NIHRDataInsights/HRCSData huggingface dataset:
Title: Control of insulin-sensitive GLUT4 stores by cellugyrin
Funder: Diabetes UK

Abstract: Delivery of the glucose transporter from intracellular GLUT4 storage vesicles (GSVs) to the cell surface in response to insulin is central to whole body glucose homeostasis and is defective in insulin-resistance and Type-2 diabetes. In the absence of insulin, the majority of GLUT4 localises to intracellular membrane vesicles/tubules. Only a subpopulation of these internal GLUT4-containing vesicles are GSVs, which translocate to the plasma membrane in response to insulin. Internal GLUT4-containing vesicles that do not translocate to the cell surface in response to insulin are marked by the protein cellugyrin. We have shown that cellugyrin plays a key role in the localisation of GLUT4, since depletion or mis-localisation of cellugyrin to the plasma membrane drives GLUT4 to the plasma membrane. In addition we have shown that cellugyrin is phosphorylated in response to insulin. With the ultimate aim of understanding how GLUT4 is sorted into its intracellular store, we now aim to build on these unpublished findings to investigate the role of cellugyrin in GSV biogenesis. This will be achieved through a programme of work pursuing the following specific aims: To determine the relationship between cellugyrin-positive and cellugyrin-negative GSVs. To determine the functional consequences of cellugyrin phosphorylation on insulin-regulated GLUT4 trafficking. Hide...


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: Understanding how BMP9 protects from diabetes-induced blood retinal barrier breakdown
Funder: Diabetes UK

Abstract: Breakdown of the blood retinal barrier (BRB) drives progression of diabetic retinopathy. BRB disruption leads to fluid extravasation into the retina, which is known as diabetic macular oedema (DMO). DMO is the most common microvascular complication of diabetes and a leading cause of visual impairment. Despite clinical improvements with treatments such as anti-VEGFs and laser photocoagulation; there are still 30-40% patients who do not respond to therapy. Therefore, the critical need for new therapeutic alternatives. We propose targeting BMP9 as a new approach to stabilise the retinal vasculature and treat DMO. BMP9 is a ligand of the TGFβ family with emerging roles in vascular function. Our preliminary data demonstrate that BMP9 stabilises the vasculature by enhancing barrier properties and inhibiting sprouting capacity. In agreement with this, a recent study reported that BMP9 prevented vascular leakage in STZ-diabetic mice. Consequently, the importance to evaluate if these results in mice translate to humans. This project will characterise the signalling pathways used by BMP9 to protect the BRB. Importantly, we will use human cells and clinically relevant in vitro diabetes models. Furthermore, we will test a BMP9-gene therapy, delivered locally to db/db mouse retinas, to protect the retinal vasculature from BRB breakdown.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Investigating Safety Signals and Real-World Effectiveness in Sodium-Glucose Co-Transporter-2 Inhibitors – A Big Data Study
Funder: Diabetes UK

Abstract: Sodium-Glucose Co-Transporter-2 Inhibitors (SGLT-2i) are now recommended as treatment for type 2 diabetes (T2DM). However, trial data have raised important questions about their safety. Furthermore, since people with T2DM participating in randomised control trials (RCTs) are not necessarily representative of the people with T2DM encountered in day-to-day practice it is important that the real-world effectiveness of SGLT-2i be correctly quantified. In this Fellowship, I will use large-scale electronic healthcare record data from all people with T2DM in Scotland to test the following hypotheses: 1) SGLT-2i are associated with an increased risk of a) amputations b) diabetic ketoacidosis (DKA) c) hospitalised hip fracture risk, and; 2) SGLT-2i have the same efficacy detected in RCTs when their use is analysed in a wider, more heterogenous population of people with T2DM. I will combine results from the Scottish datasets with other datasets (e.g. Clinical Practice Research Datalink) for meta-analysis. I will build on my clinical pharmacology training, and prior training in programming, augmenting this with training in pharmacoepidemiology. I will become expert in study design and statistical analytic methods, including meta-analysis. These skills, harnessing e-health-record data to inform on drug safety and effectiveness, have been identified as an important training goal for doctors.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE
Title: Sleep disturbance: new insights into the clinical impact in diabetes
Funder: Diabetes UK

