NIHRDataInsights/HRCSData huggingface dataset:
Title: 2012 Doctoral Fellowship: Effect of vitamin D3 supplementation on insulin resistance and cardiovascular risk factors in people at high risk of type 2 diabetes and cardiovascular disease
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: Experts have highlighted a need for more studies examining the efficacy of vitamin D supplementation in relation to non-skeletal health outcomes. Recent systematic reviews have concluded that high-quality randomised controlled trials, specifically designed to test the hypothesis that vitamin D is a direct contributor to type 2 diabetes pathogenesis, are needed and that these should be conducted in well-defined populations. These trials must also ensure that vitamin D dosage is appropriate, and is given for long enough duration, to ensure optimisation of vitamin D status. Furthermore, appropriate markers of type 2 diabetes pathogenesis, such as insulin resistance, should be employed as endpoints. The overall aim of this double-blind, placebo controlled trial is to investigate the effect of 6 months of vitamin D3 supplementation (75g/d; 3000IU) on insulin resistance (assessed using the gold standard glucose clamp technique) and cardiovascular risk factors in individuals who have pre-diabetes and, hence, are at particularly high risk of type 2 diabetes (T2D) and cardiovascular disease (CVD). Our proposed multi-disciplinary team has worked together for a number of years and has significant experience in the assessment of insulin resistance using the clamp technique and in carrying out similar nutrition intervention studies in a wide range of populations. The trial we propose therefore addresses the needs identified in previous systematic and expert reviews, and aims to evaluate the efficacy of a potentially straightforward and low-cost health care intervention. This has clear economic and social implications given the current, and projected, burden of T2D and CVD. (248 WORDS)


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: METABOLIC AND ENDOCRINE;CARDIOVASCULAR
Title: Moving towards a new personalised medicine approach to primary prevention in diabetes: the first steps
Funder: Chief Scientist Office (Scotland)

Abstract: In non-diabetics we have developed a whole new approach to the primary prevention of CV events. This involves screening for silent heart disease with BNP ± hsTnT, followed by cardiac phenotyping those with high biomarkers followed by personalised medicine against each cardiac abnormality seen on phenotyping (3P Screening). In non-diabetics, the c-statistic for screening with BNP ± hsTnT was 0•81. We now wish to see in 246 well controlled diabetics how well BNP ± hsTnT performs at identifying those with any form of silent heart disease i.e. does it perform as well in diabetes as it did in non-diabetics? A key novel twist is that we will do comprehensive cardiac phenotyping which identifies the main 5 silent cardiac abnormalities which are all known to precede CV events. This enables us to see how common multiple silent cardiac abnormalities are in well controlled diabetes. Our third endpoint is to see how good BNP ± hsTnT are at identifying when multiple silent cardiac abnormalities are present in a particular diabetic patient.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: METABOLIC AND ENDOCRINE;CARDIOVASCULAR
Title: Combinatoral Cell Therapy for Diabetes-related critical limb ischaemia
Funder: Department for the Economy, Northern Ireland

Abstract: Diabetic blood vessel complication critical limb ischaemia (CLI), a condition where blood flow to the lower extremity is impaired to the extent of threatening viability, could be treated with cell therapy to regenerate damaged tissues. We will isolate reparative cells, expand and then inject into sites of blood vessel damage. Cells from diabetics are known to be defective so we will identify and correct this defect and potentially use patient’s own cells for therapy or in combination with cells from healthy donors. We aim to provide a pioneering new treatment for CLI personalised to diabetic patients


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: METABOLIC AND ENDOCRINE;CARDIOVASCULAR
Title: Diabetes Data Science Catalyst
Funder: Diabetes UK

Abstract: The Diabetes Data Science Catalyst was launched by the British Heart Foundation (BHF) Data Science Centre in partnership with Diabetes UK, HDR UK and the BHF. Its aim is to accelerate understanding of the links between cardiovascular disease and diabetes by harnessing the power of linked data.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: METABOLIC AND ENDOCRINE;CARDIOVASCULAR
Title: Myocardial energy starvation and ketone metabolism in patients with type 2 diabetes
Funder: Wellcome Trust

Abstract: Patients with type 2 diabetes(T2D) are ‘cardiac energy-deficient’ and this deficiency contributes to their excess heart failure(HF) risk. The key mechanisms for cardiac energy deficiency are reduced myocardial blood flow, loss of metabolic flexibility over the choice of energy fuels and mitochondrial dysfunction. The contribution of these changes to the development of HF has not been systematically studied.Recent studies have highlighted the potential role of ketone bodies as a significant fuel source, and suggested an association between mild ketosis and improved clinical outcome in T2D. Two work packages will be performed. Work-package1 aims to: 1. Elucidate the mechanisms of the energy-starved state of the heart in diabetes; 2. Determine how alterations of cardiac energy metabolism differ between prediabetes, T2D, and concomitant T2D and HF; 3. Determine if ketones induce a differential response in mitochondrial respiration and whether this differential response varies along the continuum of diabetic heart disease. Data will be acquired from patients undergoing aortic valve surgery for comprehensive assessments including: cardiovascular magnetic resonance imaging and spectroscopy; coronary sinus sampling studies; high resolution respirometry and liquid chromatography-triple quadrupole-mass spectrometry metabolomics from heart samples. Work-package 2 will explore the impact of ketone infusion on cardiac energy generation and contractile function in T2D patients.

Lay abstract: Diabetes increases the risk of heart failure. Once the heart failure is established, only one in five patients survive beyond five years. This high risk of death is alarming and highlights the importance of preventing the development of heart failure in diabetes patients. One efficient way to treat or prevent heart failure is increasing the energy available for heart muscle to pump. For this we first need to better understand why diabetes patients have low energy levels in their heart. Moreover, in diabetes, heart muscle uses more ketone as an energy fuel,but it is unknown if this change aims to improve energy generation.Seeking to answer these questions, using MR scans, heart biopsy samples and special blood tests, I will pursue the problem of excess heart failure risk in diabetes, exploring new and more efficient treatment options to mitigate this risk, with results relevant for 400 million people living with diabetes.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE;CARDIOVASCULAR
Title: Anglo-Danish-Dutch study of Intensive Treatment of people with Newly diagnosed diabetes in primary care (ADDITION) - effects on cardiovascular events at five years
Funder: Department of Health (England)

Abstract: Diabetes is a common chronic condition that is associated with an increased risk of heart disease stroke amputation visual impairment and kidney damage. Currently most people become diagnosed with diabetes when they develop symptoms or a complication but there is evidence to suggest that the true onset occurs several years earlier. Although it seems logical to propose that earlier detection of the disorder would result in health benefits this has not been clearly established. Recent studies have suggested that careful attention needs to be given to raised blood glucose levels elevated blood pressure and blood cholesterol levels. There is good evidence that treating all these risk factors simultaneously is beneficial for people who have had diabetes for many years but it is not clear how effective such an approach will be in patients detected earlier by screening. This study aims to discover whether earlier detection and subsequent intensive treatment are worthwhile by quantifying the costs and benefits of such an approach. The study was set up in 2001. 55 GP practices in the Eastern region and 20 practices in the Leicestershire region agreed to participate. Following a step-wise screening procedure 1026 patients were diagnosed with diabetes. Surgeries were allocated by chance to either deliver intensive treatment (a combination of medication and advice on lifestyle changes for example diet and physical activity) or standard care according to current national guidelines. Now that five years have passed we have a unique opportunity to assess how effective this treatment has been and to see whether it has reduced the risk of developing diabetic complications such as heart attack and premature death. Results from our study will help to improve care for patients with diabetes and provide information on whether people in middle-age should be offered screening for diabetes in the UK and worldwide.


Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL;6.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE;CARDIOVASCULAR
Title: Peer support to encourage adoption and maintenance of Mediterranean diet: a feasibility and pilot study.
Funder: Medical Research Council

Abstract: Type 2 diabetes is a growing public health problem. It has been recently shown that the Mediterranean diet reduces risk of type 2 diabetes in people at high risk of cardiovascular disease, yet studies showing a benefit of the Mediterranean Diet often use very intensive methods of encouraging behaviour change, which would be expensive if rolled out to the 'at risk' or general population. Peer support strategies may be an important, flexible, low-cost method of encouraging dietary change. This project will, using focus groups (n=12) conducted with people at high risk of cardiovascular disease and interviews with relevant stakeholders including healthcare professionals, examine the feasibility of using peer support strategies to encourage adoption of the Mediterranean Diet in people at high risk of cardiovascular disease. These focus groups will inform the development of a peer support intervention. Once an appropriate peer support intervention has been developed, pilot data regarding the feasibility of using the peer support intervention, in comparison with minimal intervention and an intervention already shown to increase adherence to Mediterranean Diet, will be collected. This pilot trial will be conducted over a 1 year period in participants at high risk of cardiovascular disease (n=75). Endpoints will include the Mediterranean Diet Score, biomarkers of nutritional status, quality of life, and process evaluation data. Pilot study data will subsequently inform a large scale intervention study.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: METABOLIC AND ENDOCRINE;CARDIOVASCULAR
Title: Does physical activity protect against CVD, diabetes and disability in later life? a study of objectively measured physical activity in older adults.
Funder: Department of Health (England)

Abstract: The proportion of older adults (over 60 years) in the UK is growing and bears a high burden of morbidity and mortality, primarily from cardiovascular disease (CVD), stroke, type 2 diabetes, and mobility limitations. Although physical activity can protect against onset of these outcomes, evidence about the dose-response associations with the different dimensions of activity (including frequency, amount, intensity and type) is incomplete in older adults and will be studied here. The health consequences of taking up activity in older adulthood will be studied. Year on year continuities in activity will be evaluated in the first prospective large-scale study using actigraphs in older adults.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: METABOLIC AND ENDOCRINE;CARDIOVASCULAR
Title: Ethnic differences in risks and outcomes of the cardiometabolic syndrome: Southall And Brent REvisited: SABRE.
Funder: Wellcome Trust

Abstract: The largest and longest running British tri-ethnic cohort consisting of 2300 Europeans, 1700 South Asians and 800 African Caribbeans had baseline cardiovascular and diabetes assessments between 1989 and 1991. We propose a comprehensive combined morbidity and mortality follow up, together with non-invasive clinical measurements in survivors. 1. We will demonstrate that: 1.1 Compared with Europeans: a. South Asians experience disproportionately greater, and African Caribbeans less CHD events and coronary calcification scores, explained by differential impacts of dysglycaemia on lipids and lipoproteins b. African Caribbeans and South Asians experience disproportionately greater stroke events and lacunar infarcts on MRI explained by enhanced loss of nocturnal blood pressure dipping in association with dysglycaemia. 1.2. Clinical measurements will demonstrate ethnic group differences in structure and function of vascular target organs including left ventricular dysfunction, ventricular and large vessel remodelling, and atherosclerosis. These differences will be explained by different expressions of the cardiometabolic syndrome at baseline and follow-up. 2. The study will inform thresholds for cardiovascular risk factor interventions and for diagnosis of diabetes in British ethnic minorities.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: METABOLIC AND ENDOCRINE;CARDIOVASCULAR
Title: Genetic, Biochemical and Functional Analyses of Genes in the Highly Atherogenic Disorder Familial Combined Hyperlipidemia (FCHL).
Funder: Wellcome Trust

Abstract: Elevated levels of blood fat (including cholesterol) can run in families and substantially increase the risk of developing angina and heart attacks even in young people. An individual's blood fat levels can vary according to their diet, weight and lifestyle choices, including the amount and type of physical exercise taken. In some people, genes inherited from one's parents majorly impact on blood fat levels. Establishing in young adulthood which people have inherited a gene or combination of gen es that increases their likelihood of developing high fat levels would help reduce the debilitating consequences:heart attack and stroke due to blood clots. The project aim is to identify gene abnormalities in families with very high blood fat levels using modern day technologies and further tests to examine the consequences of the abnormalities. The results will help scientists to understand the causes of high blood fat levels in people where family data is absent. We have made good p rogress on the project and wish to further interrogate three faulty genes. Thus, our studies should help the NHS to better diagnose the cause of an individual's high fat levels and suggest more effective ways of reducing the debilitating consequences of their high fat levels.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE;CARDIOVASCULAR
Title: Causes and Consequences of Pathological Adipose Remodelling
Funder: Wellcome Trust

Abstract: This proposal addresses two factors important in obesity-related disease, namely determinants of healthy adipose remodelling in chronic positive energy balance, and mechanisms linking insulin resistance to disease. Two rare, informative human disorders will first be dissected, one featuring subcutaneous lipodystrophy due to heterozygous loss of DNA polymerase delta activity and the second a mixture of lower body fat loss and dramatic upper body adipose hyperplasia due to a missense mutation in mitofusin 2, involved in mitochondrial fusion and other processes. Physiological, tissue and cellular studies of humans and mouse models will address the role of DNA replication/repair and mitochondrial dynamics in depot-specific human adipose remodelling, and will test both mitigating strategies and relevance for common disease. The second part of the project will exploit emerging techniques for saturation mutagenesis coupled to downstream functional assays to develop “look up” tools for stratification of genetic variants by functional consequence. Saturating mutation libraries and such derived tools have myriad applications, including genetic diagnosis of rare disease, patient stratification for experimental medicine studies, and linking of functional perturbations to lifecourse human phenotypes in genotyped cohorts. The approach will be applied first to the insulin receptor, and thence other genes involved in insulin signal transduction.

