NIHRDataInsights/HRCSData huggingface dataset:
Title: Time course of development of diabetic nephropathy and its reversal by copper chelation.
Funder: Medical Research Council

Abstract: This project aims to determine the time-course of changes in key renal variables during the development of diabetic nephropathy (DN) and in response to the reversal of DN caused by TETA treatment. We and others have found that diabetes causes the build-up of catalytically active copper in the renal cortex and urine of streptozotocin-diabetic rats and we have subsequently shown that removal of copper by TETA (triethylenetetramine, a selective copper II chelator) reverses damage to the glomerular basement membrane, including its thickening and loss of heparan sulphate (HS). The development of diabetes in patients is known to be accompanied by increased urinary levels of copper as well as of HS and heparanase, although the temporal relationship between these effects is unknown. In this study, we will use an established model of diabetes to follow animals for 16 weeks in 4 groups: control, diabetic, diabetic-TETA (from week 1), diabetic-TETA (from week 9) and to collect twice weekly urine samples in order to measure urinary copper by a validated inductively coupled plasma-mass spectrometry method; carboxymethyllysine (an advanced glycation end-product thought to bind copper), H2O2 as a marker of oxidative stress, HS, heparanase and albumin will also be measured using established plate-based assays. In addition, we have developed a liquid chromatography-MS assay that can quantify specific HS disaccharides; measurement of specific HSs could add further insight to the source of urinary HS. These data will be analysed to describe a mechanistic time-course of DN development and the effects of copper chelation on DN. We hypothesise that the order in which these markers appear will shed light on the underlying mechanisms of DN and could provide both an early indication of DN risk and an effective tool for guiding TETA therapy, either in determining an optimal population to receive treatment and/or to monitor therapeutic response.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Next generation Y analogue for treatment of obesity
Funder: Medical Research Council

Abstract: Peptide YY3-36 (PYY) is a naturally occurring gut satiety hormone. When infused intravenously to mimic postprandial levels of PYY, volunteers significantly reduced food intake. In an MRC funded Phase 1 trial, five weekly injections of a long-acting analogue of PYY, Y242, volunteers had significantly reduced weight and sustained food intake reduction. However, Y242 was subject to a dose-limiting burst release over the first 2 hours after injection, associated with temporary nausea and vomiting. There was also a dose dependent local skin irritation. We have therefore developed a related Y analogue, Y3394, which is 10 times more potent than Y242, and has a slow onset. This should completely prevent the side effects and allow higher relative dosage. We now propose to take Y3394 through pre-clinical development and a Phase 1 trial to confirm the safety and tolerability, acceptability and efficacy of Y3394 in man. A safe and effective drug, working through natural satiety mechanisms and additive with other agents, would have a massive market.


Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE
Title: Hypoglycaemia worsens atherosclerosis through inflammatory pathways.
Funder: Medical Research Council

Abstract: Background: Patients with diabetes are at increased risk of atherosclerosis and associated cardiovascular morbidity. Considerable work has addressed how hyperglycaemia may be associated with these processes, but it is now becoming evident that hypoglycaemic episodes are also associated with cardiovascular risk. Whilst some of this risk is mediated by sympatho-adrenal pathways, it is becoming increasingly evident that episodes of hypoglycaemia drive inflammatory pathways. Hypothesis: My hypothesis is that hypoglycaemia primes the innate immune response and increases cardiovascular risk through monocyte mobilisation and activation. I have generated pilot data supporting this hypothesis, showing that hypoglycaemia in humans mobilises monocytes and is associated with prolonged rises in high sensitivity CRP. Objectives and methodology: To test my hypothesis in more detail I will: 1. Create a human model of in vivo hypoglycaemia followed by low dose in vivo endotoxin challenge to determine the extent to which hypoglycaemia mobilises monocytes, activates innate immunity, and primes monocytes to respond to inflammatory stimuli. 2. Create a model of acute hypoglycaemia in ApoE-/- mice, examining the extent to which episodes of hypoglycaemia mobilise monocytes from the marrow, cause the establishment of monocyte-producing haematopoietic colonies in the spleen, and accelerate atherosclerosis. 3. Determine whether blockade of monocyte trafficking by targeting the chemokine receptor CCR2 may reduce hypoglycaemia-associated accelerations in atherosclerosis pathology. Scientific and medical opportunities: These studies will create new human and mouse models that will combine to determine the extent to which acute episodes of hypoglycaemia accelerate atherosclerosis through monocyte mobilisation and monocyte activation, and show in proof of principle studies that these pro-inflammatory consequences of hypoglycaemia may be therapeutically targeted.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: METABOLIC AND ENDOCRINE
Title: Reducing animal dependency in diabetes research through pancreatic stem cells
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: This project is of relevance to the areas of islet biology and developmental biology of the pancreas where there is a significant dependency upon the use of animals for diabetes research and therapy because of inaccessibility to healthy human tissue and an absence of human β-cell lines. We have recently derived a panel of four human pancreatic endocrine progenitor cell (PEPC) lines. These cells are stable in culture and can be induced to form insulin-producing cells. We believe these cell lines will make a significant contribution to reducing and replacing the numbers of animals used in this field and will provide significant advantages over existing model systems Our project will develop protocols to optimize the long-term stability of the cell lines in xeno-free (animal-product free) cell culture conditions, and the induction of PEPC lines to insulin-secreting cells. We will document their functional capacity and global gene changes associated with these processes and thereby validate these cells as a xeno-free model for diabetes research.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: METABOLIC AND ENDOCRINE
Title: Reduction of use of experimental mice in type 1 diabetes research through non-invasive, in vivo longitudinal imaging
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Our laboratory studies the causes of type 1 diabetes (T1D), and methods for preventing or curing disease using the non obese diabetic (NOD) mouse. Until now we have always had to cull mice to excise the pancreas to examine events in the islets, and the variation in disease progression between individual mice has meant that group sizes have to be large to estimate differences between treatments. We propose to employ a completely novel method we have developed in collaboration with the University of Glasgow for imaging of transplanted islets in the pinna of the ear, to investigate and explore the efficacy of therapeutic intervention strategies for T1D. This method permits non-invasive, in vivo longitudinal imaging of immunological events in the islets, interrogating factors such as immune infiltration and beta cell mass repeatedly in the same mouse. This will enable us to further elucidate the mechanism(s) of protection from T1D afforded by various treatments, as well as explore possibilities of combining treatment with protocols that increase endogenous beta cell mass to achieve restoration of glucose control. Our preliminary studies support our proposal and suggest that this longitudinal in vivo imaging will provide insight into key events in the islet. This new technique will allow us to gain further insight into immune mediated destruction of beta cells and mechanisms for therapeutic protection, but also be a useful tool to investigate beta cell development, differentiation and function.


Research activity codes: 5.1 PHARMACEUTICALS;5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: METABOLIC AND ENDOCRINE
Title: Integration of multi-disciplinary pathology investigations and clinical characteristics to improve targeted genetic testing for MODY (maturity onset diabetes of the young)
Funder: Department of Health (England)

Abstract: Traditionally clinical diagnostic decisions have been supported by biochemistry, immunology and genetic testing which take place in different laboratories and are interpreted independently. An improved approach would involve testing all modalities on a single sample at a single centre with the test results being integrated with each other and the clinical information. We will develop a new; one tube model for diagnosing monogenic diabetes that will integrate the results of multiple biomarkers and clinical characteristics to facilitate appropriately targeted genetic testing. We will develop this integrated probability model using retrospective data and validate it in prospective studies in different racial groups.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: METABOLIC AND ENDOCRINE
Title: Improving human skeletal muscle insulin sensitivity in healthy ageing
Funder: The Dunhill Medical Trust

Abstract: The accumulation of intramyocellular lipid (IMCL) and associated metabolites is a major cause of insulin resistance. Reducing IMCL accumulation in older individuals (>63yr) via high intensity physical exercise training increases insulin sensitivity. However, whilst this response is desirable from a health standpoint, it is difficult to achieve in the general population. Carnitine translocates fatty-acids into mitochondria for ß-oxidation. We demonstrated that increasing muscle total carnitine (TC) content by >13% in young men reduced muscle glycolytic flux by 30% at rest and 60% during low intensity exercise – likely via switching to increased fat oxidation. Muscle TC is depleted in aged mice and humans, and L-carnitine feeding improves insulin sensitivity in aged and obese rats. Therefore, we aim to determine whether increasing muscle TC during 6 months of low intensity exercise training can ameliorate IMCL accumulation and insulin resistance, and improve exercise capacity, compared to exercise training alone in older individuals (65-75yr).


Research activity codes: 5.7 PHYSICAL;5.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE
Title: Investigating the epigenetic and molecular control of metabolic memory in vascular cells from Type 2 diabetes patients
Funder: The Dunhill Medical Trust

Abstract: The incidence of Type2 diabetes (T2DM) increases with age, rising from ~6% at age 40 to >20% at age 75. Decreased pancreatic beta-cell function and reduced insulin sensitivity, together with increasing obesity and inactivity are key contributors to vascular-related diabetic complications. Early diagnosis of T2DM is difficult and complications progress even after glycaemic restoration. We have discovered that human vascular smooth muscle cells (SMC) cultured from T2DM subjects (age range 50-85 years) display persistent phenotypic and functional impairment, with evidence that these are driven by elevated levels of the microRNA, miR-145. We propose that metabolic disturbances in the pre-diabetes period confer long-lasting “metabolic memory” on SMC. The purpose of this project is to explore the epigenetic basis of this cell phenotype by studying histone and DNA modifications in the miR-145 locus. Secondly we will identify the stimuli that upregulate miR-145 in human SMC, and elucidate critical underlying signalling pathways using pharmacological and molecular approaches.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Early Detection of type 1 Diabetes in Youth: the EDDY feasibility study.
Funder: Division for Social Care and Health Research (Wales)

Abstract: The incidence of type 1 diabetes (T1D) in children is increasing. If T1D is undetected or untreated, life-threatening diabetic ketoacidosis (DKA) occurs - the most common cause of death in children with T1D. Over 25% of children diagnosed with T1D in Wales present in DKA. In this study, a multi-component Community Diabetes Intervention will be developed comprising, e.g. bi-lingual information cards, leaflets, fridge magnets, education from Community Diabetes Liaison Nurses (DLNs), to increase awareness of the symptoms of T1D. Target populations are parents of children up to 18 years of age, family doctors (GPs) and practice nurses in Bridgend, Cardiff and the Vale, where approximately 45 children are diagnosed with T1D each year, 99,781 children attend school or nursery and there are 85 GP practices. Assessment of feasibility will include relevance and acceptability of the intervention, the role, contribution and impact of each component, and exploration of the patient pathway from symptoms to diagnosis, factors that might influence helpseeking behaviour, and what helps and what hinders early diagnosis. A commercial service will courier the intervention to GP practices, and to nurseries, schools and health visitors, who will disseminate the intervention to parents. Data collection methods include qualitative interviews with parents (of children with and without T1D), GPs and practice nurses, and a questionnaire completed with parents of children diagnosed with T1D during the study period. Parents, GPs and other stakeholders, e.g. Healthy Schools Practitioners, contributed to the study design and will be involved throughout. Ethical issues will be carefully considered because the study topic will be emotive for parents and potentially a sensitive area for some GPs. The long term vision, subject to this study’s findings, is to evaluate the effectiveness of a Community Diabetes Intervention, with rate of DKA as the primary outcome, using a large-scale controlled population design.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: METABOLIC AND ENDOCRINE
Title: Point-of-care tests to assist antibiotic prescribing decisions for diabetic foot ulcer infections (INDUCE pilot study)
Funder: Division for Social Care and Health Research (Wales)

Abstract: There are 160,000 people with diabetes in Wales, representing one in twenty of the population, and the lifetime risk of development of diabetic foot ulcers (DFUs) approaches 25%. Direct costs for the care of DFUs are more than £250 million in the UK and indirect costs, including amputation, are much higher. Diagnosis of DFU infection remains entirely clinical and there is no objective test at the point of patient care to assist antibiotic prescribing decisions. A cheap, rapid point-of-care test (POCT) using a pinprick blood sample for C reactive protein (CRP) has been shown to safely halve antibiotic prescriptions for chest infections in primary care. Combination of CRP and another marker, procalcitonin, has been safely used in a pilot study to distinguish between non-infected and mildly infected DFUs. This study of 45 patients required laboratory analysis of samples and so results were not available to guide clinicians at the time of ulcer assessment. The proposed pilot study of 100 DFU patients will include those with noninfected and mildly infected ulcers. Participant recruitment will be from the 10 DFU podiatry clinics in Cardiff that occur each week. More serious ulcer infections will be excluded to ensure that clinical care is not compromised. An online educational tool will also be developed for clinicians to support decision making. The pilot study will compare the POCT results to a gold standard for diagnosis of DFU infection, namely clinical impression at initial assessment and one week later, incorporating the response to any antibiotics prescribed initially. If successful, the pilot will lead to a funding application to conduct a randomised controlled trial of POCTs and the educational intervention for DFU infections in GP practices and podiatry clinics. The composite POCT will also be patented and applied to other primary care infection settings.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: METABOLIC AND ENDOCRINE
Title: Investigating a novel regulator which controls glucose uptake and weight gain and its link to type II diabetes
Funder: The Dunhill Medical Trust

Abstract: Hyperglycaemia, which characterises Type II diabetes (T2D), is linked to excessive weight gain especially in older populations. Unexpected findings from our studies showed that loss of the Brn-3b transcription factor in KO mice results in age-related weight gain and marked hyperglycaemia. Furthermore, Brn-3b was reduced in skeletal muscle and adipose tissues taken from obese mice with metabolic defects suggesting that loss of Brn-3b in such tissues might affect metabolic function. Brn-3b is also reduced in blood from human subjects with T2D, suggesting systemic changes associated with disease. As a TF, Brn-3b stimulates the glucose transporter GLUT4, required for insulin-dependent glucose uptake and so may be important for regulating glucose handling. To understand its roles in metabolism and how reduction is linked to T2D we will investigate: (1) How Brn-3b is regulated in metabolically active tissue in response to high fat diet and ageing and why reduced Brn-3b is linked with glucose intolerance/T2D. (2) If Brn-3b levels in blood can distinguish patients with T2D and its correlation with glycaemic control to test for potential diagnostic or prognostic application.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Mechanisms underlying Glucose-dependent Insulinotropic Polypeptide (GIP) secretion and function.
Funder: Wellcome Trust

Abstract: Modulating glucose-dependent insulinotropic polypeptide (GIP) secretion is a potential strategy for the treatment of diabetes and obesity. However, the cellular mechanisms underlying GIP release from K-cells are poorly characterised because the cells have not, historically, been readily distinguishable from their epithelial neighbours. I recently created transgenic mouse strains expressing a fluorescent marker under the control of the GIP promoter (GIP-Venus mice), enabling, for the first time, the identification and purification of living primary K-cells. These will be characterised by electrophysiology, single cell fluorescence imaging, gene expression analysis and secretion studies, to identify agents and pathways that modulate GIP secretion and that could be targeted to control GIP release in vivo. GIP-Venus mice will be crossed with the Immortomouse to develop K-cell specific lines, which are not currently available but would be a valuable tool for research requiring a higher cell number or longer culture times. Further transgenic mouse strains will be created, expressing the diphtheria toxin receptor under the control of the GIP promoter, enabling conditional K-cell ablation in murine models of obesity. The metabolic consequences of acute and chronic GIP depletion will be investigated in these mice, to evaluate the potential effects of reducing GIP secretion in vivo.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Adiponectin action and insulin sensitivity in skeletal muscle.
Funder: Wellcome Trust

Abstract: Diabetes is now a very common disease and it places a large burden upon the health-care system. Diabetes is a disease of poor blood sugar control caused partially by a lack of effect of insulin to cause sugar uptake by muscle. There is a lot of evidence suggesting a high fat diet reduces the effects of insulin in muscle, but it is unclear how this occurs. It now seems that a chemical in the blood, adiponectin, is important in determining the effects of insulin in muscle. However, the molecules i nvolved are largely unknown and their real significance in the body has not been determined. I will use novel techniques to change the levels of adiponectin target molecules in the muscle of rats and examine the effects of this on how adiponectin and insulin work using metabolic and molecular tests. I will then use cell culture and protein analysis to identify the additional unknown molecules involved, which I will go on to analyse further in animal studies to show the significance of these f indings. In this way I will identify additional molecules which are important in the development of diabetes and help to indicate the best targets for new drug treatments.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Enteroendocrine cell function in diabetes and obesity.
Funder: Wellcome Trust

Abstract: This program will address some of the fundamental unanswered questions about L-cell biology. L-cells produce hormones affecting glucose homeostasis and appetite, and are the target of current drug development programs for type 2 diabetes. The prediction is that stimulating GLP-1 release from L-cells will provide oral therapies that could be used alongside recently-licensed DPPIV inhibitors. Understanding L-cell physiology is critical to the success of this type of approach, but has been hindered by difficulties in identifying and culturing intestinal endocrine cells. We made transgenic mice with fluorescently labelled L-cells, and developed methodologies to characterise the cells by expression analysis, electrophysiology and imaging, providing a first opportunity to study primary L-cells at a single cell level. This technology will be used to probe the physiology of the L-cell using a range of electrophysiological and optical recording techniques, and to address key questions and hypot heses about L-cell function, such as that electrogenic transporters act as sensors of the luminal constituents, that L-cells from different gut regions are not identical and that the cells exhibit plasticity in number/function in an altered metabolic environment. In parallel, we will develop new technologies to study L-cells from humans, and downstream targets of GLP-1 in the intestine.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE