NIHRDataInsights/HRCSData huggingface dataset:
Title: Does ZnT8 Autoimmunity More Accurately Reflect Beta Cell Destruction Compared With Other Islet Autoantibodies?
Funder: Diabetes UK

Abstract: It is unclear why loss of beta cell function in type 1 diabetes proceeds at variable rates before and after diagnosis. Zinc Transporter 8 autoantibodies (ZnT8A) aid identification of people at high risk of diabetes. The HLA Class I genotype A*24 is negatively associated with ZnT8A. We have observed ZnT8A loss before diagnosis of diabetes. Could this be linked of A*24? After diagnosis ZnT8A is lost rapidly compared to other islet autoantibodies. However, studies investigating ZnT8A as a marker of C-peptide have reported variable results. Additionally, polymorphisms in the ZnT8 gene are associated with insulin production but not development of type 1 diabetes. Overall, ZnT8 humoral responses are heterogeneous in terms of epitope specificity, titre, affinity, and loss. At diagnosis, the epitope specificity of ZnT8A may lead to loss of sensitivity in islet cell antibody (ICA) staining in animal compared with human pancreas. This test is still used to inform diabetes aetiology in the NHS. We hypothesise that detailed characteristics of ZnT8 autoimmunity and function will help elucidate progression to diabetes, loss of C-peptide after diagnosis, and the validity of ICA tests. This knowledge could help identify individuals for trials aimed at preserving beta-cell function and reducing diabetes complications.


Research activity codes: 6.3 MEDICAL DEVICES
Health categories: METABOLIC AND ENDOCRINE
Title: Towards targeted dietary support for shift-workers with Type 2 diabetes: a mixed-method study
Funder: Diabetes UK

Abstract: The number of people who work shift-work is on the rise, and this includes people with type 2 diabetes (T2D). Changes to circadian rhythms can increase blood glucose concentrations and the risk of CVD. Our preliminary workforce survey and patient and public involvement work shows that shift-workers with T2D are not being supported to manage their T2D. There is an urgent need to develop targeted interventions for these individuals. The first step is to understand more about glucose control and dietary intake in shift-workers with T2D and barriers to management. Therefore, we will recruit 70 people who do night-shift work who have T2D. We will ask them to wear continuous glucose and activity monitors, and record their food intake and sleep patterns. We will also develop a behavioural questionnaire to identify the barriers to management amongst the shift-workers by using semi-structured interviews based on the theoretical domains framework and analysed using a deductive framework and inductive thematic analysis Following completion of data collection, a triangulation protocol will be used to identify potential intervention strategies. Our lay steering group will oversee the study, and in concert with other key stakeholders, will help us identify the best candidate intervention(s) to take forward.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: METABOLIC AND ENDOCRINE
Title: The role of HIF2α in non-alcoholic fatty liver disease
Funder: Wellcome Trust

Abstract: non-alcoholic fatty liver disease (NAFLD), marked by fat accumulation (steatosis), inflammation and scarring of the liver, affects about one third of people. There are no specific treatments available. We believe the activation of a component of the hypoxia response, HIF2&alpha;, contributes to this disease. HIF2&alpha; responds to hypoxia (low oxygen levels) in part by limiting the capacity of mitochondria to burn fat, an oxygen demanding process. In the liver, this reduced fat oxidation could contribute to steatosis in NAFLD. We will investigate this using mice that lack HIF2&alpha; in their livers. These will be fed a diet that induces NAFLD. We will measure metabolic features, such as fuel oxidation, and disease severity to determine whether interfering with HIF2&alpha; increases fat oxidation in NAFLD, and whether this improves disease severity. We will also investigate what activates HIF2&alpha; in NAFLD using cell culture approaches. Finally, we will investigate treatment options for NAFLD that target HIF2&alpha;. Some of these options are already in clinical trials for other diseases and could be adapted for NAFLD treatment. With this project, we aim to increase our understanding of the harmful processes involved in a very common disease, and use this to explore novel treatment avenues.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Prognostic proteomic signatures of type 2 diabetes and related metabolic traits
Funder: Wellcome Trust

Abstract: Molecules that can be measured in the blood, such as proteins, show differences in people who will develop T2D, even years before being diagnosed. Recent improvements in technologies, now allow us to measure thousands of proteins (so called proteomics) from a single blood sample. We propose that proteomics can provide information on the causes of T2D and on a person’s risk to develop this disease. In two large studies, we will look for proteins that have different levels between people who will develop T2D and those who won’t. We will use this information to: 1) identify those proteins that can help predict which people will develop T2D and related complications, and can help to classify patients into subgroups with similar characteristics. 2) To evaluate which proteins can cause T2D when altered, and which proteins are altered as a result of developing T2D. This project will improve our understanding of the mechanisms causing T2D and help identify proteins that could be used as treatment targets. Additionally, it could improve how we treat patients by identifying individuals at high risk of T2D and related complications and by identifying subgroups of patients with specific characteristics and risks for complications.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Genetic and Molecular Characterisation of Postprandial Insulin Resistance
Funder: Wellcome Trust

Abstract: Diabetes is a health concern currently affecting approximately 451 million individuals worldwide. Ninety per cent of individuals with diabetes are diagnosed with type 2 diabetes (T2D), typically in late adulthood. T2D is characterised by an inability of the body to control blood sugar levels. In part, this is due to cells of the body being unable to optimally respond to insulin, a hormone required to regulate blood sugar levels; a condition known as insulin resistance. There have been many efforts to understand how genetic changes result in an individual’s increased risk of T2D in adulthood, however, the mechanism by which these changes result in increased risk are largely poorly understood. This research aims to understand the genetic contribution to insulin resistance, using an interdisciplinary approach. Using large population studies we aim to identify novel changes in DNA which are associated with insulin resistance. In addition, we will identify rare mutations in genes thought to be involved in insulin action, and examine using cellular models the molecular impact of these. This will enable a better understanding of the genetic contribution to insulin resistance and how this contributes to T2D, as well as potentially highlighting novel targets for treatment and prevention.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Characterising adipocyte protein trafficking/secretion in response to fed and fasted signals in metabolic health and disease
Funder: Wellcome Trust

Abstract: Fat tissue plays a key role in storing energy as fat after feeding, and releasing this energy when needed (fasting). In order to change between storing and releasing energy, fat cells have to change the proteins at its surface to allow transport of nutrients in and out of the cell. In addition, fat cells release proteins that signal to other tissues in the body depending on whether food has just been consumed (‘fed’), or if the body has not received any food for several hours (‘fasted’). In this project we will study how the hormones, insulin (present in a fed state) and noradrenaline (present in a fasted state) change how proteins are localised within fat to promote energy storage/release, and how these hormones change the proteins fat cells secrete. In obesity the ability of fat cells to store and release energy and secrete different hormones depending if the body is in a fed or fasted state appears to be disrupted. By also studying this in cells treated to mimic the obese-state we will shed light on how changes to these processes may contribute to the metabolic disturbances associated with obesity (e.g. type 2 diabetes).


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: New insights into MODY: using UK Biobank to discover the true causes, penetrance, phenotype and prevalence
Funder: Diabetes UK

Abstract: Maturity-Onset Diabetes of the Young (MODY) is a genetic form of diabetes. Correct diagnosis of specific subtypes of MODY can personalise treatment and improve outcomes. Exome-sequencing data from the UK Biobank, a unique population-based study of 500,000 people, is becoming freely available to researchers in 2019. We will use data from the UK Biobank together with our local cohort of >5000 people with monogenic diabetes to address key unanswered questions about the pathogenicity, penetrance, clinical presentation and prevalence of MODY. The answers to these questions have important implications for people with MODY, their families and the wider population. It will also will provide new biological insights into the MODY genes. The questions we will answer in this project are: 1. Which genes should be diagnostically reported as causing MODY? 2. If a person has a mutation in a MODY gene what is their chance of getting diabetes? 3. What are the additional clinical features in people with MODY gene mutations and how common they are? 4. What proportion of adults with MODY mutations are misdiagnosed with Type 1 or Type 2 diabetes and wrongly treated?


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: METABOLIC AND ENDOCRINE
Title: Sx16 phosphorylation as a regulatory mechanism controlling insulin-stimulated glucose transport
Funder: Diabetes UK

Abstract: Insulin stimulates the trafficking of the facilitative glucose transporter GLUT4 from intracellular stores (‘GLUT4 storage vesicles’, or GSVs) to the plasma membrane. This insulin-regulated delivery of GLUT4 to the cell surface is dysfunctional in insulin-resistance and Type-2 diabetes and studies have supported the hypothesis that GLUT4 sorting and/or trafficking are impaired in these patients. Our team has identified a key role for the t-SNARE Syntaxin-16 (Sx16) in intracellular trafficking of GLUT4; phosphorylation of Sx16 prevents the formation of productive SNARE complexes and abrogates GLUT4 sorting into GSVs. The specific aims of this proposal therefore are: i. To generate phospho-mimetic and phospho-resistant mutations in Sx16 using genome editing in 3T3-L1 adipocytes to define how phosphorylation of Sx16 modulates GLUT4 trafficking. ii. To use pharmacological and genetic inhibition of the kinases AMPK and SIK2 to determine their effects on GLUT4 sorting and ascertain whether these are the main kinases responsible for Sx16 regulation, and in tandem iii. To identify other kinase(s) involved in Sx16 phosphorylation and to test their role in GLUT4 trafficking in vivo. iv. To develop an ELISA-based assay for phospho-Sx16 levels in tissues and perform proof-of-concept experiments to validate it as a potential diagnostic tool.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: Cellular senescence, aging and diabetes
Funder: Diabetes UK