Abstract: Clinical need: Current management strategies for type 2 diabetes (T2D) are insufficient and therefore novel approaches are needed. Sleep disturbance (abnormal duration/quality of sleep, or day-to-day variation in sleep timing (so-called ‘social jet-lag’)) is common in modern society and has been linked to hyperglycaemia; e.g. in laboratory-based studies involving healthy volunteers, sleep restriction appears to cause hyperglycaemia. However, it is unclear whether managing sleep disturbance could have a major role in diabetes care. Solution: We will establish whether sleep disturbance: a) improves prediction of new-onset T2D beyond that achieved using standard risk factors; b) causes hyperglycaemia; and c) is related to glucose control and diabetes complication risks in people with diabetes. Methods: We will apply statistical techniques including Mendelian Randomisation to newly-available data in 502,643 UK Biobank participants including sleep traits (questionnaire and activity monitoring), genetic and HbA1c data, prevalent (baseline) and incident diabetes (questionnaires and primary and secondary care record linkage). Expected benefits: We will achieve major advances by establishing whether managing sleep disturbance could be useful in diabetes care. For example, showing that sleep disturbance causes hyperglycaemia will inform the design of clinical trials of sleep-targeted interventions to prevent or treat T2D.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Development of tools to investigate the role of DNA structures in diabetes
Funder: Diabetes UK

Abstract: The insulin-minisatellite or insulin-linked polymorphic region (ILPR) resides in the promoter region of the gene coding for insulin (INS). The region consists of a 14 base-pair tandem repeat DNA sequence of 5'-ACAGGGGTGTGGGG-3'/3'-TGTCCCCACACCCC-5' and located 363 bp upstream of the transcription start site. Mutations or differences in the length of the ILPR has been linked to the development of both Type-1 and Type-2 diabetes. The ILPR can form alternative DNA secondary structures such as G-quadruplexes and i-motifs. We predict that it is possible to modulate insulin transcription specifically by targeting the i-motif forming sequences in the ILPR. Through work funded by Diabetes UK we have identified several compounds which can specifically stabilise i-motif DNA structures in the ILPR, in biophysical assays. Through support from a Wellcome Trust Pathfinder award we know which of these compounds can alter gene expression. This project aims to develop the compounds as new chemical biological probes and learn more about how DNA structure affects the ILPR. This would lead to several tools and proteins as well as both genetic and epigenetic information about this important region of DNA and its role in the development of diabetes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Fine-tuning islet NAD levels to prevent beta-cell de-differentiation in type 2 diabetes
Funder: Diabetes UK

Abstract: Recent studies have demonstrated that pancreatic beta-cell de-differentiation mediates loss of functional beta-cell mass in type 2 diabetes, whereby beta-cells de-differentiate into progenitor cells. The resulting in loss of beta-cell mass leads to reduced insulin secretion and onset of hyperglycaemia. Importantly, this process is reversible, meaning that strategies to reverse de-differentiation and maintain beta-cell identity could represent new therapeutic tools for treatment and prevention of T2D. Our supporting data suggests that maintenance of sufficient levels of beta-cell nicotinamide adenine dinucleotide (NAD) is essential for preventing de-differentiation. Since tissue NAD levels are reduced in T2D, this implies that declining NAD levels may be a causal for onset of beta-cell de-differentiation. Conversely, strategies to boost islet NAD supply represent novel treatment approaches to increase beta-cell mass by preventing or reversing de-differentiation. This study will combine immunofluorescence, lineage-tracing and islet functional studies to: Characterise the effects of manipulating islet NAD levels on beta-cell de-differentiation status and beta-cell mass in vivo and ex vivo Determine whether boosting islet NAD levels can prevent beta-cell de-differentiation and increase beta-cell mass in pre-clinical models of T2D. These experiments will generate proof-of-concept data showing whether therapeutically increasing islet NAD levels could represent an attractive, novel T2D treatment strategy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: Evaluating a decellularised pancreas matrix for islet bioengineering and diabetes therapy
Funder: Diabetes UK