Lay abstract: Risk of diabetes, heart attacks and strokes with weight gain varies among people. How fat tissue responds to extra storage demands appears important. Fat tissue is complex and variable among body regions, and is not well understood. This project starts from two rare, severe human genetic disorders. In one impaired copying/repair of genes produces fat loss under the skin, and in another a defect in linking mitochondria (the cell’s power-generating organs) produces dramatic accumulation of upper body fat. By studying people, cells and mice with the same gene changes we will investigate how gene copying/repair and mitochondrial linkage keep fat tissue healthy, and whether this malfunctions in common disease. We will also use emerging techniques to study all possible changes in a gene simultaneously rather than one by one, starting with the insulin receptor. This will accelerate diagnosis of rare disease and studies of gene changes in the general population.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE;CARDIOVASCULAR;CANCER AND NEOPLASMS
Title: Nutrition, Development and Lifelong Health: Studies in Developing and Transitioning Populations
Funder: Medical Research Council

Abstract: Past research in this programme has shown that the maternal undernutrition, and low birthweight and infant weight gain typical of poor rural populations in India are associated with reduced lean mass, bone mass and cognitive function in childhood and/or adult life, and an increased risk of low birthweight and stunting in the next generation. When early life undernutrition is followed by rapid childhood and adolescent weight gain or excessive adult weight gain, features that are enabled by economic transition and urbanisation, there is a high risk of insulin resistance and metabolic syndrome, type 2 diabetes and CVD. In women, this transition increases the risk of gestational diabetes, which also causes insulin resistance and diabetes in the next generation. Poor diet quality, leading to inadequate intakes of a range of vitamins and minerals, is common among poor rural and urban women, and is associated with lower birthweight. Vitamin B12 deficiency is common in India for cultural reasons, and may be a particularly important nutritional deficit in this population. Maternal vitamin B12 deficiency is associated with low birthweight, insulin resistance in the children, and increased maternal adiposity and gestational diabetes. A major focus of our future work will be on intervention studies. Of several possible intervention points in the dual cycle of risk, we have chosen the adolescent and young adult age group, with the objective of improving the health of young women before pregnancy, improving pregnancy outcomes and reducing metabolic/CVD risk in the children. Interventions will be designed not only for overtly undernourished women, but also for middle class urban women because they too, and their children, are at risk. Alongside these intervention studies, we will continue to follow-up our existing birth cohorts, to better define associations between early life factors and risk markers for later disease, disease endpoints (CVD and T2DM), bone health and cognition. In the Delhi study, we will explore inter-generational associations for these outcomes, by studying children of the cohort. Like the other ERC programmes, we will utilise the intervention and cohort studies to explore epigenetic mechanisms as a possible link between early nutrition and later outcomes. Other international collaborations will include studies of social factors in early life in relation to adult health and disease, and studies of the economic impact of impaired early development.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: METABOLIC AND ENDOCRINE;CARDIOVASCULAR;GENERIC HEALTH RELEVANCE
Title: Using genetics to understand causal mechanisms underlying adverse outcomes of obese pregnancies
Funder: Wellcome Trust

Abstract: More than 1 in 5 UK pregnant women are clinically obese, a condition associated with heterogeneous health outcomes for mother and baby. Only limited understanding of the associations (e.g. gestational diabetes and high birth weight, hypertension and preterm birth/low birth weight) has been possible in traditional observational studies due to complex interrelated exposures and outcomes. My research will use human genetics to dissect causal pathways and understand how a higher maternal BMI can lead to such diverse outcomes. I hypothesise that maternal effects on fetal growth and gestational duration are moderated by fetal genetics. My first aim is to understand how a fetus regulates its own growth and gestational duration in different maternal environments. We will apply results of new genome-wide association studies of placental weight and umbilical cord insulin to give mechanistic insights. My second aim is to understand how raised maternal BMI impacts gestational duration and growth, and my third aim is to examine whether fetal genetics can influence the maternal environment. By identifying causal mechanisms, this fellowship will be an advance towards better targeting of antenatal healthcare and advice to pregnant women, according to their level of risk to reduce the incidence of adverse pregnancy outcomes.

Lay abstract: Maternal obesity (an excessive amount of body fat) is one of the most common risk factors in pregnancy. Risks associated with obesity are varied but can result in problems for both mother (pregnancy-related diabetes, high blood pressure) and her baby (small or large birthweight, early delivery). While these risks are known, we are not certain what the processes (mechanisms) are that link the mother’s obesity with effects on her pregnancy and fetus. We will use human genetics data in babies, mothers and fathers with information on growth, pregnancy duration and other measures, to find out how a fetus regulates its own growth, how the mother’s glucose and blood pressure affect the fetus, and whether the genetics of the fetus can influence changes in the mother’s body in pregnancy. Clarifying these underlying mechanisms is essential for improved, targeted antenatal healthcare for women and their babies according to their level of risk.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE;CARDIOVASCULAR;REPRODUCTIVE HEALTH AND CHILDBIRTH