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Diabetes: Birmingham launches five new research studies

Written by Louise Stanley on . Posted in Clinical trials, Health inequalities, Inflammation and chronic disease.

BHP founder-member the University of Birmingham has announced the launch of five new major studies aimed at improving the prevention, treatment and management of type 1 diabetes – with a particular focus on children and young adults.

The new studies include:

  • The ELSA Study: Led by Professor Parth Narendran, the ELSA Study (EarLy Surveillance for Autoimmune diabetes) will see researchers interviewing families, doctors, nurses and schools, to determine if, and how, the UK should develop a testing and monitoring programme that will identify children at risk of type 1 diabetes. The ELSA Study is being funded by the National Institute for Health Research (NIHR), and is being carried out in collaboration with Birmingham Health Partners, Birmingham Community Healthcare NHS Foundation Trust and the Department of Health and Social Care, as well as the Universities of Cardiff, Warwick, Oxford and Imperial College London.
  • Diabetes and health inequalities: Through £1.9m funding from NIHR, Professor Tim Barrett’s team will ask children and young people with diabetes and their families from poorer and/ or ethnic minority backgrounds how language issues, feelings, income, living conditions and food availability affect how they manage diabetes. They will identify new ways to make diabetes management easier and more successful, and will test these systems in trials involving NHS hospitals.
  • Immunotherapies for diabetes: The greatest barrier to the development of specific immunotherapies for type 1 diabetes is that we currently do not understand the mechanism of how immunotherapies switch off the immune response to our own proteins. A clinical study led by Professor David Wraith, and funded by $735,000 from The Leona M. and Harry B. Helmsley Charitable Trust, will be carried out in collaboration with Cardiff University. It will test a new peptide developed by the University of Birmingham, work which was also funded by the Helmsley Charitable Trust with a $610,000 grant. The new peptide has the potential to control the T-cell immune response in people who are either at risk of developing type 1 diabetes or are newly diagnosed. In this study, the team will assess the changes in immune cells from the site of injection, the draining lymph nodes and peripheral blood. This will be the first in-depth analysis of the molecular changes responsible for antigen-specific immunotherapy in type 1 diabetes.
  • Sight loss and diabetes: Two separate projects led by Dr Jose Romero Hombrebueno will explore the function of membrane-bound cell organelles, known as mitochondria, which generate most of the chemical energy needed to power the cell’s biochemical reactions. The researchers will examine the role of mitochondrial function in both the development of multiple health conditions as the consequence of type 1 diabetes, and also the role it plays in developing diabetic retinopathy – an eye condition that can cause sight loss and blindness in people who have diabetes. The latter research is being funded by Diabetes UK, while the former is being funded by the European Foundation for the Study of Diabetes.
  • Exercise and type 1 diabetes: Led by Dr Alex Wadley and funded by the Rosetrees Trust, this research will examine how a home-based exercise programme impacts autoimmunity in patients with newly diagnosed type 1 diabetes. The project will evaluate whether exercise slows the progression of type 1 diabetes by altering the number and activity of white blood cells in the circulation that have the potential to attach to, enter and degrade the pancreas. Although evidence supports a role for exercise to promote general health and wellbeing in patients with type 1 diabetes, this project aims to provide novel evidence that exercise can directly slow the progression of the disease upon diagnosis.

Parth Narendran, Professor of Diabetes Medicine at the University of Birmingham’s Institute of Immunology and Immunotherapy, said: “The UK has one of the highest incidences of type 1 diabetes in the developed world, at 25 per 100,000 per year, and type 1 diabetes is the most common form of diabetes in children. It occurs when cells that make insulin don’t work as they should, and people with the condition have to self-inject insulin for their entire lives. Studies have recently shown that some medicines can safely delay people getting type 1 diabetes. Some countries, such as the US and Australia, already have surveillance systems to identify people at risk of developing type 1 diabetes and to offer them participation in prevention trials and also to reduce their chances of developing type 1 diabetes as an unexpected emergency. The UK does not have such a system in place. Until now, nobody in the UK has explored whether parents and children would welcome such a system, and how it would work. Through ELSA we will potentially be able to change NHS healthcare policy which would result in the early detection and prevention of this condition and its associated long-term complications.”

