NIHRDataInsights/HRCSData huggingface dataset:
Title: Exploring patients lack of engagement with structured diabetes education in order to enhance future service provision
Funder: Diabetes UK

Abstract: Structured diabetes education (SDE) is widely regarded as the cornerstone of effective self-management. Current approaches to SDE tend to involve the patient being asked to attend a group or one-to-one sessions with healthcare professionals. Many people with diabetes, particularly adolescents with type 1 and newly diagnosed adults with type 2, choose not to attend SDE. This research proposes to explore the reasons people choose not to engage and to develop ideas on how best to ‘reach out’ to diverse populations. The study has three phases: 1. A quantitative survey using structured questionnaires that can be completed via an interview or online. 2. Case studies to investigate why some organisations have very high engagement rates whilst others have relatively low engagement of users. 3. Qualitative semi-structured interviews to explore the results of the previous two phases in greater depth with people who did not engage with SDE, plus parents of adolescents and to seek their views on future developments. The goal of the project is to influence the evolution of SDE nationally and internationally and to inform the commissioning agenda. It is envisaged that the results will translate into a toolkit and lead to interventions for future evaluation.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: METABOLIC AND ENDOCRINE
Title: Barriers to good transitional diabetes care in UK universities
Funder: Diabetes UK

Abstract: Transitional care for young people with Type 1 diabetes (T1DM) is important, as many already have poor glycaemic control, psychological morbidity, and poor engagement with services. The further transition to university from school for young adults with T1DM can be a time of great disruption to family and clinical support. We have substantial pilot data from UK universities (2011), suggesting major shortcomings in coordination of care. The aims of this proposal are to a) describe the current model(s) of care for young adult school leavers with T1DM attending all 156 UK universities with an emphasis on care coordination and access to services, b) to identify obstacles to good glycaemic control – clinical, lifestyle, family support, and communication, and c) to capture the views of 500 patients with T1DM at UK universities, of health care professionals (HCP) in 156 university medical services (UMS), and secondary care diabetes teams linked to universities . This data will be collected using piloted survey questionnaires administered by a research associate (RA) over 24 months with direct contact with clinical teams, and a range of qualitative and quantitative assessments of patient and HCP views to identify models of care and barriers to engagement.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: METABOLIC AND ENDOCRINE
Title: Overcoming barriers to high quality care in diabetes through professional behaviour change
Funder: Diabetes UK

Abstract: Moving clinical research findings into routine care is recognised as an inconsistent process with implications for the quality of care offered to people with diabetes. Providing evidence-based care often requires clinicians to change their behaviour. Based on findings from an on-going UK-wide study of theory-based factors associated with high quality diabetes care, we aim to evaluate the effectiveness and cost of an intervention targeting primary care clinicians to improve the behaviours involved in high quality type 2 diabetes care. We will conduct a theory-based two-armed cluster randomised controlled trial in 40 general practices in the North of England. We will target improvement in five underperformed clinical behaviours highlighted in NICE’s quality standards: prescribing for hypertension and glycaemic control, providing self-management and weight advice, and general education. The intervention will be delivered within group sessions by a community diabetologist, patient representative, psychologist and a nurse. The main outcome will be change in the proportion of patients prescribed (using anonymised computer records) and advised (using anonymous patient surveys). We will also investigate whether the intervention was delivered as designed (fidelity) by coding audiotaped interventions, and operated as hypothesised (process evaluation) by analysing responses to theory-based postal surveys before and after the trial.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;7.3 MANAGEMENT AND DECISION MAKING
Health categories: METABOLIC AND ENDOCRINE
Title: Diabetes education for adults with learning disabilities with Type 2 diabetes and their carers
Funder: Diabetes UK

Abstract: People with LD are at a higher risk of developing T2D due to higher obesity levels and poor diets compared to the general population. This project aims to enable people with LD to self-manage their T2D, in association with their carers. The programme will be implemented in four stages. In stage 1, focus groups will be held with adults with LD, their carers and relevant stakeholders to explore and adapt the current programme DESMOND. Stage 2 will examine and psychometrically evaluate the existing psychosocial and self-management instruments that are currently used within the DESMOND programme in the light of proposed changes for use with this group of individuals. Stage 3, will further address the feasibility of delivering the education programme. In the final stage an RCT will be used to test the efficacy of the revised DESMOND programme for adults with LD who have T2D. A desired change in both HbA1c and weight will be evaluated as the primary outcome measures, with a range of secondary psychosocial measures also being tested in terms of stability and change. Within the framework of a randomised trial, the analysis will be conducted using parallel latent growth curve models.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: METABOLIC AND ENDOCRINE
Title: Retinal vessel attenuation – a potential biomarker for early diagnosis of renal and vision complications in diabetes?
Funder: Diabetes UK

Abstract: Retinal blood vessels are amenable to direct non-invasive visualisation and measurement allowing investigation of early microvascular changes prior to development of diabetic complications such as retinopathy and nephropathy. Clinical data derived from the Northern Ireland (NI) DIAbetes MONitoring Database (DIAMOND) and the separate NI Diabetic Retinopathy Screening Programme (DRSP) will be merged to identify individuals with multiple measurements of kidney function (serum creatinine; urinary albumin/creatinine ratio). These individuals will be stratified into two groups using estimated glomerular filtration (eGFR) equations. The stable kidney function group (chronic kidney disease CKD stage 1 and stage 2) are those individuals in whom eGFR measurements remained >60mL/min/1.73m2 throughout the preceding 5 year screening period. Retinal vessel measurements in this “stable” kidney function group will be compared with retinal vessel data in individuals with progressive kidney failure. This “kidney failure” group will contain individuals in whom eGFR declined over 5 years to <60mL/min/1.73m2. Retinal vessel measurements will then be correlated with risk of developing progressive chronic kidney disease or retinal complications, non-proliferative or proliferative retinopathy. This research will help determine whether measuring retinal vessel diameters, as part of the diabetic retinopathy screening programme, would offer additional clinical value in identifying patients at highest risk of developing renal failure or sight threatening retinopathy.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: METABOLIC AND ENDOCRINE
Title: Role of the Type 2 diabetes associated zinc transporter SLC30A8/ZnT8 in the control of glucagon secretion.
Funder: Diabetes UK

Abstract: This project will use genetic and cellular experiments to explore the role of a zinc transporter protein in the production of the hormone glucagon. Findings could help inform the development of therapies to control glucagon release in Type 1 and Type 2 diabetes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Novel Mechanisms of Glucolipotoxic Islet Cell Death
Funder: Diabetes UK

Abstract: There is an ongoing diabetes epidemic, with 220 million cases worldwide and diabetes related deaths predicted to double by 2030. While the detrimental effects of long term high fat / high glucose diets are clear, the associated mechanisms of diabetogenic dysfunction remain poorly defined. It is however known that diabetes develops when beta-cell function is unable to meet insulin demand, due to compromised insulin secretory capacity or functional failure and destruction of beta-cell mass. Glucolipotoxicity-induced islet inflammation and programmed cell death are thought to underlie the developing dysfunction, with these processes being amplified through the cytokine IL-1betaImportantly, ourselves and others have generated preliminary data which indicates that strategies encompassing a reduction in IL-1beta-induced acetylation might offer a protective mechanism to prevent islet cell death in T2D. Crucially however, the molecular targets for acetylation currently remain unknown. This project will identify the genes and transcription factors associated with islet immune signalling pathways that trigger destruction of beta cells through glucolipotoxicity-induced cell death pathways, plus the chemokines that induce islet invasion by destructive immune cells. Together, this work will generate a new set of target molecules and pathways that are associated with glucolipotoxic islet cell damage and destruction, and potentially amenable to therapeutic manipulation


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: In situ imaging of beta cell function in mice deleted for Type 2 diabetes-associated genes
Funder: Diabetes UK

Abstract: Despite significant investment into type 2 diabetes (T2D) research, disease incidence continues to grow. The recent advent of genome-wide sequencing has invigorated the field by allowing identification of gene polymorphisms linked with T2D. At the single-cell level, gene-silencing/transduction approaches have provided evidence for a role of T2D-associated genes in normal insulin secretion. At the whole-animal level, beta-cell specific deletion of the same genes leads to glucose intolerance. However, extrapolating findings between these two levels is complicated by the dependence of beta-cells on their native tissue context for proper function. Moreover, insulin secretion is not simply a reflection of unitary beta-cell activity, but requires the concerted function of thousands of cells residing within an islet. Therefore, to link defective insulin exocytosis with impaired insulin fluctuations in the blood, studies are required to assess how T2D-associated genes alter beta-cell function at the single-cell and population levels in the intact tissue. The aim of the current study is to employ multiphoton imaging and optogenetics as tools to visualise and influence beta-cell function in situ. By applying these techniques to murine models of T2D, it is hoped that new insights into the influence of identified risk genes on beta-cell behaviour can be obtained.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Regulation of glucagon secretion by GLP-1: a role for GLP (9-36) mediated by a novel GLP-1 receptor?
Funder: Diabetes UK

Abstract: The regulation of glucagon secretion in health and disease and its modulation by GLP-1 in particular remain poorly understood. The density of the previously-cloned GLP-1 receptor (GLP1R) is very low in a-cells suggesting that the effects of GLP-1 on glucagon secretion are mediated by paracrine effects. Preliminary data from our laboratory suggests that physiologically-relevant GLP-1 levels (1-10 pM) suppress glucagon release by a direct (non-paracrine) action. In addition, the supposedly-inactive metabolite GLP-1 (9-36) remains capable of suppressing glucagon secretion in islets from mice lacking GLP-1Rs. These data support the existence of a novel GLP-1 receptor (i.e. ‘GLP1R2’) or mechanism that is present in alpha-cells (but not beta-cells) and mediates the inhibitory effect on glucagon secretion. Using secretion, electrophysiological and pharmacological techniques on human and mouse islets (including GLP-1R knock-out mice) and alpha-cells in vitro I plan to determine how these effects are mediated. I will also establish the molecular identity of the novel GLP-1 receptor and the downstream signalling mechanisms that culminate in suppression of glucagon secretion. This project will form the basis of my on-going interest in fine control of islet hormone secretion and establish my role as an independent researcher.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: Novel amphibian skin peptide-analogues for the treatment of type-2 diabetes
Funder: Diabetes UK

Abstract: The discovery and development of exendin-4 from lizard saliva into a GLP-1 mimetic for the treatment of type-2 diabetes has sparked new interest in bio-prospecting for novel peptides from unexpected sources. Recent peptidomic studies in our laboratory have led to the isolation and characterization of a number of novel peptides from amphibian skin secretions which exhibit significant incretin-like effects on pancreatic beta cells. Based on our preliminary results, we have selected some these peptides for the proposed studies. We will conduct structure-function studies with synthetic substituted-analogues and assess their insulinotropic effects and glucose lowering actions. We will also investigate their cellular mechanisms of action plus in vivo changes in gene expression, insulin sensitivity, glucose metabolism, circulating insulin and islet function in relation to treatment of type-2 diabetes.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE
Title: Beta-secretase inhibition as a novel approach to treat Type 2 diabetes associated with obesity
Funder: Diabetes UK

Abstract: A major feature of Type 2 diabetes (T2D) is its strong association with obesity. Excess ectopic lipid accumulation is considered to be a primary driver for induction of peripheral insulin resistance, which when coupled with pancreatic beta cell functional insufficiency, leads to T2D. Current treatments for T2D, particularly associated with obesity, are not optimal, and on numerous instances are incompletely effective. Thus any new drug that improves peripheral insulin sensitivity concomitant with reduced ectopic lipid deposition will be well received. There is increasing evidence that T2D and Alzheimer’s disease (AD) share common risk factors, including obesity, with AD also characterised by impaired glucose metabolism. Excess activity of the protease beta-secretase (BACE1) is an important driver for AD pathology. We have shown that BACE1-null mice, on normal diet, are lean, highly insulin sensitive with improved glucose disposal. When placed on a chronic high fat diet they resist diet-induced obesity (DIO) and retain better insulin sensitivity and glucose homeostasis than wild type controls on the same diet. Now we wish to define which tissues are responsible for the improved insulin sensitivity and determine whether administration (subcutaneously and orally) of drugs that inhibit BACE1 can reverse or prevent T2D associated with obesity.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE
Title: Using human genetics to understand the role of adiponectin in type 2 diabetes and insulin resistance.
Funder: Diabetes UK

Abstract: The purpose of this investigation is to provide a major advance in understanding the role of the adipokine hormone adiponectin in insulin resistance and type 2 diabetes. Our study will be the most powerful yet performed on Adiponectin. We will: First, test the hypothesis that reduced adiponectin levels are causally related to diabetes and insulin resistance. We will perform a Mendelian randomization study using newly identified and known genetic variants in the ADIPOQ gene. We will use >36,000 individuals from 16 studies with measures of adiponectin and insulin resistance and more than 4000 type 2 diabetes patients with adiponectin measures and equivalent numbers of controls. Second, recruit volunteers by genotype, based on a low frequency-large effect variant that is predicted to alter splicing of the ADIPOQ gene. We will genotype this SNP in ~5000 individuals from the Exeter10,000 resource. We will approach approximately 100 individuals (50 of each genotype) and ask them if they would be willing to undergo a small subcutaneous fat biopsy. We anticipate recruiting 5-10 individuals from each genotype. Third, test the hypothesis that variants in the ADIPOQ gene alter mRNA stability or splicing. We will use reverse transcriptase and quantitative real time PCR to test RNA extracted from fat samples from consented volunteers. Finally we will test the hypothesis that any splicing differences observed in mRNA experiments are translated into differences in the adiponectin protein.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Cellular and molecular insights into the T1D pancreas
Funder: Diabetes UK

Abstract: Type 1 diabetes (T1D), caused by immune cells erroneously attacking insulin producing islet beta cells is increasingly considered to be caused by a failure in T cell regulation. Previous studies have described the immune cells responsible for beta cell destruction in detail. In this project, these studies will be taken further by studying immune subsets in pancreatic lymph nodes (where T cells become “activated” to destroy beta cells) from individuals with T1D compared to controls. Levels of expression of recently described genetic regulators called microRNAs, which can be studied accurately in autopsy T1D pancreas, will also be compared to controls. Using sophisticated microscopy techniques, islets and pancreatic lymph nodes can be isolated from autopsy pancreas and their microRNAs isolated and identified. All the experiments outlined in this application will be carried out in parallel in the NOD mouse and control pancreas. This will allow us to compare between the human and NOD islet autoimmunity and to prepare the way for future functional experiments. Overall this project is likely provide novel insights into the cellular and molecular mechanisms underlying T1D.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Towards understanding ethnic differences in the progression to Type 2 diabetes: a preliminary phentotyping study in people with recent-onset diabetes in SE London
Funder: Diabetes UK

Abstract: OBJECTIVE: to determine the phenotype of type 2 diabetes mellitus (T2DM) in UK black West African (BWAO) and white European origin (WEO) people. BACKGROUND: BWAO populations are at increased risk of T2DM. Their incidences of atherogenic lipid profiles and myocardial infarction are lower; hypertension, stroke and premature mortality more common. The mechanisms warrant investigation, to allow appropriate targeting of early interventions. HYPOTHESES: We hypothesise that, compared to people of WEO, people of BWAO with early T2DM will have (1) markedly greater insulin deficiency as a result of (2)exaggerated peripheral insulin resistance. Additionally (3)low visceral and hepatic fat accumulation will lead to (4)relatively preserved hepatic insulin sensitivity in BWAO people. PLAN OF INVESTIGATION: We will measure, in 20 BMI, age-matched BWAO and 20 WEO males with recent-onset T2DM: whole body insulin sensitivity (2-step euglycaemic-hyperinsulinaemic clamp); hepatic and peripheral glucose metabolism and lipolysis (stable isotope infusions); insulin secretory function (meal tolerance test and graded glucose infusion); and ectopic fat accumulation (magnetic resonance imaging and spectroscopy). Future studies will investigate these processes in normal and impaired glucose BWAO and WEO people in order to characterise the processes underlying progression to T2DM and to look at responses to a potential therapeutic intervention.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Is CTLA-4-dependent Treg function compromised in autoimmune diabetes?
Funder: Diabetes UK

Abstract: T1D arises as a consequence of a dysregulated T cell response to insulin-producing pancreatic beta cells. T cell responses are normally subject to stringent regulation by the regulatory T cell (Treg) population, and this depends at least in part on the function of the CTLA-4 protein. Some data suggest that Treg function is defective in T1D and variation at the ctla-4 locus is associated with disease. Whilst CTLA-4 is undoubtedly a major regulator of immune responses, in disease settings it may not be CTLA-4 itself that is faulty but the pathways that impact upon its function. In this respect we have identified a novel molecular mechanism of CTLA-4 function which is critically dependent on the ability of CTLA-4 to traffic correctly through the cell. We therefore wish to test the hypothesis that CTLA-4 function is compromised in individuals with T1D and that this limits their capacity to provide appropriate immune regulation. We wish to test whether the trafficking of CTLA-4 is intact in people with T1D and address how these and other pathways affect CTLA-4 function. We will test the hypothesis that CTLA-4 function is compromised in individuals with T1D and that this limits their capacity for appropriate immune regulation. regulatory T cell (Treg) population, and this depends at least in part on the funct


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Downstream mechanisms underlying leptin modulation of POMC neuronal excitability and energy homeostasis
Funder: Diabetes UK

Abstract: Central application of the adipokine leptin improves glucose homeostasis in type- 1 and 2 diabetic mice. The precise mechanisms that underlie the actions of leptin in the brain are unclear although, a hypothalamic neuronal population expressing pro-opiomelanocortin (POMC) has been implicated. Deletion of upstream signalling molecules in POMC-expressing neurons prevents leptin and insulin regulation of excitability and transcription. The aim of this proposal is to target downstream signalling in POMC neurons to determine if modulating only leptin-induced excitation could produce an energy homeostatic phenotype that could be used to alter the progression of type-2 diabetes. We will examine S6-kinase-1 (S6K1) which is important in glucose homeostasis and an ion channel protein (Cacna1e) that may underlie leptin-induced depolarization of POMC neurons. Mice expressing cre-recombinase driven by the POMC promoter (POMCCre) will be used to delete S6K1 or inhibit transcription of Cacna1e in POMC neurons. The effects of blocking these downstream molecules will be examined with respect to electrical excitability and energy homeostasis in mice fed on normal chow and a high fat diet.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE