NIHRDataInsights/HRCSData huggingface dataset:
Title: Development of a long-acting growth hormone antagonist to address the unmet need for treatment in acromegaly
Funder: Medical Research Council

Abstract: Uncontrolled acromegaly, a disease of excess growth hormone (GH) secretion from a pituitary tumour, has a standardised mortality ratio twice that of the background population. First-line medical treatment with somatostatin analogues controls disease in only 60% of patients leaving 40% with increased mortality (Ref 1). Pegvisomant, a pegylated GH antagonist, controls acromegaly in >95% of patients; however, is rarely used because it is not considered cost-effective. Pegvisomant has low bioactivity, requires high dose, high volume daily injections, and has substantial cost of goods making it expensive and inconvenient. A cost-effectiveness study concluded Pegvisomant would require a reduction in cost by one third to achieve an acceptable incremental cost-effectiveness ratio (ICER) of £30K/QALY (Ref 15). Thus, few patients receive Pegvisomant leaving patients with uncontrolled disease. We developed a fusion technology, Profuse, for making a superior long-acting GH antagonist. The Profuse GH antagonist (GHA) is potent, has low cost of goods, requires only weekly injections and economic evaluation predicts an ICER <£20k/QALY. Profuse links GH antagonist to native GH binding protein delaying clearance and allowing weekly injections. The molecule is potent (reduced dose), has no requirement for post-purification modification (pegylation) reducing cost and potential side-effects and is stable in solution allowing use of a pen device. The DPFS application is for a 3 year grant to deliver a Profuse GH antagonist ready for clinical proof-of-concept. It is the first phase required to bring the Profuse antagonist to market, namely, late pre-clinical candidate selection, manufacture process development, formulation and toxicology. The next stages (funded separately) are a Phase 1/2a proof of concept trial in patients, followed by Phase 2 & 3 trials for market authorisation.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE
Title: Mobile phone text-messaging to support treatment for people with type 2 diabetes in sub-Saharan Africa: a pragmatic individually randomised trial
Funder: Medical Research Council

Abstract: Non-communicable long-term conditions and associated failure to use effective medicines place a major burden on the health of patients and health care systems. Current strategies to address problems of motivation and volition in taking medicines as intended are costly and of limited effectiveness. Mobile phones and other forms of digital health technology offer promise in delivering more effective support to patients around medicines adherence, but studies have not generally explored broader implementation within health care, comparative effectiveness and costs in low-resource settings. We have carried out a study using a novel system to send individualised text messages linked to available health care data for people with hypertension. We now plan to extend this work to people with diabetes, in different health-care settings and include formal qualitative methods and evaluation of costs. We propose to (i) test the impact of educational and motivational messages, and prompts delivered through a system of SMS text-messaging on diabetes risk biomarkers, health status and satisfaction with care in a randomized trial; (ii) determine the factors associated with successful implementation of the system using a mixed-methods approach; (iii) study the costs of implementing the system and of its cost-effectiveness. The primary trial outcome is HbA1c with secondary measure including blood pressure and the ratio of total-cholesterol to HDL-cholesterol. The SMS text-message system has already been used with hypertensive patients in a low-income setting with 87% follow up of patients over one year. We are an international collaboration with expertise in diabetes research in sub-Sarahan Africa. We have statistical support from a UK registered primary care clinical trials unit, engineering support from a world-leading biomedical engineering based mHealth group, able to provide support for clinical measurement at the proposed research sites.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: METABOLIC AND ENDOCRINE
Title: The Bangladesh D-Magic Trial. Diabetes Mellitus: Action Through Groups or Information for Better Control?
Funder: Medical Research Council

Abstract: Aim: To evaluate and understand the impact and cost-effectiveness of mHealth and a community mobilisation interventions to raise awareness, change behaviour and reduce the prevalence of diabetes and pre-diabetes and NCD risk-factors in rural Bangladesh. Design: Three-arm cluster randomised control trial with 60 clusters. 20 clusters will receive the mHealth intervention, 20 will receive the participatory community mobilisation intervention and 20 will be designated control clusters, receiving only standard services. All study clusters will benefit from health systems strengthening initiatives. Participants: Adults aged 20 years and above residing in the 60 study clusters (impact evaluation); health service providers, policy-makers and community groups (process and economic evaluation). Methods: Sample surveys of 6000 participants will take place before and after intervention implementation. Diabetes prevalence will be estimated from random capillary blood glucose levels. Anthropometric and blood pressure measures and survey data on participant demographic and socio-economic characteristics, lifestyle and behavioural risk factors, diabetes awareness indicators and health seeking behaviour will be gathered. Process and cost data will be gathered using mixed methods. Primary outcome: Prevalence of diabetes and pre-diabetes in individuals aged 20 years or more between intervention and control arms after the intervention Selected secondary outcomes: self-awareness of diabetic status; smoking prevalence; physical inactivity; mean population diastolic and systolic blood pressure; mean population body mass index; mean population waist and hip circumference ratio; awareness of diabetes symptoms; utilisation of diabetic services. Process evaluation will address the aim of understanding the operational factors affecting intervention delivery and impact. An economic evaluation will address the aim of understanding the interventions' cost-effectiveness.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: METABOLIC AND ENDOCRINE
Title: Characterisation of the role of NPAT in metformin regulation of body weight and glycaemic control; moving GWAS data to biological function
Funder: Medical Research Council

Abstract: Metformin is the most common diabetes treatment despite the fact its mechanism of action remains unclear and it does not reduce blood glucose in all patients. Our previous work produced compelling genetic evidence that variations in the genes for the cell growth-regulating gene ATM and the transcription factor NPAT are associated with metformin response. We now wish to gain biological and molecular insight into how NPAT actually influences metformin action, and whether alterations in NPAT function could contribute to the development of obesity and diabetes. We aim to 1) establish the detailed physiological and metabolic consequences of NPAT deletion in mice, 2) establish the detailed physiological and metabolic consequences of NPAT deletion specifically in the liver of mice, 3) investigate the functional consequences of the genetic variations in the coding regions of NPAT in cellular systems and 4) investigate the functional consequences on glucose homeostasis, metformin response and hormone action of increasing or decreasing NPAT protein in cellular systems. The work will include metabolic phenotyping of 2 mouse models (NPAT-/-, and NPAT liver -/-). We will perform hyperinsulinemic-euglycemic and hyperglycemic clamps, glucose, pyruvate, leptin and insulin tolerance tests, food intake, and indirect calorimetry on mice placed on a high fat diet with or without metformin. This will establish the outcome of altered NPAT expression on energy metabolism and response to metformin in the intact animal. In cell-based studies where NPAT is deleted, mutated or overexpressed we will establish its influence on specific aspects of glucose metabolism, cellular bioenergetics and metformin action. This will include generation of stable cells that express each point mutant of NPAT identified in the human GWAS. Finally, we will use the information gained to guide human studies on diabetes treatment (funded by the Wellcome Trust), which are ongoing within our group.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Bone marrow adipose tissue as a novel regulator of metabolic homeostasis
Funder: Medical Research Council

Abstract: Bone marrow adipose tissue (MAT) comprises up to 70% of bone marrow volume in healthy adults and further increases under conditions of altered metabolic homeostasis, such as caloric restriction (CR). My previous research identifies MAT as an endocrine organ that has systemic effects. These observations suggest that MAT directly impacts metabolic homeostasis, knowledge that might reveal new approaches for treating diabetes and other metabolic diseases. However, in stark contrast to white or brown adipose tissues (WAT or BAT), study of MAT has been extremely limited; hence, the physiological and pathological roles of MAT are poorly understood. My research will address this major gap in knowledge by investigating the characteristics, formation and metabolic function of MAT. My first objective is to establish unique MAT characteristics. To do so I will use RNAseq, proteomics and metabolomics to globally characterise MAT, WAT and BAT from rats, followed by targeted analysis of these tissues from humans. This will provide crucial insights into MAT biology directly relevant to human health. My second objective is to determine if increased glucocorticoid action mediates MAT expansion during CR. To do so I will use surgical and pharmacological tools to block glucocorticoid activity in mice fed control or CR diets. This will shed new light on why CR causes MAT expansion. My third objective is to determine if MAT impacts metabolic homeostasis. To do so I will create a new mouse model that lacks MAT. I will then study these mice to determine if lack of MAT has metabolic consequences, both on a normal diet and during CR. Finally, my fourth objective is to establish new mouse models for specific, inducible genetic targeting of MAT. These unique models will open avenues for future research to shed new light on MAT formation and function. Such knowledge might reveal new mechanisms of metabolic regulation, thereby allowing development of new strategies to treat metabolic diseases.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: All-optical deconstruction of the islet wiring patterns underlying insulin secretion in health and disease
Funder: Medical Research Council

Abstract: Beta cell connectivity describes the phenomenom whereby the islet context improves insulin secretion by providing a three-dimensional platform for intercellular signaling processes. Thus, the precise flow of information through homotypically interconnected beta cells leads to the large-scale organization of hormone-releasing activities, producing a gain-of-function in hormone release. Importantly, a growing number of studies suggest that such cell-cell communication may be targeted by both environmental and genetic factors in T2DM to perturb normal beta cell function and insulin release. Using rapid Nipkow imaging combined with mathematical graph theory, we have shown that beta cells wire themselves as glucose- and incretin-responsive subnetworks, which support synchronised activity. Such subnetworks display small-world properties and their topology is dominated by a few cells that host the majority of the functional connections, linking and pacemaking distant regions of the islet. These superconnected cells, or "hubs", may provide an important route for the intra-islet regulation of insulin secretion, and may represent a novel target for T2DM insults. By melding cutting-edge optogenetic and photopharmaceutical approaches, we now aim to: 1) remote control the function of single beta cells within islets using halorhodopsin and a photoswitchable sulfonylurea; 2) optically deconstruct the islet circuitry underlying insulin secretion; 3) gain a handle on hub cell function using online analysis of islet dynamics and hormone output; and 4) determine the susceptibility of islet wiring patterns and hub cell function to T2DM insults. The outcome of these studies will be the characterisation of a novel mode of regulation of insulin secretion, which may be targeted to improve the functional beta cell mass during T2DM.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: MICA: MRC APBI STratification and Extreme Response Mechanism IN Diabetes - MASTERMIND
Funder: Medical Research Council

Abstract: Our vision is that a stratified medicine approach will result in more effective use of glucose-lowering therapy for patients with Type 2 diabetes (T2D). The rationale for this stratified approach is based on: i)T2D patients showing considerable inter-individual variation in their underlying pathophysiology ii) the increasing number of classes of glucose lowering therapies that work by very different mechanisms of action iii) pilot study evidence that variation in response to therapy is, in part, robustly explained by differences in patients' underlying pathophysiology. This extension will involve 2 strands: 1. An experimental strand that will involve a 3 way crossover study of third line oral therapy (a thiazolidinedione, DPP4 inhibitor and SGLT2 inhibitor) in patients with inadequate glycaemic control on metformin and sulphonylurea. This work will test specific hypotheses from pilot work with the primary outcome being HbA1c on therapy and secondary outcomes of side effects and patient preference. 2. A data analysis strand that will use routine clinical, academic and commercial trial data to assess how drug response is related to clinical features and routine biochemistry. We will examine short and long term glycaemic response and side effects. The key outcomes of this work are: 1. Robust evidence to inform guidelines for the most appropriate use of glucose lowering medication for specific subgroups of patients with Type 2 diabetes. This will enable better targeting of old drugs and enable earlier more focussed use of the newer more expensive therapies in patients where old drugs are less effective. 2. Key methodology development for hypothesis generation and subsequent testing/validation of stratification in Type 2 diabetes. This will cover both data analysis and study design. 3. Establishing a large bioresource of individuals with well characterised comparative response to commonly used drugs for biomarker assessment and discovery by industry and academia.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: METABOLIC AND ENDOCRINE
Title: Adjuvant Rituximab - a potential cure for the young patient with Graves' hyperthyroidism
Funder: Medical Research Council

Abstract: Young people with Graves' hyperthyroidism can be managed with anti-thyroid drugs (ATD), surgery (total thyroidectomy) or radioiodine (RI). None of these interventions provides a realistic prospect of cure in the short term and all have disadvantages that are particularly pertinent in the young patient. Only 25% of young patients with Graves' hyperthyroidism remit after a 2 year course of ATD and this will be a chronic condition for most patients with a requirement for long-term thyroxine replacement and a significant impact on quality of life. Novel approaches to management are needed and B lymphocyte depletion with rituximab (RTX) has shown promise in adults with Graves' hyperthyroidism. RTX has disease-modifying properties and is standard care for some paediatric autoimmune conditions. The aim of this proposed single-arm 'proof of concept' trial is to establish whether a single dose of RTX, administered with a short course of ATD therapy, is likely to improve remission rates in young people with Graves' hyperthyroidism. 27 subjects with newly-diagnosed Graves' hyperthyroidism aged 12 to 20 years will receive a single dose of 500mg RTX 2 to 6 weeks post-diagnosis. Subjects will have commenced ATD and this will be stopped 12 months post RTX. In the interim the dose of ATD will be adjusted to maintain a euthyroid state. Thyroid function tests, immunological markers including thyroid stimulating hormone receptor (TSHR) and peroxidase antibodies, serum immunoglobulin levels and peripheral blood lymphocyte subset analysis (including CD19+ and CD27+) will be measured throughout the trial. The primary end-point will be the proportion of patients who are in remission off ATD 2 years post RTX. 40% or more patients in remission at 2 years following a single dose of RTX and a 12 month course of ATD would constitute a clinically meaningful improvement in outcome, above that normally observed, that would provide the foundation for a definitive trial.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: METABOLIC AND ENDOCRINE
Title: A mechanistic investigation into the emergent functional dynamics of the HPA axis
Funder: Medical Research Council

Abstract: The major hormonal system that enables a rapid response to stressors is the hypothalamic-pituitary-adrenal (HPA) axis. This complex neuroendocrine system regulates the secretion of vital glucocorticoid hormones (CORT), and a critical aspect of its function is an ultradian oscillation in hormone release. These oscillations in blood CORT levels are paralleled in the brain; thus neurons throughout the CNS are exposed to this dynamic signal. In hippocampal cells, for example, these rapid changes in CORT levels induce bursts of transcriptional activity and enhance glutamate transmission via non-genomic mechanisms. Alterations in these oscillations are associated with a wide variety of physiological and pathological conditions, including chronic stress, but the reasons for these dynamic changes are poorly understood. The aim of my research proposal is to characterise the fundamental mechanisms that regulate the ultradian oscillation; and the changes that occur in the oscillation when these mechanisms break down. To achieve this, I will use an integrative approach, combining mathematical modelling with in vitro cellular imaging approaches and in vivo experimental physiology, which will enable me to study the dynamics of the system at multiple scales, and to understand the key mechanism underpinning the oscillatory activity of the system. Elucidating these mechanisms will not only help to realise normal physiological function, but will also help to understand why these dynamics change in disease; leading to the development of, or protection from, pathological consequences.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Investigating the inter-relationship between diabetes and children's educational achievement.
Funder: Medical Research Council

Abstract: Aims A child with diabetes will learn to self-manage their blood glucose. The quality of this management will have direct health implications which may impact educational outcomes (including attendance and achievement) which in turn may affect self-management and other health outcomes. The overall aim of the research is to better understand the interface between health outcomes and educational outcomes for children with diabetes. We will consider how other factors such as the characteristics of the child, their families, and the health services they use influence these relationships. We will use advanced statistical approaches including linking datasets, missing data approaches, longitudinal analysis and variance functions to provide robust estimates of these relationships. Methodological objectives 1. To use robust data to combine information from multiple health and education datsets. 2. To model multilevel data structures, including cross-classified clusters, longitudinal within individual trajectories of health and education measures, and modelling cluster (individual and clinic) variance functions of blood glucose management. 3. To use advanced multiple imputation to deal with missing data in complex data structures. Substantive objectives 1. To model the effects of health on education for children with diabetes, and the characteristics of individuals. 2. To model trajectories of health and education for children with diabetes to unpick the direct effects of health on education, the reverse causality of education on health and the unobserved characteristics which simultaneously affect both health and education. To identify important time varying characteristics and effects of the timing of important transitions in health and educational trajectories. 3. To quantify the effect of cross-classified multilevel clusters such as schools, diabetes clinics, families and how characteristics of clusters modify relationships between health and education.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Determining the role of arcuate nucleus glucokinase in the regulation of glucose homeostasis
Funder: Medical Research Council

Abstract: In the UK over one in sixteen people have diabetes with the prevalence due to rise from 3.9 to 5 million by 2025. Diabetes has devastating complications, reduces life expectancy by up to 14 years and costs the NHS £23.7 billion/year. Classically, glucose homeostasis was thought to be controlled primarily by the direct secretion of insulin from the pancreas in response to blood glucose levels. Most therapies are directed here. However, recent data suggests that the central nervous system, particularly the arcuate nucleus within the hypothalamus, plays a major role in glucose homeostasis. However the precise mechanism of action is unclear. Glucokinase has an important role in glucose sensing. Within the hypothalamus, one of the main sites of glucokinase expression is the arcuate nucleus. However, its role is unknown. Investigating the effects of arcuate nucleus glucokinase using transgenic rodents is difficult since no promoters exist which allow for targeting. My group have overcome this by utilising viral rAAV encoding glucokinase to increase the expression of glucokinase confined only to the arcuate nucleus. I have carried out pilot studies to investigate the effect of increased arcuate glucokinase on glucose homeostasis using glucose tolerance and insulin tolerance tests. My data shows that increased arcuate glucokinase activity improves glucose tolerance to a similar magnitude to that produced by glucagon-like peptide. There was no effect on insulin tolerance. This suggests that glucokinase within the arcuate nucleus has a role in the regulation of glucose stimulated insulin release or glucose effectiveness. My pilot data supports a role for increasing glucose stimulated insulin release with increased glucokinase within the arcuate nucleus. My proposed experiments will allow me to establish whether it would be beneficial to develop glucokinase activators which access the brain as well as the periphery hence providing alternative mechanisms to treat diabetes.


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