Timothy Barrett, Professor of Paediatrics and Child Health at the University of Birmingham’s Institute of Cancer and Genomic Sciences, said: “Diabetes causes high blood sugar levels, which can lead to eye and kidney damage if the condition is not well managed. We know that better sugar control reduces this risk, however, children with diabetes from poorer and/ or ethnic minority groups, often have worse sugar control, while these complications often develop when they are young adults who are working and starting families. There is little evidence to show any previous interventions have helped in reducing health inequalities for children with diabetes in different groups. We will work with young people, their families, and diabetes clinicians to develop an action plan that families feel comfortable with and that will support them to improve their self-management.”

Professor David Wraith, Director of the University of Birmingham’s Institute of Immunology and Immunotherapy, said: “Studies have shown that immunotherapies could play a vital role in treating type 1 diabetes, and it’s essential that we can develop new drugs that could specifically target cells that cause the body’s immune response to behave the wrong way in a person with type 1 diabetes. Our project will help improve our understanding of how the human body’s immune system responds to therapies, which in turn will help the development of new treatments.”

Dr Jose Romero Hombrebueno, Hale-Rudd Lecturer in Experimental Ophthalmology at the University of Birmingham’s Institute of Inflammation and Ageing, said: “It is estimated that 224 million people will have diabetic retinopathy and 70 million will have sight-threatening diabetic retinopathy by 2040. Nearly 90-95% of patients with type 1 diabetes and 78% with type 2 diabetes are expected to develop minimal retinal damage after having diabetes for more than 15 years. Therefore it’s essential that we carry our research that will help advance our knowledge of the underlying causes and potential ways to treat or prevent vision loss in those with diabetes.”

Dr Alex Wadley, of the University of Birmingham’s School of Sport, Exercise and Rehabilitation Sciences, said: “It’s estimated that around 70% of patients with type 1 diabetes do not meet the current recommended exercise guidelines of 150 minutes per week. We are using a home-based exercise programme, which has proven highly popular and safe for individuals with type 1 diabetes, to evaluate how regular exercise impacts the immune system of newly diagnosed patients. Type 1 diabetes is a disease where the body’s own white blood cells attack the pancreas and stop insulin production, resulting in high blood sugar. Regular participation in exercise is key to supporting health and wellbeing in people with type 1 diabetes, but we don’t know how exercise directly impacts these white blood cells that do the damage. With limited therapies available for patients currently, we hope that our findings can promote the use of exercise as an important lifestyle choice for patients and impact standard treatment approaches for type 1 diabetes nationally.’’

New drug treatment regimen shows promise for patients with lupus

Written by Louise Stanley on . Posted in Clinical trials, Inflammation and chronic disease.

The results of a randomised controlled trial, published in Annals of Internal Medicine, found that a new drug treatment regimen – using belimumab soon after rituximab – reduced a disease-related autoantibody and severe disease flares in lupus patients.

Systemic lupus erythematosus (SLE or lupus) is a long-term autoimmune condition, causing a variety of problems including joint pain, skin rashes, kidney disease and tiredness. While there is no known cure for this debilitating disease, the BEAT-Lupus clinical trial found that the combination of belimumab and rituximab shows promising results; reducing severe lupus flares by 3-fold for patients who had persistent, severe lupus disease requiring rituximab therapy at the beginning of the study.

Senior author Professor Caroline Gordon, Emeritus Professor of Rheumatology and member of the Institute of Inflammation and Ageing’s Rheumatology Research Group, together with colleagues from University College London conducted a phase 2 randomised trial involving 52 patients with SLE that was refractory to conventional treatment and whose physicians had recommended rituximab therapy. Patients were treated with rituximab and then randomly assigned four to eight weeks later to receive intravenous belimumab or placebo for 52 weeks.

The researchers found that IgG anti-dsDNA antibody levels were lower in belimumab-treated patients at 52 weeks compared with placebo-treated patients (geometric mean, 47 versus 103 IU/mL; 70% greater reduction from baseline). The risk for severe flare was reduced significantly with belimumab versus placebo (hazard ratio, 0.27), with three and 10 severe flares in the belimumab and placebo groups, respectively. There was no increase seen in the incidence of serious adverse events in the belimumab group.

Professor Michael Ehrenstein, Chief Investigator of the BEAT-Lupus trial, said: “Thanks to the dedication of the lupus teams at participating hospitals we are delighted to not only have completed recruitment, but also to provide preliminary evidence for a clinical benefit of the combination of rituximab and belimumab, compared to patients treated with rituximab alone.”

“These findings support further exploration of belimumab after rituximab as the first combination biologic therapy for patients with SLE, at least in those whose disease is refractory to conventional therapy and/or requires high corticosteroid dosages,” the authors write.

Professor Gordon previously pioneered the methodology for assessing lupus disease activity and flares using the BILAG-2004 index. The main secondary clinical outcome of reduction of severe lupus flare in the BEAT-Lupus trial was based on this work, and flare was defined using this index.

She explained: “We were delighted to find that this treatment regimen not only reduced disease causing autoantibodies but also reduced severe flares which cause very distressing symptoms and disruption to patients’ lives. This study offers the hope that this combination of drugs will be useful in the future if the results are confirmed in a larger trial.”

The study was funded primarily by Versus Arthritis; GlaxoSmithKline provided belimumab free of charge, as well as some additional funding.

Contraceptive pill can reduce type 2 diabetes risk in women with polycystic ovary syndrome

Written by Louise Stanley on . Posted in Inflammation and chronic disease.

A study led by BHP founder-member the University of Birmingham has revealed for the first time that the contraceptive pill can reduce the risk of type 2 diabetes by over a quarter in women with polycystic ovary syndrome (PCOS).

The research findings also show that women with PCOS have twice the risk of developing type 2 diabetes or pre-diabetes (dysglycemia) – highlighting the urgent need to find treatments to reduce this risk.

In addition to the risk of type 2 diabetes, PCOS – which affects 10% of women world-wide – is also associated with a number of other conditions in the long-term, such as endometrial cancer, cardiovascular disease, and non-alcohol related fatty liver disease (NAFLD).

Symptoms of PCOS include irregular periods or no periods at all, which can lead to fertility issues, and many suffer from unwanted hair growth (known as ‘hirsutism’) on the face or body, hair loss on the scalp, and oily skin or acne. These symptoms are caused by high levels of hormones called androgens in the blood of women with PCOS.

Women with PCOS also often struggle with weight gain and the cells in their body are often less responsive to insulin – the hormone that allows the body to absorb glucose (blood sugar) into the cells for energy. This reduced response to insulin can lead to elevated blood glucose levels and can cause the body to make more insulin, which in turn causes the body to make more androgens. The androgens further increase insulin levels – driving a vicious circle.

The University of Birmingham-led team of scientists carried out two studies to firstly identify the risk of developing type 2 diabetes and pre-diabetes in women with PCOS, and secondly to investigate the impact of the use of combined oral contraceptives, often referred to as ‘the pill’, on the risk of type 2 diabetes and pre-diabetes in women with PCOS. The pill is often given to women with PCOS to improve the regularity of menstrual bleeds.

Using UK patient GP records of 64,051 women with PCOS and 123,545 matched control women without PCOS, they first carried out a large population-based cohort study to analyse the risk of type 2 diabetes and pre-diabetes. They found that women with PCOS were twice at risk of type 2 diabetes or pre-diabetes, compared to those without PCOS. They also identified hirsutism (excessive hair growth) – a clinical sign of high androgen levels – as a significant risk factor for type 2 diabetes and pre-diabetes among women with PCOS.

