NIHRDataInsights/HRCSData huggingface dataset:
Title: The role of non-enzymatic glycation on aggregation prone diabetes related polypeptides: a multidisciplinary approach from biophysics to cell toxicity
Funder: Diabetes UK

Abstract: We aim at understanding the precise effect of glycation on protein aggregation. Glycation is a pathological process that is highly relevant in diabetes patients as it plays a crucial role in diabetes complications and in the normal aging process. Increasing evidence suggests a link between diabetes and aging-related neurodegenerative processes such as Alzheimer and Parkinson diseases that are more common in diabetic patients. We plan to study the role of glycation on the structure, aggregation pathway and toxicity of peptides amylin, Abeta and -synuclein. We shall capitalize on our experience in studies of proteins involved in neurodegeneration and on our recent work (supported by a short DiabetesUK grant) that enables us to reproducibly produce highly purified recombinant monomeric amylin both in a glycated and non-glycated form in quantities amenable for biophysical studies. We shall use a combination of techniques that range from computational methods, various spectroscopies and microscopy methods to cyto-toxicity to study how glycation affects a) the structure of the monomeric peptides and the morphology of the resulting aggregates, b) the aggregation pathways, and c) cyto-toxicity. This approach will enable us to understand the mechanicistic effects of glycation on amyloidogenesis and is highly relevant for understanding the diabetes complications.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: Investigation into the role of phosphatidyl-inositol-4-phosphate patches and Efr3 in insulin-dependent dispersal of GLUT4 clusters in the plasma membrane of adipocytes.
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 the facilitative glucose transporter GLUT4 and is defective in individuals suffering from insulin-resistance and Type-2 diabetes. Understanding the molecular mechanisms which underlie this process therefore represents an important step in the development of rational therapies for these disease states. It has recently been discovered that in addition to regulating delivery of GLUT4 from intracellular stores to the plasma membrane, insulin also regulates the spatial organisation of GLUT4 at the cell surface. This project builds upon findings from our lab to understand the molecular mechanisms that control this recently described effect of insulin. The student will investigate how patches at the cell surface of adipocytes that are enriched in phosphatidyl-inositol-4-phosphate contribute to GLUT4’s localisation and functionality and also how these patches are regulated by insulin.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: Mechanism of action of metformin in hepatocytes: inhibition of glucotoxicity
Funder: Diabetes UK

Abstract: Metformin is a commonly prescribed drug for treatment of type 2 diabetes. However, its molecular mechanism of action remains debated and it is therefore a focus of vigorous diabetes research because improvement in the understanding of its molecular targets may enable development of second generation drugs with improved efficacy. Key contentious issues are the mechanism by which metformin attenuates hepatic gluconeogenesis and whether metformin therapy mitigates the elevated hepatic lipogenesis which occurs commonly in type 2 diabetes. This project is to test the hypothesis that a major mechanism of action of metformin is the counter-regulation of the glucose-induction of hepatic gluconeogenic and lipogenic enzymes. The specific aims are: (i) To determine the rate of accumulation of metformin by primary hepatocytes and to optimise a protocol for pre-loading of hepatocytes with physiological metformin doses; (ii) To test the effects of therapeutic doses of metformin, based on intracellular accumulation, on candidate mechanisms of action of metformin including cellular adenine nucleotides and metabolites and on gene expression and transcription factor recruitment of glucose-responsive genes; (iii) To determine whether the counter-regulatory effects of metformin on glucose-regulated gene expression are linked to the inhibition of glucokinase translocation.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE
Title: Characterising the metabolic disruption caused by brief periods of reduced physical activity in people with a family history of type 2 diabetes mellitus (T2DM).
Funder: Diabetes UK

Abstract: The benefits of exercise in preventing obesity, T2DM and cardiovascular disease (CVD) are widely known. However, PA is a distinct behaviour from exercise, often related to activities of daily living. Technology (e.g. non-manual jobs, household devices) has facilitated physical inactivity such that modern lifestyles are increasingly characterised by sedentary behaviour. Physical inactivity, especially in those who do not regularly exercise, has serious health implications predisposing individuals to T2DM and CVD. This research will test the hypothesis that individuals with a family history of T2DM (FH+) are more susceptible to the detrimental metabolic effects of inactivity than those without a family history (FH-). To study the impact of a short-term period (21 days) of sedentary behaviour, healthy volunteers with FH+ and FH- will be transitioned from high to low levels of ambulatory activity (from ~10,000 to 1,500 steps daily) to quantify the magnitude of effects of inactivity, and determine the relative sensitivity of FH+ vs. FH-. We will measure changes in: i) Metabolic health: insulin sensitivity and beta-cell function ii) Body composition: lean body mass, visceral and liver fat. iii) Vascular function: endothelial function, induced by a 21 day period of low PA, and the reversibility of these changes upon resumption of habitual physical activity after a further 21 days.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Control of GLUT4 sorting by Syntaxin 16 and mVps45.
Funder: Diabetes UK

Abstract: A key action of insulin on adipose and muscle cells is to initiate a signalling cascade that changes the trafficking facilitative glucose transporter GLUT4, releasing it from a specialised intracellular store and delivering it to the cell surface. Individuals with insulin-resistance and Type 2 Diabetes exhibit significantly impaired insulin-stimulated glucose transport, and this appears to be largely due to a failure of GLUT4 translocation. Understanding how GLUT4 trafficking is controlled at the molecular level is therefore an essential step in the development of effective therapies against the current global epidemic of insulin-resistance and diabetes. This proposal seeks to understand the sorting of GLUT4 into its specialised storage compartment. We will build our published and unpublished data to further our understanding of the role that the SNARE protein Syntaxin-16 plays in this process, and in particular how insulin regulated dephosphorylation of Syntaxin-16 controls GLUT4 sorting. Using assays and tools established in the lab we will: 1. define the precise step(s) regulated by Sx16 in GLUT4 trafficking in 3T3-L1 adipocytes. 2. investigate the functional consequences of insulin-stimulated Sx16 dephosphorylation on GLUT4 trafficking. 3. investigate the cellular levels and phosphorylation status of Sx16 in individuals with insulin resistance.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Repertoire and function of invariant Natural Killer T cells in human Type 1 diabetes: Paving the way for translation
Funder: Diabetes UK

Abstract: Lipid-specific invariant Natural Killer T cells (iNKT) are key regulatory immune cells that mediate immunological tolerance to self tissues. Age-related or early “premature” decline of the iNKT repertoire and function is associated with autoimmune inflammation in animals and humans. Conversely, restoring the iNKT repertoire to healthy levels in autoimmune prone mice prevents the onset of disease in models of T1DM, arthritis and multiple sclerosis. Thus, targeting iNKT cells may also offer new ways of treating human T1DM. However, a deeper understanding of the changes in iNKT repertoire and function, both during early stages and progression of human T1DM is required. We have recently shown that functionally different human iNKT subsets can be identified using new molecular tools developed in our laboratory. Our preliminary findings in 10 people with T1DM and age-/gender-matched controls indicate significant changes in these iNKT subsets and their functions in early T1DM. To corroborate and extend these findings, we propose to carry out cross-sectional and longitudinal studies to characterise the composition and function of the iNKT repertoire in early T1DM compared to age- and gender-matched healthy matched controls. The results of these studies will provide the foundations for future rational iNKT-targeting diagnostics and therapeutics in T1DM.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Characterisation of epitope-specific autoimmune responses associated with progression to type 1 diabetes
Funder: Diabetes UK

Abstract: Insulin and IA-2 autoantibodies are important for characterising the prodrome of type 1 diabetes and prediction of the disease. These antibodies show selective binding to dominant epitopes of their antigens and this can discriminate risk of disease. Autoantibodies recognizing epitopes associated with diabetes progression may therefore contribute to the pathogenesis of beta-cell destruction. We and others have identified critical residues in the conformational epitopes of insulin and IA-2 that are crucial to autoantibody binding in type 1 diabetes. This information will be used to characterise B- and T-cell autoimmune responses to major epitopes of these antigens in a mouse model of the disease. We will achieve this by • Expressing, processing and purifying native and mutant forms of human insulin and IA-2 that differ at these critical residues • Characterising these molecules to ensure their structural and immunological integrity • Evaluating T- and B-cell immune responses elicited by the mutant human insulin and IA-2s in mice expressing the human high risk HLA class II susceptibility haplotype DRB1*04 - DQ8. This will further our understanding of insulin and IA-2 autoantibody epitope responses, as a first step in determining whether epitope-specific vaccination may be useful for prevention of type 1 diabetes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Identification of diabetes-associated epitopes by NMR
Funder: Diabetes UK

Abstract: Autoantibody-secreting B-cells are potential targets of immune intervention therapy for Type 1 diabetes, as demonstrated by the established effects of B-cell depletion to both prevent diabetes in animal models and prolong beta cell function in Type 1 diabetic patients. Characterisation of antibody epitopes will provide information on the specificity of autoimmune responses in diabetes that is critical for the development of therapies that deplete only those B-cells that are implicated in the disease process, thereby avoiding general immune deficiency. Current methodology available to define regions of autoantigens recognised by antibodies in diabetes provide only limited structural information on antibody epitopes. Nuclear magnetic resonance (NMR) provides a powerful technology for detailed analysis of protein-protein interactions that could be developed as a novel approach to better understand structures recognised. The objective of this project is to develop NMR-based approaches for rapid identification of epitopes for autoantibodies in diabetes. The specific aims are to optimise protocols for NMR chemical shift mapping using recombinant fragments of well-characterised IA-2 autoantibodies previously obtained as EBV-transformed B-cell lines. The project will establish NMR as an important tool for epitope discovery in Type 1 diabetes, a critical step towards development of B-cell-targetted therapies for prevention of disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Metabolomic profiling to improve characterisation of the risks of diabetes and cardiovascular disease in British Europeans, South Asians and African Caribbeans.
Funder: Diabetes UK

Abstract: The escalating global burden of type 2 diabetes falls disproportionately upon people of South Asian and African Caribbean origins. Causal mechanisms underlying progression to type 2 diabetes remain inadequately understood in all populations, as do , in particular, mechanisms underpinning ethnic differences in diabetes. Emerging technologies, such as proton nuclear magnetic resonance (NMR) spectroscopy, allow the high-throughput profiling and quantifying of metabolites (metabolomics), enabling a comprehensive, efficient and highly cost-effective assessment of complex metabolic networks. We will analyse 3035 stored baseline (1988-91) blood samples from a west London community-based prospective cohort of European, South Asian and African Caribbeans aged 40-69 (the SABRE Study). Baseline measurements included fasting and post-glucose challenge bloods, detailed anthropometry and health/lifestyle questionnaire. Incident diabetes, cardiovascular disease and other morbidities over the ensuing 20 years have been recorded via medical record review, participant questionnaire, clinical follow-up and mortality flagging. We will use NMR spectroscopy to identify >100 low molecular weight metabolites and lipoprotein subclasses and >100 derived variables. We will examine and compare metabolites in each ethnic group across the range of glucose tolerance at baseline and identify key metabolites and profiles which predict onset of diabetes and cardiovascular disease during the 20 year follow-up.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: A comparison of the effects of high-intensity interval training and moderate/vigorous intensity walking on glycaemic control in Type 2 diabetes
Funder: Diabetes UK

Abstract: Although exercise is considered one of the three cornerstones of diabetes care programmes (together with diet and medication), the majority of individuals with Type 2 diabetes do not achieve the minimum recommended levels of physical activity. One of the key-barriers to exercise appears to be lack of time. We have recently shown that a novel exercise intervention requiring 80% less time than current physical activity recommendations is effective at improving insulin sensitivity in sedentary men. This intervention consists of three 10-min cycling sessions per week including two short sprints. In the proposed study we will compare the effectiveness of this novel exercise intervention with that of current physical activity recommendations in individuals with Type 2 diabetes. We will compare: 1) the effectiveness of the interventions at increasing glycaemic control, 2) effects on various other health measures (aerobic capacity, blood pressure, blood lipid and inflammatory profile) to assess the impact on risk of diabetes-related cardiovascular disease, and 3) perceptions on the two exercise interventions (through measures of enjoyment and rating of perceived exertion). Positive results will provide individuals with Type 2 diabetes with an alternative means to manage their condition.


Research activity codes: 6.7 PHYSICAL
Health categories: METABOLIC AND ENDOCRINE
Title: Labeling of islets for non-invasive and longitudinal imaging in pre-diabetic or diabetic NOD mice
Funder: Diabetes UK

Abstract: Type 1 diabetes is an inflammatory disease caused by the autoimmune destruction of beta cells in the islets of Langerhans. Our laboratory has studied the mechanisms of disease for many years with the objective to identify therapies that can stop or decrease islet destruction. We are now in the process of developing a method for non-invasive in vivo imaging of islets transplanted into the pinna of the ear which so far has given very good results. In this proposal to Diabetes UK we ask for funds to extend these studies into NOD mice, which is a mouse strain that develops diabetes spontaneously, but in which there are no available suitable transgenic mice with fluorescent islets to facilitate imaging. We ask for funding to develop a protocol for labelling of NOD islets for future use in studies of proposed therapies for type 1 diabetes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Does neurocognitive training have the potential to improve dietary self-care in type 2 diabetes?
Funder: Diabetes UK

Abstract: Dietary self-care is considered the most difficult aspect of diabetes self-management. Successful dietary self-care depends on cortical top-down inhibition of emotional responses to food in sub-cortical regions. Top-down inhibitory control mechanisms may be strengthened by simple neurocognitive training tasks testing working memory. However, whether these training tasks can be used to strengthen dietary self-care in people with diabetes remains to be determined. In this pilot study we aim to test the effects of neurocognitive training on food-related responses in people with type 2 diabetes. We will randomise participants (N = 2 x 24) into either 8 weeks of neurocognitive training or placebo training. We will examine whether this training affects (1) cognitive biases to food stimuli; (2) food choice in a real-life eating situation; and (3) food intake in daily life. Assessments will be carried out before, after and at 3-month follow-up to assess its long-term effects. Semi-structured interviews will be conducted allowing participants to express their views on the training. Using semi-structured interviews, we will seek an understanding of participant’s perceptions about acceptability of the training, the impact on their quality of life and overall experience of the training. The semi-structured interviews will be analysed using template analysis.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: METABOLIC AND ENDOCRINE
Title: Assessment and translation of novel biomarkers for diagnosis of maturity onset diabetes of the young due to HNF1A mutations
Funder: Diabetes UK

Abstract: In this project, I will evaluate innovative new screening tests to identify those at high risk of HNF1A-MODY, the commonest form of monogenic diabetes, with the aim of bringing personalised treatment into young adult diabetes clinics. HsCRP and plasma glycan profile can discriminate HNF1A-MODY from other forms of diabetes with high discriminative accuracy. This proposal will assess their sensitivity, specificity and diagnostic precision compared to HNF1A sequencing in a large group of unselected patients (n=1200) with young-onset diabetes from the UK and Croatia. I will also investigate whether the microRNAs miR-103 and miR-224 are further specific biomarkers for HNF1A-MODY. The data generated will be included in a diagnostic model that will predict the probability of an individual with young-onset, non-autoimmune diabetes having HNF1A-MODY. The model will be tested in a clinical network of young-adult clinics and will be used to guide referral for genetic testing. The overarching aim is to increase diagnosis rates of monogenic diabetes and to improve treatments and outcomes for patients and their families. Translation of this work could be expected over a 3-5 year period. This project will provide training in molecular biology, genomics, interpretation of genetic sequencing, statistics and clinical experience in monogenic diabetes.


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 glucose control in non-critically ill inpatients with type 2 diabetes
Funder: Diabetes UK

Abstract: The present project represents horizontal translation of Artificial Pancreas research from type 1 to inpatients with type 2 diabetes. Two open-label single-centre randomised clinical studies will be performed. The first study will assess safety and efficacy of fully automated closed-loop operation in comparison to conventional therapy: 40 inpatients with insulin-treated T2D (20 per arm) will be studied over 72 hours. The primary efficacy endpoint is the proportion of time with glucose levels within target range (5.6-10.0 mmol/l). The follow up study will assess ability of closed-loop to achieve two levels of the target glucose range. This responds to evolving consensus on having a higher glucose target for older patients and patients with an elevated glycated haemoglobin to reduce the risk of hypoglycaemia. The primary efficacy endpoint is proportion of time with glucose levels within target range (low target arm: 5.6-10.0 mmol/l; high target arm: 7-12mmol/l). We will analyse data collected in 30 inpatients with insulin-treated T2D (15 per target range) studied over 72 hours. Safety will be assessed by frequency of hypoglycaemia and other adverse events. The overall success will be evaluated by attaining satisfactory safety and efficacy of closed-loop quantified in terms of glucose control and risk of hypoglycaemia.


Research activity codes: 6.3 MEDICAL DEVICES
Health categories: METABOLIC AND ENDOCRINE
Title: Understanding the underlying causes of hypoglycaemia unawareness
Funder: Diabetes UK

Abstract: The ventromedial nucleus of the hypothalamus is critical for the normal endocrine and behavioural counter-regulatory responses to hypoglycaemia. This nucleus contains a mixed population of neurones, some of which are exquisitely adapted to respond to hypoglycaemia. It has been proposed that these cells lose their sensitivity after recurrent hypoglycaemia, but some workers report increased sensitivity. These controversies largely arise because the precise cell phenotypes have remained unknown. We have now identified that “glucose-inhibited” (GI) neurones contain the transmitter, pituitary adenylate cyclase-activated polypeptide (PACAP). By using a Pacap-IRES-cre mouse and the latest viral technologies, we are able to directly assess the sensitivity of these neurones, describe their connections and manipulate their activity selectively in vivo. We propose that these GI neurones project to the hypothalamic paraventricular nucleus to activate corticotrophin-releasing hormone (CRH) neurones via Vipr2 receptors. Using Pacap-IRES-cre and Crh-IRES-cre mice we will ascertain the role of this pathway in the response to recurrent hypoglycaemia and the development of hypoglycaemia-associated autonomic failure (HAAF)/hypoglycaemia unawareness. We will determine if HAAF is dependent on reduced responsiveness of the primary sensory GI neurones, “fatigue” in the hypothalamic outputs or the development of habituation in the system, similar to that which occurs after repeated stress.


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