Abstract: Diabetes is a major world health problem that results from the loss or malfunction of insulin producing islet β cells. Regenerative cell-based approaches will allow us to replenish the islet tissue and cure diabetes. The extracellular matrix plays a vital role in regulating cellular differentiation. Tissue specific characteristics such as the composition of matrix proteins and matrix stiffness are important factors in creating the correct environment that directs stem cell differentiation. The goal of this project is to use the natural matrix of decellularised pancreas as a scaffold to create bioengineered islets. The proposed research will evaluate the effectiveness of a decellularised pancreas matrix in supporting β cell differentiation from induced pluripotent stem cells (iPSC) compared to existing culture methods. We will evaluate the role of the matrix at different stages of differentiation, and the ability of co-seeding mesenchymal stromal cells into the matrix to support iPSC differentiation. Rigorous evaluation of β cell function will be performed, including expression of β cell markers and islet hormones, functional evaluation of calcium flux and glucose-induced insulin secretion under standard and perifusion conditions, and the ability of differentiated β cells to cure diabetes by transplantation into diabetic mice.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: METABOLIC AND ENDOCRINE
Title: Role of the GSK3-NRF2 axis in beta cell decline in type 2 diabetes
Funder: Diabetes UK

Abstract: Type 2 diabetes occurs when insulin production from pancreatic beta cells is insufficient to prevent the hyperglycemia that defines diabetes. Insulin production declines during progression of the disease, resulting in worsening glucose control and poorer responses to available therapeutic strategies. Recent work in models of type 2 diabetes has implicated the protein kinase GSK3 and the cytoprotective transcription factor Nrf2, in the development of beta cell defects and type 2 diabetes. Our group has discovered that GSK3 modifies Nrf2, promoting its degradation. We propose that this ‘GSK3-Nrf2 interaction’ is a key regulator of beta cell biology, and its disruption contributes to development of diabetes. The proposed project will generate mechanistic supporting evidence for this hypothesis, with the aim to identify novel opportunities to prevent beta cell damage in type 2 diabetes. Specifically, we will establish whether the GSK3 regulation of Nrf2 in vitroinfluences beta cell function, growth and survival. Moreover, we will assess beta cell function, growth and survival, and progression toward type 2 diabetes, following beta cell-specific genetic manipulation of Nrf2 in vivo. These data will clarify the therapeutic potential for modification of this pathway in the treatment of diabetes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: A facility for high resolution synchronised quantification of in vivo metabolism and behaviour
Funder: Wellcome Trust

Abstract: Studying neurobehavioural and metabolic disease requires precise measurement of movement/behaviour, energy balance, and systemic metabolism in living animals. Current platforms are imprecise, and mice are often studied under conditions compromising fidelity of disease modelling (e.g. “normal” room temperature imposes a thermal challenge, confounding modelling of human energy balance). We now seek a 16 cage indirect calorimetry system with environmental cabinet and 8-cage stable isotope module for precise, integrated quantification of murine metabolism, energy balance and behaviour. This offers: • 5x faster cage flow rate than competitors, sampling every 2.5 minutes for respirometry at 0.001%/0.0001% (O2/CO2) resolution, allowing analysis in hypometabolic states (caloric restriction/thermoneutrality/small or aged animals). Ambient in-cage CO2 minimises hypercapnic compromise of behavioural testing, and home cage environment minimises acclimatisation/downtime. • Direct water balance measurement. • Laser-based, multiplexed detection of 13CO2/C18O2/CO2/H2O, permitting synchronised, rapid measurement of oxidation of >10,000 substrates. • Behaviour capture at 1Hz, resolving disease-relevant abnormalities invisible to legacy systems. Outputs include behaviour time budget and position probability mapping. 1Hz integrated mass measurement detects feeding and drinking to 0.002 grams, quantifying “microfeeding” (c.30% food intake). • Computer architecture configured in a standalone network supporting synchronised metabolic/behavioural analysis even in large, long term experiments, increasing statistical power and permitting multiple hypothesis testing.

Lay abstract: Diseases affecting movement and behaviour (e.g. developmental or acquired brain disorders) or metabolism (e.g. obesity, diabetes, fatty liver) can only fully be studied in living people or animals where these abnormalities can be measured. Studying mice is immensely valuable in investigating such common diseases, for example allowing us to work out the role of inherited factors, and to test new treatments before they are risked in people. The state-of-the-art equipment we request allows eating, movement and metabolism to be recorded minute by minute, with the highest possible precision, for several days. When necessary this can be done under temperature conditions that make mice resemble humans most closely. This is combined with precision engineering which minimises disturbance to the mice studied and allows rapid turnaround. Together these technical advances will ensure the maximum information is gained about major human metabolic and behavioural disorders while minimising the number of mice used.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Infrastructure Funding - ADDRESS-2 - After Diabetes Diagnosis REsearch Support System-2
Funder: Diabetes UK

Abstract: ADDRESS-2 is a research cohort which is recruiting and studying people with incident type 1 diabetes and their siblings from 160 participating NHS hospitals, across England, Wales and Scotland. The patients are characterised clinically, biochemically and immunologically. The cohort currently includes 6,547 patients (children ≥5 years, and adults) recruited within 6 months of diagnosis. More than half the patients donate a blood sample for autoantibody, DNA and other analyses. Adults constitute 46% of the total making ADDRESS-2 the largest incident case cohort of adult patients in the world. It also includes 1,275 unaffected siblings. The primary aim of the cohort is to facilitate recruitment of people with incident type 1 diabetes into intervention trials shortly after diagnosis of their diabetes, in an attempt to prevent or limit beta cell loss. Prevention trials in people at high risk will also be supported. The protocol is being modified to include younger children (≥12 months) and in ways which will enable more patients to be recruited very rapidly after diagnosis. The cohort also supports a large number of other studies investigating different aspects of type 1 diabetes and patients give permission for their health status to be followed via NHS health records.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: METABOLIC AND ENDOCRINE
Title: Reversal of Type 2 diabetes Upon Normalisation of Energy intake in non-obese people (ReTUNE)
Funder: Diabetes UK

Abstract: Type 2 diabetes in non-obese individuals is frequently regarded as having a different aetiology from that affecting obese people. However, experimental evidence does not support this, and the concept of a personal level of tolerance of total body fat allows potential understanding of BMI-independent occurrence of the disease. It is proposed to test the published Personal Fat Threshold hypothesis and to identify plasma markers which may be of assistance in the management of individuals. People classified by BMI as normal or marginally overweight (BMI<27kg/m2) will be asked to undergo stepwise weight loss with quantification of insulin secretion, liver and pancreatic fat and markers of adipose tissue over-expansion. The primary aim is to determine whether Type 2 diabetes in non-obese individuals can be reversed by weight loss, with potentially profound consequences for clinical management of this group. The secondary aims are to identify markers of adipose tissue overexpansion as potential biomarkers of the Personal Fat Threshold, to examine the relationship between the threshold and pancreatic fat content, to define changes in fatty acid compositions of lipoproteins and to evaluate and refine a Diet Decision Aid to facilitate long term individual normalisation of energy intake.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: KATP channel-dependent and –independent regulation of the glucagon-secreting pancreatic α-cell
Funder: Diabetes UK

Abstract: Insufficient insulin secretion/action and dysregulation of glucagon secretion underlie hyperglycaemia which is the hallmark of untreated diabetes. The cellular regulation of glucagon-producing alpha-cells remains poorly understood. We have established that glucose regulates glucagon secretion by an ‘intrinsic mechanism’ that is mediated by membrane depolarisation caused by closure of KATP channels. This finding (recently reported in Cell Metabolism) provides the conceptual framework for the proposed study, which aims to develop a complete mechanistic understanding of the regulation of glucagon secretion. The planned experiments will: 1) investigate the cellular regulation of glucagon secretion by nutrients, hormones/neurotransmitters and pharmacological agents; 2) define the cross-talk between intrinsic and paracrine regulation in health and disease; 3) establish how glucagon secretion becomes disrupted in diabetes and 4) devise novel pharmacotherapies that target alpha-cells. The experiments proposed are based on a wealth of preliminary data. The research questions will be examined by a battery of advanced electrophysiological, optical, biochemical and molecular biological techniques using rodent and human islets. The research outlined here will provide important information on the physiological regulation of glucagon secretion and how it becomes disrupted in diabetes. Ultimately, it may result in new therapeutic paradigms that specifically target glucagon secretion.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: Insulin vesicle dynamics in Type 2 Diabetes
Funder: Diabetes UK

Abstract: Insulin is processed from proinsulin and packaged in secretory vesicles in pancreatic beta (β-) cells. Dysfunctional β-cells are central to Type 2 Diabetes (T2D) progression. This results in inappropriate dynamics of insulin secretion and increased proinsulin release. The aim of my fellowship is to characterise the regulation of secretory vesicle dynamics and exocytosis that are compromised and contribute to T2D pathogenesis. Exocytosis is the cellular mechanism that delivers insulin from vesicles to the circulation. Vesicular traffic and exocytosis are regulated by precisely orchestrated sequences culminating in the opening of a fusion pore that allows the release of insulin. Aberrant kinetics of exocytosis and release from immature vesicles (high proinsulin content) are associated with some T2D-risk genes. My project proposes to characterise the vesicle dynamics in human β-cells from islets (donors with/ without T2D) and from human β-cell lines (EndoC-βH1) by measuring the secreted proinsulin/insulin ratio (perifusion assays), exocytosis (electrophysiology, light and electron microscopy) and fusion pore dynamics (electrophysiology) in response to: normal and hyperglycaemic environment, and drugs modulation of T2D-risk associated genes expressions T2D-related intravesicular biochemical perturbation Identification of these regulatory elements has potential for understanding T2D pathogenicity, defining mechanisms for existing drugs and offers opportunities for novel therapeutic developments.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: Extreme Early onset Type 1 Diabetes
Funder: Diabetes UK

Abstract: This study is of extremely early Type 1 diabetes (EET1D), a novel subtype of polygenic T1D recently described by the applicant, that occurs in the first 12 months of life. Aim Study 1. To confirm if EET1D is an autoimmune disease leading to beta cell loss. To identify if there are islet-specific autoantibodies and CD8 T cells resulting in a rapid decline in beta-cell function in EET1D. Study 2. To investigate the mechanisms and pathogenic processes (genetic, intrauterine, immunological) that lead to the early presentation in EET1D Methods The study utilises the >100 patients with EET1D identified in Exeter in both cross sectional and longitudinal studies. These will be compared with duration matched childhood T1D (diagnosed 1-10 years) and age matched monogenic neonatal diabetes. Study 1 will assess islet autoantibodies, islet T-cell autoimmunity, and C-peptide. Study 2 will assess mechanisms of early onset using HLA sequencing, intra-uterine environment (eg non-inherited maternal alleles and possible maternal or fetal enteroviral infection) and changes in autoimmunity over the first 2 years of the disease. Study of this group will yield unique insights into the mechanisms of EET1D but also give a wider understanding of development of the fetal/neonatal immune system.


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