Abstract: In this project, Professor Narita and Professor Ben Porath will address the roles of beta-cell senescence in ageing and diabetes in depth. Their aim is to uncover whether beta-cell senescence contributes to, or, alternatively acts to counteract diabetes. In either case, they will explain the molecular mechanisms behind the functional effects of senescent beta-cells. Using a variety of human and mouse models, they will study how beta-cell senescence affects the disease. Regulation of gene activity, which is reprogrammed in senescence, underlies changes in function. The project will employ cutting edge genomic analyses to uncover how gene regulation is reorganized in senescent beta-cells.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: Exploring beta cell reprogramming by glucocorticoids
Funder: Diabetes UK

Abstract: Glucocorticoids are released from the hypothalamic-pituitary-adrenal axis in response to acute and chronic stress, and exert potent metabolic effects. Excessive glucocorticoid exposure has been shown to be deleterious for pancreatic beta cell function and insulin release. However, glucocorticoids at physiological levels are essential for many homeostatic processes, including glycaemic control. Our preliminary data show that, while glucocorticoids impair voltage-dependent Ca2+ channel function and Ca2+ fluxes, insulin secretion is maintained due to upregulation of amplifying cAMP signals, preserved beta cell metabolism and an increased number of insulin granules docked at the membrane. This steroid-regulated positive feedback loop is targeted by free fatty acids, leading to beta cell dysfunction and insulin insufficiency. Pertinently, failure of this protective mechanism may contribute to diabetes in states of glucocorticoid excess such as Cushing’s syndrome, which is associated with frank dyslipidaemia. The aim of the present project is to therefore apply cutting-edge imaging and transcriptomic techniques to rodent and human islets, alongside mouse metabolic phenotyping, to understand how glucocorticoid regulates beta cell function, and how this interacts with adiposity to drive type 2 diabetes risk.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: VELOCITY: Evaluating Fetal Growth in Pregnancies Complicated by Pre-Exisiting Diabetes
Funder: Diabetes UK

Abstract: The evaluation of fetal growth in pregnancies complicated by maternal diabetes is important for the detection of both fetal growth restriction and fetal macrosomia (fetal overgrowth). Both conditions are associated with significantly increased morbidity and mortality not only to the fetus but also to the mother and are important causes of stillbirth and shoulder dystocia. The current tools used for fetal growth evaluation are limited, particularly in pregnancies complicated by diabetes, and there is an urgent need for the development of more accurate methods which detect earlier deviations in fetal growth. This project aims to evaluate the use of longitudinal fetal thigh 3D volume measurements and placental function markers in conjunction with continuous blood glucose monitoring at different stages of pregnancy. 3D volume measurements will be used to predict fetal growth trajectory and identify pathological deviations in fetal growth. Analysis of continuous blood glucose and placental function markers will allow us to interrogate the relationship between fetal growth trajectory, glycaemic control and placental function and develop more accurate tools for early identification of abnormal fetal growth. In the future this will enable interventions to be targeted much more effectively with the ultimate aim of improving long-term maternal and infant health.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: METABOLIC AND ENDOCRINE
Title: Role of Syntaxin4 tyrosine phosphorylation in insulin-sensitivity
Funder: Diabetes UK

Abstract: Insulin binding its receptor on fat and muscle cells stimulates glucose transport into these cells by increasing the numbers of glucose transporters (GLUT4) on their surface. This is achieved by delivery of GLUT4-containing vesicles from intracellular site(s) to the plasma membrane via regulated membrane trafficking events. This insulin-regulated delivery of GLUT4 vesicles to the cell surface is dysfunctional in patients with Type-2 diabetes. The delivery of GLUT4 vesicles to the cell surface requires SNARE protein complex formation; in Diabetes UK-funded work, we have shown that insulin increases SNARE complex formation, suggesting that this may be a mechanism by which insulin stimulates GLUT4-vesicle fusion with the plasma membrane. Recently, we have shown that tyrosine phosphorylation of one specific SNARE protein, Syntaxin4, by the insulin receptor modulates both SNARE complex formation and delivery of GLUT4 to the cell surface. In this proposal, we will 1) Establish the functional consequences of insulin-stimulated Syntaxin4 phosphorylation in adipocytes; 2) Characterise phospho-specific antibodies that recognise phospho-Y115 and phospho-Y251 within Syntaxin4, and 3) Determine the extent to which phosphorylation of Syntaxin4 correlates with insulin-sensitivity in humans.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: A Feasibility Study and Process Evaluation of a Psychosocial Education Model for Young People with Type 1 Diabetes- the Youth Empowerment Skills (YES)
Funder: Diabetes UK

Abstract: Adolescence is a period of intense physiological, psychological and social change. It can be a challenging period for young people with Type 1 diabetes and is associated with worsening glycaemic control and care disengagement. We have co-designed with young people a psychologically modelled educational programme -Youth Empowerment Skills (YES); that aims to facilitate a positive adaption to living with diabetes while improving knowledge and self-management behaviours. Integrated programme components include: social and peer-based learning; immersive simulations; and an outreach youth-worker. Aim: Test the feasibility of the YES programme (acceptance, implementability, recruitment and completion); and estimate its efficacy in relation to metabolic and psychosocial outcomes. Setting: Diabetes services in diverse inner-city/urban areas. Population: Young people with Type 1 diabetes(aged 14-18 years). Methods: A feasibility RCT (waiting-list design) with integrated process evaluation designed following the MRC Complex Intervention Evaluation Framework. We will randomise 60 young people to either YES intervention or waiting-list control and evaluate outcomes at 6-months; at this point the waiting list participants will be offered YES with further follow-up at 12 months. Impact: The study will deliver an optimised intervention to: enable young people with Type 1 diabetes to engage more constructively with their diabetes; and improve self-management activation.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: METABOLIC AND ENDOCRINE
Title: B cell chemotaxis in type 1 diabetes mellitus
Funder: Diabetes UK

Abstract: B lymphocytes have multiple functions which may contribute to pathogenesis of type 1 diabetes. Although autoantibodies are currently the best markers of an immune response to the pancreatic β-cells, less is known of the function of the B lymphocytes that produce them, and in particular the role of B lymphocytes found in the islet infiltrates. In preliminary studies, we demonstrated alterations in the expression of chemokines, CXCL10 and 11 in serum, as well as their receptor CXCR3 on memory B lymphocytes in patients with type 1 diabetes. The data suggest an altered chemokine ligand and receptor expression profile of B lymphocytes, which could lead to changes in their migration and homing to the pancreatic islets. We aim to a) study functional differences in the B lymphocytes expressing CXCR3 in their response to chemokine ligands, as well as b) identify whether these CXCR3-expressing B lymphocytes are specifically found in the islets, in human pancreas tissue sections. We will study these distinctive features of memory B cells in type 1 diabetes, which may provide a biomarker related to B cells in type 1 diabetes and increase our understanding of why B lymphocytes migrate to and reside in the islet infiltrate.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Enabling people with diabetic peripheral neuropathy to drive safely & stay independently mobile for longer
Funder: Diabetes UK

Abstract: Driving is very important to people for maintaining independence, but our research has shown that several aspects of driving are compromised by diabetic peripheral neuropathy (DPN). Using our extensive experience of driving research, including drivers with diabetes, we will test the long-term effectiveness of an intervention for improving driving performance and safety for drivers with DPN. We aim to reverse the pattern of impairment through skill-specific training, and so enable them to stay safely and independently mobile. We identify in a driving simulator the specific pattern of changes in driving that develop as a consequence of DPN, including crucially impaired use of the accelerator pedal, using an automated, algorithm-based analysis. We can then alert the driver that their driving is affected, and how. Participants will then drive in the simulator with a visual feedback driver assistance system that warns them when their use of the accelerator is unsafe. This therapeutic intervention will train drivers to reverse the effects of neuropathy on their driving. Training at monthly intervals will reveal how the benefits accrue over an extended period, and assess the long-term effectiveness of such training; this is the first step towards incorporating the technique into an in-vehicle driver assistance system.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: METABOLIC AND ENDOCRINE
Title: Targeted next generation sequencing (NGS) using a custom-made gene panel and functional profiling of variants for the characterisation of children with severe short stature phenotypes.
Funder: Barts Charity

Abstract: The Centre for Endocrinology (CFE) at WHRI has an international reputation in the diagnosis/management of children with growth disorders. In 2008, we established a genetic sequencing service for patients with short stature and growth hormone resistance/insensitivity (GHI), a rare and poorly understood condition. Of 129 patients referred to our centre to date, our comprehensive genetic testing service has pinpointed a genetic diagnosis in a significant (~50%) proportion of patients. National/international demand for this service is growing. We propose a custom-made gene-panel, which will allow rapid analysis of all genes known to cause this disorder in one test, with the potential to transform the diagnosis and management of patients across Europe. We have the expertise to find new genes in the unsolved cases and will assess how each genetic defect disrupts normal molecular pathways to identify new targets for treatment.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: METABOLIC AND ENDOCRINE