To investigate the impact of the pill on type 2 diabetes or pre-diabetes, the researchers, including experts at the RCSI University of Medicine and Health Sciences, then carried out a further nested case control study of 4,814 women with PCOS. The scientists found that use of combined oral contraceptives reduced the odds of developing type 2 diabetes and pre-diabetes in women with PCOS by 26%.

The researchers behind the study, published in Diabetes Care, are now planning to carry out a clinical trial to further evidence their findings in the hope it will lead to changes in global healthcare policy.

Co-senior author Professor Wiebke Arlt, Director of the University of Birmingham’s Institute of Metabolism and Systems Research, said: “We knew from previous, smaller studies, that women with PCOS have an increased risk of type 2 diabetes. However, what is important about our research is that we have been able to provide new evidence from a very large population-based study to show for the very first time that we have a potential treatment option – combined oral contraceptives – to prevent this very serious health risk.”

Joint first author Dr Michael O’Reilly, Health Research Board Emerging Clinician Scientist and Clinical Associate Professor at RCSI University of Medicine and Health Sciences, added: “We hypothesise that the pill reduces the risk of diabetes by dampening the action of androgens. How does this work? The pill contains oestrogens which increase a protein in the blood called sex hormone-binding globin (SHBG). SHBG binds androgens and, thereby, renders them inactive. Thus, if the pill is taken, SHBG increases. This decreases the amount of unbound, active androgens, lowering their impact on insulin and diabetes risk.”

Joint first author Anuradhaa Subramanian, also of the University of Birmingham, added: “With one in 10 women living with PCOS, which is a life-long metabolic disorder, it is incredibly important that we find ways of reducing its associated health risks.”

Co-senior author Krish Nirantharakumar, Professor in Health Data Science and Public Health at the University of Birmingham’s Institute of Applied Health Research, added: “Importantly, our data highlight that normal weight women with PCOS were also at increased risk of type 2 diabetes and pre-diabetes. This parallels our previous finding of increased NAFLD risk in normal weight women with PCOS, further challenging the notion that PCOS-related metabolic complications are only relevant in the context of obesity. These data suggest that, rather than obesity in isolation, PCOS-specific factors, including androgen excess, underpin the increased metabolic risk.”

The study was supported by funding from Health Data Research UK, Wellcome Trust, the Health Research Board, and the National Institute for Health Research Birmingham Biomedical Research Centre which is based at BHP founding members the University of Birmingham and University Hospitals Birmingham NHS Foundation Trust.

The research was also carried out in collaboration with the University of Colombo in Sri Lanka, and McGill University in Canada.

Specific cell population plays key role in effect of arthritis and people’s pain

Written by Louise Stanley on . Posted in Inflammation and chronic disease.

Research led by scientists at BHP founder-member the University of Birmingham has identified a new specific population of cells that plays a key role in the affect arthritis has on the body and the subsequent pain felt by patients.

The research team, led by scientists from the University ’s Institute of Inflammation and Ageing, conducted a clinical trial involving 52 patients with osteoarthritis – the most common type of arthritis in the UK – which causes joints to become painful and stiff.

All of the patients had osteoarthritis in their knee and were aged between 35 and 85. Of these patients, 29 had early stage disease, while 22 had end-stage disease.

The team, including experts from the University of Bath and Birmingham’s Royal Orthopaedic Hospital, measured levels of inflammation of the lining of the knee joint at different anatomical sites using MRI scans.

Patient-reported pain severity and pain location was recorded using a knee map, where patients marked the anatomical location of where they felt most pain and where they felt least pain or no pain. The researchers then collected joint lining tissue biopsies from parts of the knee where patients reported feeling pain, as well as areas where patients felt no pain.

Corresponding author Dr Simon Jones, of the Institute of Inflammation and Ageing, said: “Inflammation of the joint lining membrane is a known characteristic feature of osteoarthritis. However, its association with joint pain has previously not been clear because both the amount and specific location of inflammation and the location and severity of pain varies among patients.

“Our findings showed that in patients with osteoarthritis of the knee, inflammation of the joint lining membrane tissue was associated with both the location and severity of patient reported joint pain.

“Critically, for the first time we were able to demonstrate that joint lining tissue at the site of patient-reported pain contained a different gene signature, with specific populations of cells – called synovial fibroblasts – that promoted joint inflammation and the growth and survival of nerve cells.”

A gene signature contains information about the activity of a specific group of genes in a cell or tissue. Gene signatures can show how likely certain diseases of conditions can develop or spread and can be used to help diagnose disease, make a prognosis and plan treatment.

Dr Jones added: “Current pain relief medications for patients with knee osteoarthritis are limited in their effectiveness and can cause adverse side effects. Our data provides the rationale to develop therapeutic drugs that are designed to control the activity of specific joint lining cells in order to alleviate joint pain in osteoarthritis patients.”

The research, funded by Versus Arthritis, was carried out over a period of almost four years and is published in the journal EBioMedicine.

AI to improve treatments for people with multiple long-term conditions

Written by Louise Stanley on . Posted in Health inequalities, Inflammation and chronic disease.

The NIHR has awarded £2.5 million for new artificial intelligence (AI) research led by the University of Birmingham. The study will use AI to produce computer programmes and tools to help doctors improve the choice of drugs for patients with clusters of multiple long-term conditions.

Called the OPTIMAL study (OPTIMising therapies, discovering therapeutic targets and AI assisted clinical management for patients Living with complex multimorbidity), the research aims to understand how different combinations of long-term conditions – and the medicines taken for these diseases – interact over time to worsen or improve a patient’s health.

The study will be led by Dr Thomas Jackson and Professor Krish Nirantharakumar at the University of Birmingham and carried out in collaboration with the University of Manchester, University Hospitals Birmingham NHS Foundation Trust, NHS Greater Glasgow & Clyde, University of St Andrews,and the Medicines and Healthcare Products Regulatory Agency. Both the University of Birmingham and University Hospitals Birmingham are founding members of BHP.

An estimated 14 million people in England are living with two or more long-term conditions, with two-thirds of adults aged over 65 expected to be living with multiple long-term conditions by 2035.

Dr Thomas Jackson, Associate Professor in Geriatric Medicine at the University of Birmingham, said: “Currently, when people have multiple long-term conditions, we treat each disease separately. This means we prescribe a different drug for each condition, which may not help people with complex multimorbidity, which is a term we use when patients have four or more long-term health problems.

“A drug for one disease can make another disease worse or better, however, presently we do not have information on the effect of one drug on a second disease. This means doctors do not have enough information to know which drug to prescribe to people with complex multimorbidity.”

Krish Nirantharakumar, Professor in Health Data Science and Public Health at the University of Birmingham, added: “Through our research, we can group such people based on their mixes of disease. Then we can study the effects of a drug on each disease mix. This should help doctors prescribe better and reduce the number of drugs patients need. This will lead to changes in healthcare policy which would benefit most people with complex multimorbidity.”

The research is one of a number of studies being funded by the NIHR’s Artificial Intelligence for Multiple Long-Term Conditions (AIM) call, which is aligned to the aims of the NHSX AI Lab, that combine data science and AI methods with health, care and social science expertise to identify new clusters of disease and understand how multiple long-term conditions develop over the life course.

The call will fund up to £23 million of research in two waves, supporting a pipeline of research and capacity building in multiple long-term conditions research. The first wave has invested nearly £12 million into three Research Collaborations, nine Development Awards and a Research Support Facility, including the University of Birmingham-led study.

Improving the lives of people with multiple long-term conditions and their carers through research is an area of strategic focus for the NIHR, with its ambitions set out in its NIHR Strategic Framework for Multiple Long-Term Conditions Research.

Professor Lucy Chappell, NIHR Chief Executive and chair of the AIM funding committee, said: “This large-scale investment in research will improve our understanding of clusters of multiple long-term conditions, including how they develop over a person’s lifetime.

“Over time, findings from this new research will point to solutions that might prevent or slow down the development of further conditions over time. We will also look at how we shape treatment and care to meet the needs of people with multiple long-term conditions and carers.”

To date NIHR has invested £11million into research on multiple long-term conditions through two calls in partnership with the Medical Research Council, offering both pump-priming funds and funding to tackle multimorbidity at scale.

AI identifies patients with heart failure that respond to beta-blocker treatment

Written by Louise Stanley on . Posted in Early diagnosis and detection, Health inequalities, Inflammation and chronic disease.

Researchers at BHP founder-member the University of Birmingham have developed a new way to identify which patients with heart failure will benefit from treatment with beta-blockers.

Heart failure is one of the most common heart conditions, with substantial impact on patient quality of life, and a major driver of hospital admissions and healthcare cost.

The study involved 15,669 patients with heart failure and reduced left ventricular ejection fraction (low function of the heart’s main pumping chamber), 12,823 of which were in normal heart rhythm and 2,837 of which had atrial fibrillation (AF) – a heart rhythm condition commonly associated with heart failure that leads to worse outcomes.

Published in The Lancet, the study used a series of artificial intelligence (AI) techniques to deeply interrogate data from clinical trials.

The research showed that the AI approach could take account of different underlying health conditions for each patient, as well as the interactions of these conditions to isolate response to beta-blocker therapy. This worked in patients with normal heart rhythm, where doctors would normally expect beta-blockers to reduce the risk of death, as well as in patients with AF where previous work has found a lack of effectiveness. In normal heart rhythm, a cluster of patients was identified with reduced benefit from beta-blockers (combination of older age, less severe symptoms and lower heart rate than average). Conversely in patients with AF, the research found a cluster of patients who had a substantial reduction in death with beta-blockers (from 15% to 9% in younger patients with lower rates of prior heart attack but similar heart function to the average AF patient).

The research was led by the cardAIc group, a multi-disciplinary team of clinical and data scientists at the University of Birmingham and fellow BHP founder-member University Hospitals Birmingham, aiming to integrate AI techniques to improve the care of cardiovascular patients. The study uses data collated and harmonized by the Beta-blockers in Heart Failure Collaborative Group, a global consortium dedicated to enhancing treatment for patients with heart failure.

First Author Dr Andreas Karwath, Rutherford Research Fellow at the University of Birmingham and member of the cardAIc group, added: “We hope these important research findings will be used to shape healthcare policy and improve treatment and outcomes for patients with heart failure.”

Corresponding author Georgios Gkoutos, Professor of Clinical Bioinformatics at the University of Birmingham, Associate Director of Health Data Research UK Midlands and co-lead for the cardAIc group, said: “Although tested in our research in trials of beta-blockers, these novel AI approaches have clear potential across the spectrum of therapies in heart failure, and across other cardiovascular and non-cardiovascular conditions.”

Corresponding author Dipak Kotecha, Professor & Consultant in Cardiology at the University of Birmingham, international lead for the Beta-blockers in Heart Failure Collaborative Group and co-lead for the cardAIc group, added: “Development of these new AI approaches is vital to improving the care we can give to our patients; in the future this could lead to personalised treatment for each individual patient, taking account of their particular health circumstances to improve their well-being.”

The research used individual patient data from nine landmark trials in heart failure that randomly assigned patients to either beta-blockers or a placebo. The average age of study participants was 65 years, and 24% were women. The AI-based approach combined neural network-based variational autoencoders and hierarchical clustering within an objective framework, and with detailed assessment of robustness and validation across all the trials.

The research was presented this week at the ESC Congress 2021, hosted by the European Society of Cardiology – a non-profit knowledge-based professional association that facilitates the improvement and harmonisation of standards of diagnosis and treatment of cardiovascular diseases.