infarction (MI) is associated with guarded clinical prognosis. Studies improving glucose levels in T2D following MI relied on HbA1c as the main glycaemic marker, failing to address potential adverse effects of hypoglycaemia and glucose variability. We describe the design of the LIBERATES trial that investigates the role of flash glucose monitoring in optimising glycaemic markers in high vascular risk individuals with T2D. This multicentre trial is designed to recruit up to 150 insulin and/or sulphonylurea-treated T2D patients, within 5 days of a proven MI. Individuals will be randomised 1:1 into intervention and control groups using flash glucose monitoring sensors and traditional self-monitoring of blood glucose, respectively. The control group will also wear a blinded continuous glucose monitoring sensor. The primary outcome is the difference in time spent in euglycaemia (defined as glucose levels between 3.9-10.0 mmol/l), comparing study groups 3 months following recruitment, assessed daily for 14 days and as an average. Secondary and exploratory end points include time spent in hypoglycaemia and hyperglycaemia, HbA1c, quality of life measures, major adverse cardiac events and cost-effectiveness of the intervention. This study will establish the role of flash glucose monitoring in glycaemic management of individuals with T2D sustaining a cardiac event.(Trial Registration: ISRCTN14974233, registered 12th June 2017).
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http://dx.doi.org/10.1177/1479164120957934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919208PMC
January 2021

Lipidomic profiling of plasma free fatty acids in type-1 diabetes highlights specific changes in lipid metabolism.

Biochim Biophys Acta Mol Cell Biol Lipids 2021 01 1;1866(1):158823. Epub 2020 Oct 1.

School of Medicine, University of St Andrews, Medical and Biological Sciences Building, St Andrews, Fife KY16 9TF, United Kingdom. Electronic address:

Type-1 diabetes mellitus (T1DM) is associated with metabolic changes leading to alterations in glucose and lipid handling. While T1DM-associated effects on many major plasma lipids have been characterised, such effects on plasma free fatty acids (FFA) have not been fully examined. Using gas chromatography-mass spectrometry, we measured the plasma concentrations of FFA species in individuals with T1DM (n = 44) and age/sex-matched healthy controls (n = 44). Relationships between FFA species and various parameters were evaluated. Plasma concentrations of myristate (14:0), palmitoleate (16:1), palmitate (16:0), linoleate (18:2), oleate (18:1c9), cis-vaccenate (18:1c11), eicosapentaenoate (20:5), arachidonate (20:4) and docosahexanoate (22:6) were reduced in the T1DM group (p < 0.0001 for all, except p = 0.0020 for eicosapentaenoate and p = 0.0068 for arachidonate); α-linolenate (18:3) and dihomo-γ-linolenate (20:3) concentrations were unchanged. The saturated/unsaturated FFA ratio, n-3/n-6 ratio, de novo lipogenesis index (palmitate (main lipogenesis product)/linoleate (only found in diet)) and elongase index (oleate/palmitoleate) were increased in the T1DM group (p = 0.0166, p = 0.0089, p < 0.0001 and p = 0.0008 respectively). The stearoyl-CoA desaturase 1 (SCD1) index 1 (palmitoleate/palmitate) and index 2 (oleate/stearate) were reduced in T1DM (p < 0.0001 for both). The delta-(5)-desaturase (D5D) index (arachidonate/dihomo-γ-linolenate) was unchanged. Age and sex had no effect on plasma FFA concentrations in T1DM, while SCD1 index 1 was positively correlated (p = 0.098) and elongase index negatively correlated with age (p = 0.0363). HbA1c was negatively correlated with all plasma FFA concentrations measured except α-linolenate and dihomo-γ-linolenate. Correlations were observed between plasma FFA concentrations and cholesterol and HDL concentrations, but not LDL concentration or diabetes duration. Collectively, these results aid our understanding of T1DM and its effects on lipid metabolism.
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http://dx.doi.org/10.1016/j.bbalip.2020.158823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695620PMC
January 2021

Estimated glucose disposal rate demographics and clinical characteristics of young adults with type 1 diabetes mellitus: A cross-sectional pilot study.

Diab Vasc Dis Res 2020 May-Jun;17(5):1479164120952321

Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds UK.

Background: Estimated glucose disposal rate (eGDR) is a practical measure of Insulin Resistance (IR) which can be easily incorporated into clinical practice. We profiled eGDR in younger adults with type 1 diabetes mellitus (T1DM) by their demographic and clinical characteristics.

Methods: In this single centre study, medical records of TIDM were assessed and eGDR tertiles correlated with demographic and clinical variables.

Results: Of 175 T1DM individuals, 108 (61.7%) were males. Mean age (±SD) was 22.0 ± 1.6 years and median time from diagnosis 11.0 years (range 1-23). Individuals were predominantly Caucasian (81.7%), with 27.4% being overweight (BMI: 25-30 kg/m) and 13.7% obese (BMI > 30 kg/m). Mean total cholesterol (TC) levels were significantly lower in high and middle eGDR tertiles (4.4 ± 1 and 4.3 ± 0.8 mmol/l, respectively) compared with low eGDR tertile (4.8 ± 1,  < 0.05 for both). Triglyceride (TG) levels showed a similar trend at 1.1 ± 0.5 and 1.1 ± 0.5 mmol/l for high and middle eGDR tertile compared to low eGDR tertile (1.5 ± 1 mmol/l,  < 0.05 for both). Renal function was similar across eGDR tertiles and no difference in retinopathy was detected.

Conclusion: TC and TG are altered in individuals with T1DM and low eGDR, suggesting that this subgroup requires optimal lipid management to ameliorate their vascular risk.
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http://dx.doi.org/10.1177/1479164120952321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919212PMC
September 2020

Omega-3 polyunsaturated fatty acid supplementation versus placebo on vascular health, glycaemic control, and metabolic parameters in people with type 1 diabetes: a randomised controlled preliminary trial.

Cardiovasc Diabetol 2020 08 12;19(1):127. Epub 2020 Aug 12.

School of Food Science and Nutrition, Faculty of Environment, University of Leeds, Leeds, LS2 9JT, UK.

Background: The role of omega-3 polyunsaturated fatty acids (n-3PUFA), and the potential impact of n-3PUFA supplementation, in the treatment and management of type 1 diabetes (T1D) remains unclear and controversial. Therefore, this study aimed to examine the efficacy of daily high-dose-bolus n-3PUFA supplementation on vascular health, glycaemic control, and metabolic parameters in subjects with T1D.

Methods: Twenty-seven adults with T1D were recruited to a 6-month randomised, double-blind, placebo-controlled trial. Subjects received either 3.3 g/day of encapsulated n-3PUFA or encapsulated 3.0 g/day corn oil placebo (PLA) for 6-months, with follow-up at 9-months after 3-month washout. Erythrocyte fatty acid composition was determined via gas chromatography. Endpoints included inflammation-associated endothelial biomarkers (vascular cell adhesion molecule-1 [VCAM-1], intercellular adhesion molecule-1 [ICAM-1], E-selectin, P-selectin, pentraxin-3, vascular endothelial growth factor [VEGF]), and their mediator tumor necrosis factor alpha [TNFα] analysed via immunoassay, vascular structure (carotid intima-media thickness [CIMT]) and function (brachial artery flow mediated dilation [FMD]) determined via ultrasound technique, blood pressure, glycosylated haemoglobin (HbA1c), fasting plasma glucose (FPG), and postprandial metabolism.

Results: Twenty subjects completed the trial in full. In the n-3PUFA group, the mean ± SD baseline n-3PUFA index of 4.93 ± 0.94% increased to 7.67 ± 1.86% (P < 0.001) after 3-months, and 8.29 ± 1.45% (P < 0.001) after 6-months. Total exposure to n-3PUFA over the 6-months (area under the curve) was 14.27 ± 3.05% per month under n-3PUFA, and 9.11 ± 2.74% per month under PLA (P < 0.001). VCAM-1, ICAM-1, E-selectin, P-selectin, pentraxin-3, VEGF, TNFα, CIMT, FMD, blood pressure, HbA1c, FPG, and postprandial metabolism did not differ between or within groups after treatment (P > 0.05).

Conclusions: This study indicates that daily high-dose-bolus of n-3PUFA supplementation for 6-months does not improve vascular health, glucose homeostasis, or metabolic parameters in subjects with T1D. The findings from this preliminary RCT do not support the use of therapeutic n-3PUFA supplementation in the treatment and management of T1D and its associated complications. Trial Registration ISRCTN, ISRCTN40811115. Registered 27 June 2017, http://www.isrctn.com/ISRCTN40811115 .
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http://dx.doi.org/10.1186/s12933-020-01094-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425064PMC
August 2020

The ABO Locus is Associated with Increased Fibrin Network Formation in Patients with Stable Coronary Artery Disease.

Thromb Haemost 2020 Sep 30;120(9):1248-1256. Epub 2020 Jun 30.

Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.

Background:  The locus has been associated with increased risk of myocardial infarction (MI) in patients with coronary artery disease (CAD), but the underlying mechanisms are unknown. As altered fibrin clot structure has been demonstrated to predict MI in CAD patients, we examined the association between the risk variant and fibrin clot properties, and investigated the effects of other CAD-associated risk variants.

Methods:  We included 773 stable CAD patients. Patients were genotyped for 45 genome-wide CAD risk variants, including rs495828 at the locus. We used a genetic risk score (GRS) for CAD calculated as the weighted sum of the number of risk alleles based on all 45 variants. Fibrin clot properties were evaluated using a turbidimetric assay. We studied clot maximum absorbance, a measure of clot density and fiber thickness, together with clot lysis time, an indicator of fibrinolysis potential.

Results:  The rs495828 risk allele was present in 13.2% of patients and associated with higher clot maximum absorbance (adjusted effect size per risk allele: 1.05 [1.01 - 1.09],  = 0.01) but not with clot lysis time ( = 0.97). The rs12936587 ( = 0.04), rs4773144 ( = 0.02), and rs501120 ( = 0.04) were associated with clot lysis time; however, after Bonferroni correction, no significant associations were found between any of the remaining 44 CAD-associated variants and fibrin clot properties. The GRS was not associated with fibrin clot properties (-values > 0.05).

Conclusion:  The risk allele was associated with a more compact fibrin network in stable CAD patients, which may represent a mechanism for increased MI risk in risk variant carriers.
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http://dx.doi.org/10.1055/s-0040-1713753DOI Listing
September 2020

Diabetes and atherothrombosis: The circadian rhythm and role of melatonin in vascular protection.

Diab Vasc Dis Res 2020 Mar-Apr;17(3):1479164120920582

The LIGHT Laboratories, Leeds Institute of Cardiovascular and Metabolic Medicine and Leeds Teaching Hospitals Trust, University of Leeds, Leeds, UK.

Obesity-related euglycaemic insulin resistance clusters with cardiometabolic risk factors, contributing to the development of both type 2 diabetes and cardiovascular disease. An increased thrombotic tendency in diabetes stems from platelet hyperactivity, enhanced activity of prothrombotic coagulation factors and impaired fibrinolysis. Furthermore, a low-grade inflammatory response and increased oxidative stress accelerate the atherosclerotic process and, together with an enhanced thrombotic environment, result in premature and more severe cardiovascular disease. The disruption of circadian cycles in man secondary to chronic obesity and loss of circadian cues is implicated in the increased risk of developing diabetes and cardiovascular disease. Levels of melatonin, the endogenous synchronizer of circadian rhythm, are reduced in individuals with vascular disease and those with deranged glucose metabolism. The anti-inflammatory, antihypertensive, antioxidative and antithrombotic activities of melatonin make it a potential therapeutic agent to reduce the risk of vascular occlusive disease in diabetes. The mechanisms behind melatonin-associated reduction in procoagulant response are not fully known. Current evidence suggests that melatonin inhibits platelet aggregation and might affect the coagulation cascade, altering fibrin clot structure and/or resistance to fibrinolysis. Large-scale clinical trials are warranted to investigate the effects of modulating the circadian clock on insulin resistance, glycaemia and cardiovascular outcome.
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http://dx.doi.org/10.1177/1479164120920582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607413PMC
September 2020

Sodium-Glucose Cotransporter 2 Inhibitors in the Era of COVID-19 Pandemic: Is the Benefit to Risk Ratio Still Favorable?

J Diabetes Sci Technol 2020 Jul 2;14(4):745-747. Epub 2020 Jun 2.

Division of Endocrinology and Metabolism and Diabetes Centre, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Greece.

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http://dx.doi.org/10.1177/1932296820932155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673172PMC
July 2020

Fibrinogen interaction with complement C3: a potential therapeutic target to reduce thrombosis risk.

Haematologica 2021 06 1;106(6):1616-1623. Epub 2021 Jun 1.

Leeds Institute for Cardiovascular and Metabolic Medicine, Leeds, UK.

Complement C3 binds fibrinogen and compromises fibrin clot lysis thereby enhancing thrombosis risk. We investigated the role of fibrinogen-C3 interaction as a novel therapeutic target to reduce thrombosis risk by analysing: i) consistency in the fibrinolytic properties of C3, ii) binding sites between fibrinogen and C3 and iii) modulation of fibrin clot lysis by manipulating fibrinogen-C3 interactions. Purified fibrinogen and C3 from the same individuals (n=24) were used to assess inter-individual variability in the anti-fibrinolytic effects of C3. Microarray screening and molecular modelling evaluated C3 and fibrinogen interaction sites. Novel synthetic conformational proteins, termed Affimers, were used to modulate C3-fibrinogen interaction and fibrinolysis. C3 purified from patients with type 1 diabetes showed enhanced prolongation of fibrinolysis compared with healthy control protein [195±105 and 522±166 seconds, respectively (p=0.04)], with consistent effects but a wider range (5-51% and 5-18% lysis prolongation, respectively). Peptide microarray screening identified 2 potential C3-fibrinogen interactions sites within fibrinogen β chain (residues 424-433, 435-445). One fibrinogen-binding Affimer was isolated that displayed sequence identity with C3 in an exposed area of the protein. This Affimer abolished C3-induced prolongation of fibrinolysis (728±25.1 seconds to 632±23.7 seconds, p=0.005) and showed binding to fibrinogen in the same region that is involved in C3-fibrinogen interactions. Moreover, it shortened plasma clot lysis of patients with diabetes, cardiovascular disease or controls by 7-11%. C3 binds fibrinogen β-chain and disruption of fibrinogen-C3 interaction using Affimer proteins enhances fibrinolysis, which represents a potential novel target tool to reduce thrombosis in high risk individuals.
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http://dx.doi.org/10.3324/haematol.2019.239558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168514PMC
June 2021

Circulating MicroRNA Levels Indicate Platelet and Leukocyte Activation in Endotoxemia Despite Platelet P2Y Inhibition.

Int J Mol Sci 2020 Apr 21;21(8). Epub 2020 Apr 21.

King's British Heart Foundation Centre, King's College London, London SE5 9NU, UK.

There is evidence for the effects of platelet inhibition on innate immune activation. Circulating microRNAs (miRNAs) have been implicated as markers of platelet and leukocyte activation. In the present study, we assessed the effects of P2Y inhibitors on platelet and leukocyte miRNAs during endotoxemia. Healthy volunteers were randomly assigned to receive oral ticagrelor ( = 10), clopidogrel ( = 8) or no drug ( = 8) for one week, followed by an intravenous bolus of 2 ng/kg endotoxin. Serum was collected at baseline, after one week of antiplatelet treatment and 6 and 24 h after endotoxin administration. MiRNAs were screened using LNA-based qPCR, followed by TaqMan-qPCR validation of candidates. Clinical validation was performed in 41 sepsis patients. Platelet-enriched miR-197, miR-223 and miR-223* were decreased in volunteers following antiplatelet therapy. Endotoxin increased platelet miRNAs, whilst the opposite effect was seen for leukocyte-enriched miR-150. Neither of these endotoxin-mediated effects were altered by P2Y inhibitors. Sepsis patients with fatal outcomes ( = 12) had reduced miR-150 levels compared with survivors ( = 29). In conclusion, we show that miR-150 is downregulated in experimental endotoxemia and can predict survival in sepsis but is unaffected by P2Y inhibition. While P2Y inhibition reduces platelet-associated miRNAs in healthy volunteers, it fails to attenuate the response of platelet miRNAs to endotoxemia.
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http://dx.doi.org/10.3390/ijms21082897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215420PMC
April 2020
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