NIHRDataInsights/HRCSData huggingface dataset:
Title: Icosapent ethyl for the treatment of hypertriglyceridaemia [ID3831]
Funder: Department of Health and Social Care

Abstract: Hypertriglyceridemia is a form of dyslipidaemia characterised by high concentrations of triglycerides in the blood and is a risk factor for cardiovascular disease (CVD)[1]. Triglyceride levels can be raised due to either primary causes (an inherited genetic condition) or secondary causes (other influences on triglycerides such as diet, lifestyle and medical conditions such as kidney disease, non-alcoholic fatty liver disease, gout, obesity and type 2 diabetes)[2]. Some people with hypertriglyceridemia have normal levels of high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol. Others have mixed dyslipidaemia, defined as hypertriglyceridemia along with elevations in cholesterol levels (hypercholesterolaemia)[3]._x000D_ _x000D_ People with hypertriglyceridemia are at increased risk of CVD. This may be due to the build-up of fatty deposits in arteries (atherosclerosis) which can lead to angina, and an increased risk of blood clots, myocardial infarction and stroke[4]. It can be associated with damage to arteries in organs such as the brain, heart, kidneys and eyes. CVD is a common cause of death in England, accounting for approximately 136,317 deaths in 2018, and it is a major cause of disability and reduced quality of life[3]._x000D_ _x000D_ NICE guideline CG181 recommends advising people at high risk of, or with, CVD to eat a cardioprotective diet, engage in physical activity and stop smoking. Statins are recommended for both primary prevention of CVD (in people with increased risk of CVD in whom lifestyle modification is ineffective or inappropriate) or secondary prevention of cardiovascular events in people with CVD. There are around 6.1 million people living with CVD in England and around 6.5 million adults in England are currently taking lipid-lowering drugs such as statins for primary or secondary prevention of CVD. No treatments are recommended specifically for the management of hypertriglyceridemia in people who are taking statins. Fibrates, nicotinic acid, bile sequestrants and omega-3 fatty acids are currently not recommended for the primary or secondary prevention of CVD._x000D_ _x000D_ References_x000D_ 1. Yuan et al., Hypertriglyceridemia: its etiology, effects and treatment. CMAJ, 176 (8) 1113-1120; 2007_x000D_ 2. Heart UK; Triglycerides. Accessed August 2020_x000D_ 3. British Heart Foundation, England factsheet, July 2020. Access August 2020_x000D_ 4. Peng et al., Hypertriglyceridemia and atherosclerosis. Lipids in Health and Disease, 16: 233; 2017

Lay abstract: To appraise the clinical and cost effectiveness of icosapent ethyl with statin therapy within its marketing authorisation for preventing cardiovascular events in people with elevated triglycerides.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE
Title: Exploring Potential for Type 2 Diabetes Remission: A mixed methods study using population-based diabetes register data and interviews with primary healthcare professionals.
Funder: Chief Scientist Office, Scotland

Abstract: People want to know whether type 2 diabetes can be reversed. Experts disagree about whether this is possible. The word “remission” (When blood sugar fall to normal non-diabetes levels without medications ) is often used, however we do not know whether remission means reversal of type 2 diabetes. We do not know how many people achieve remission of type 2 diabetes and whether this improves their long term health. We know little about GPs’ and practice nurses’ views about remission, whether they discuss remission with patients, how they support remission and whether they think remission is only realistic for some patients. This PhD will summarise previous research and provide new information on type 2 diabetes remission. The Scottish diabetes register will be used to discover how many people in Scotland with type 2 diabetes have achieved remission, how long they stay in remission and whether they differ from other people with type 2 diabetes. I will explore how remission affects health issues like blood pressure and complications of type 2 diabetes such as heart and eye disease. I will interview GPs and nurses to seek their views about remission and what kinds of support they need to support patients wanting to achieve remission.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: METABOLIC AND ENDOCRINE
Title: The iDiabetes Platform: Enhanced Phenotyping of patients with diabetes for Precision Diagnosis, Prognosis and Treatment.
Funder: Chief Scientist Office, Scotland

Abstract: 5% of the Scottish population have diabetes, of which 90% have type 2 diabetes, a condition more common in socio-economically disadvantaged individuals. Diabetes, which is associated with the potential for major adverse health outcomes, is diagnosed solely by increased blood sugar level. Why someone has developed diabetes is rarely tested. This applies when diagnosing type 1 diabetes (resulting in some patients being misdiagnosed and treated with insulin unnecessarily) and when diagnosing type 2 diabetes (when little attempt is made to work out if someone developed diabetes due to reduced insulin production, reduced insulin action, or both). Similarly, for diabetes patients, we are poor at identifying and treating patients who are high risk of developing heart or liver, or kidney disease, yet we know that some medications work better than others in those at risk of these conditions. A more precise approach to diagnosis and treatment is required. The intelligent Diabetes (iDiabetes) platform will add precision approaches to improve outcomes of patients with diabetes. ‘Enhanced phenotyping’ of patients with diabetes will be undertaken during routine reviews. Additional clinical measures will be taken, and new tests undertaken automatically on routine blood samples – including two tests of heart function (BNP and hsTroponin) and tests for liver fat and fibrosis (scarring), as well as tests for insulin production and insulin resistance. We will also include DNA tests to allow the use of ‘genetic risk scores’ to flag people at increased risk of heart disease despite no other obvious signs. We will also use genetic results to inform on the best diabetes treatment for patients. We will use the enhanced phenotyping results to inform on precision care. For patients with type 1 diabetes, we will assess insulin production, risk of very low blood sugars and diabetes complications. We will reassess the diagnosis of patients with substantial insulin production and consider stopping or reducing insulin. For patients with type 2 diabetes, we will inform patients of their individualised risks; and inform patients and their doctors what diabetes treatments might be best. We will identify patients with diabetes who have pre symptomatic markers of heart, liver or kidney disease and recommend treatments that reduce these risks. Importantly, by randomly allocating groups or clusters of patients to iDiabetes or standard care we will test if the iDiabetes platform is effective and cost-efficient, enabling the roll out of precision diabetes care beyond Tayside.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: METABOLIC AND ENDOCRINE
Title: Evaluation of Footwear Fit Guidelines Under Pressure in At-Risk Feet
Funder: Diabetes UK

Abstract: Background: Incorrectly fitted shoes are implicated in one in five diabetes related foot ulcers, yet there is a lack of consensus around the clinical definitions of fit. Recommended toe gaps vary widely from 6 mm to 20 mm depending on the footwear guidance referred to but no research to date has assessed their effectiveness in minimising in-shoe pressures. Aims: To conduct a pilot study in people with diabetes and neuropathy to compare mean pressures in shoes fitted according to different footwear guidelines. By comparing pressures in 'correctly fitting' shoes as proscribed by these guidelines, we can carry out the first study assessing their effectiveness in minimising pressure. Investigation Plan: Footwear and foot dimension assessments using specialist equipment including digital calipers. The ambulatory and standing in-shoe pressures of 60 people with diabetes and neuropathy will be assessed via Pedar pressure monitoring insoles, and pace/gait monitored using stopwatches and GENEActiv accelerometers. Neuropathy is confirmed by using both 10-g monofilament at three sites and VPT measured at the hallux as >25V using a biothesiometer, with measurement of HbA1c, insulin resistance and body composition. Incorrect fitting is determined by reference to Touvaruela-Carrión, Chantelau and Gede and Diabetic Foot Australia Guidelines.


Research activity codes: 6.7 PHYSICAL;7.1 INDIVIDUAL CARE NEEDS
Health categories: METABOLIC AND ENDOCRINE
Title: Developing a mouse model of type 2 diabetes remission
Funder: Diabetes UK

Abstract: It has been shown that type 2 diabetes can be put into remission following weight loss resulting from a strictly controlled diet. However, while effective for those with diabetes of a short duration, it is less so for those with longer term diabetes because the beta cells become irreversibly damaged. The changes in beta cells which determine the capacity for recovery have not been identified and here we propose to develop a mouse model of type 2 diabetes remission to identify them. Using the db/db mouse model of type 2 diabetes, we propose to use caloric restriction after varying lengths of diabetes. While caloric restriction results in improved glycaemic control up to 12 weeks of age, we anticipate that longer periods of diabetes will render the beta cells incapable of recovery. Establishing a mouse model where we can reliably produce beta cells both capable and incapable of recovery will allow us to undertake detailed analyses in future studies to identify what determines the capacity for beta cell recovery and hence diabetes remission.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Use of capillary blood ketone meters to improve ambulance service care of hyperglycaemic patients: a feasibility study (KARMA2 study)
Funder: Diabetes UK

Abstract: Ambulance clinicians do not have blood ketone meters: they rely on non-specific clinical signs and symptoms for hyperglycaemic care strategies. Hospital-based guidelines advocate immediate start of intravenous fluid therapy on diabetic ketoacidosis (DKA) diagnosis, which does not reliably happen in the ambulance setting. The aims of this feasibility study are to determine whether ambulance clinicians can reliably and safely identify DKA using blood ketone meters, commence fluid therapy, and gather necessary data to inform a stepped-wedge, controlled trial. During an 8-month period (4-month control:4-month intervention; 400:400 patients), 120 ambulance clinicians will determine presence of ketones, using finger-prick blood testing, from consenting hyperglycaemic patients requiring emergency care by the East of England Ambulance Service NHS Trust. Prevalence and severity of hyperglycaemia, incidence rate of DKA and ability of paramedics to commence fluid therapy for DKA will be explored. Ambulance and hospital staff will also be invited to take part in an interview to share their views of DKA care and the impact of ambulance ketone meters. Study findings will be disseminated to key stakeholder groups, and used to inform the need to proceed to a full stepped-wedge, controlled trial evaluating the clinical and cost-effectiveness of ambulance ketone meters on DKA management.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: METABOLIC AND ENDOCRINE
Title: Identifying novel insulin secretion disorders caused by mitochondrial dysfunction to highlight fundamental pathways within the β-cell
Funder: Diabetes UK

Abstract: Mitochondria are fundamental for insulin secretion in beta-cells. Our preliminary data suggests that mitochondrial dysfunction is an underappreciated cause of congenital disorders of insulin secretion (neonatal diabetes and congenital hyperinsulinism). The student will analyse genome sequencing data from individuals with neonatal diabetes or hyperinsulinism and additional features associated with mitochondrial dysfunction to identify novel genetic causes of disease. The genetic findings will be replicated in the world’s largest cohorts of individuals with diabetes, hyperinsulinism or suspected mitochondrial disease to identify further individuals with the same genetic aetiology. The student will perform deep phenotyping studies to clinically characterise these novel genetic disorders. The results of these studies will provide a diagnosis for families with monogenic disease and will offer important insights into which genes modulate mitochondrial function in beta-cells. This new knowledge could identify novel biological pathways and therapeutic targets important for type 2 diabetes. This studentship offers a fantastic opportunity for the student to join a leading multidisciplinary team studying genetics of diabetes. Whilst in Exeter, they will be fully supported to develop computational and molecular genomics skills, whilst focussing on clinically relevant questions which will impact the lives of people living with disorders of insulin secretion.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Structure/function studies of GLUT4’s glycan; a novel therapeutic target for diabetes?
Funder: Diabetes UK

Abstract: A major action of insulin is to increase the rate of glucose transport into fat and muscle. This is achieved through regulated trafficking of the facilitative glucose transporter GLUT4, and is defective in individuals suffering from insulin-resistance and Type-2 diabetes. Understanding the molecular mechanisms that underlie GLUT4 trafficking therefore represents an important step in the development of rational therapies for these disease states. Research in this area has focused on information contained within the protein sequence of GLUT4 with far less attention being paid to the role of post translational modifications received by the transporter, in particular the single N-linked carbohydrate moiety carried by GLUT4. This represents an important knowledge gap as recent studies have implicated a role for circulating serum lectins (glycan-binding proteins) in the development of insulin-resistance. The student will investigate both the structure and function of GLUT4’s glycan with the overall aim of defining its role in GLUT4 trafficking and exploring its utility as a therapeutic target.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: Pancreatic beta-cell autophagy and its regulation by glucose metabolism
Funder: Diabetes UK

Abstract: It is well established that loss of functional pancreatic β-cell mass is central to the development of type 2 diabetes (T2D). We and others have shown that autophagy is essential for the maintenance of β-cell mass in response to excess nutrients and that deregulation of this pathway contributes to the β-cell demise evident in T2D. Preliminary work in our laboratory has identified glucose sensing as a key pathway regulating β-cell autophagy. Further study shows that this sensing mechanism is lost in an in vitro model of T2D in which autophagy is impaired. We thus hypothesise that the loss of appropriate glucose-regulated autophagy may contribute to the deregulation of β-cell autophagy evident in T2D. The objectives of the proposed study are to: i) Define the signalling pathways contributing to glucose-mediated regulation of autophagy. ii) Identify the glucose-sensing mechanisms regulating autophagy. iii) Determine how these pathways are altered by manipulation of glucose metabolism and in models of T2D. This study will provide a useful insight into the mechanisms underlying autophagy deregulation in T2D which will be key to the design of more effective therapies to preserve a functional β-cell mass.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: Insulin receptor phosphorylation of SNARE proteins at the plasma membrane.
Funder: Diabetes UK

Abstract: Insulin binding its receptor results in delivery of GLUT4 from intracellular GLUT4-storage vesicles to the cell surface. Recent work from the applicants’ laboratory has provided molecular detail revealing how the processes of insulin receptor signalling and altered membrane trafficking may be linked. We have shown that tyrosine phosphorylation of the SNARE proteins involved in GLUT4-storage vesicle fusion with the plasma membrane promotes the assembly of SNARE complexes and thus enhances their fusion with the plasma membrane. Preliminary data from our group suggests that the insulin receptor is in close proximity to the SNARE fusion machinery and thus directly phosphorylates these proteins. We hypothesise that this constitutes a key functional link between receptor signalling and membrane trafficking which may be impaired in insulin resistance. This project will test this hypothesis. Accordingly, the PhD student on this project will: Quantify the extent of co-localisation of the SNARE machinery involved in the regulation of glucose transport and the insulin receptor; Determine whether this is acutely regulated by insulin; Identify the mechanism(s) which control this co-location. Test the hypothesis that this co-location may be impaired in models of insulin resistance/type 2 diabetes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: Regulation of G-protein-coupled receptors in the development of type 2 diabetes
Funder: Diabetes UK

Abstract: The purpose of this proposed PhD studentship is to identify novel targets for the treatment of type 2 diabetes and obesity with a specific focus on G-protein-coupled receptors (GPCRs). Type 2 diabetes and obesity are on the increase worldwide. Despite efforts by government legislation and healthcare professionals into healthy lifestyle promotion, these co-morbidities continue to rise exponentially. This has been further highlighted by the recent public health emergency where individuals with type 2 diabetes testing positive for COVID-19 have poor prognosis. Therefore, there is a critical need for novel therapeutics to halt this increase and limit the burden on the NHS. GPCRs play an important role in almost all physiological processes including appetite regulation and glucose homeostasis, where functional disruption leads to pathophysiology. Due to their localisation at the plasma membrane and their tissue specificity, GPCRs are highly sought after as targets by the pharmaceutical industry. The main objective of this studentship is to elucidate which specific GPCRs are altered during the development of type 2 diabetes and obesity with the aim of understanding disease progression and identifying new targets which can be exploited for the development of future therapeutics.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Prediction of T1D in early life using the T1D GRS, biomarkers, demographics and environmental exposures in a combined risk score
Funder: Diabetes UK

Abstract: We aim to use our newly developed type 1 diabetes genetic risk score (T1D-GRS) and other risk factors (autoantibodies, demographics and environmental factors), in datasets from world-leading studies (T1DGC, TEDDY, TRIALNET) to predict who is at highest risk of development of T1D. This allows: education about early signs of onset to minimize morbidity; study of the clinical and cellular pathophysiology of the early stages of the T1D; and testing of interventions to prevent progression from islet autoimmunity to clinical diabetes. This studentship will firstly work on improving the original T1D-GRS using bioinformatics and interaction modelling in T1DGC. We will build on strong pilot data by modelling the ability of the T1D-GRS, in combination with autoantibodies and demographics, to predict progression of autoimmunity and T1D in TRIALNET. Finally we will validate and develop these findings in the TEDDY study and add the rich environmental exposure dataset collected in this study. This PhD studentship offers training in statistical genetics, bioinformatics and prediction modelling using world-class datasets. This will set the student up for a career combining bioinformatics with diabetes research – an increasingly important and rapidly expanding field. The key scientific outcome will be improved prediction of T1D.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: METABOLIC AND ENDOCRINE
Title: Inhibition of adipose tissue lipolysis to enhance the effectiveness of a walking programme to improve insulin sensitivity in people with prediabetes
Funder: Diabetes UK

Abstract: Over one third of the UK adult population is now prediabetic, meaning that they have a high risk of developing type 2 diabetes (T2D). Therefore, developing life-style/pharmaceutical interventions to chronically improve insulin sensitivity in overweight/obese people with prediabetes should have a high priority for future use in clinical management. In obesity, insulin resistance is associated with lipid (intramuscular triglyceride; IMTG) accumulation in skeletal muscle. Exercise stimulates the breakdown of IMTG in young, healthy, active individuals. However, obese individuals cannot breakdown IMTG during exercise, and as a result lipid metabolites accumulate in skeletal muscle that are known to induce insulin resistance. Previous research of the applicant in Maastricht has shown that in healthy trained men, acute ingestion of Acipimox (a specific inhibitor of adipose tissue lipolysis) before a bout of cycling exercise increases IMTG breakdown during exercise, and increases whole-body insulin sensitivity in the post-exercise period. The overall aim of the current proposal is to determine whether ingestion of Acipimox during each session of a 12-week exercise programme consisting of steady walking 3 times/week can improve whole body and muscle insulin sensitivity and glucose control in people at risk of developing T2D by reducing the accumulation of the mentioned lipid metabolites.


Research activity codes: 5.1 PHARMACEUTICALS;5.7 PHYSICAL
Health categories: METABOLIC AND ENDOCRINE