NIHRDataInsights/HRCSData huggingface dataset:
Title: Dysregulation of glucagon secretion in diabetes: impact of genetics and metabolism
Funder: Diabetes UK

Abstract: Diabetes is a bihormonal disorder resulting from inadequate insulin secretion combined with defective glucagon secretion (too much and too little under hyperglycaemic and hypoglycaemic conditions, respectively). Accumulating evidence implicates ATP-regulated K+-channels (KATP-channels) in the metabolic regulation of glucagon secretion. Whereas an increase in glucose from 1 to 6 mM inhibits glucagon secretion in human islets from non-diabetic donors (ND), it stimulates glucagon release in patients with type-2 diabetes. This defect can be reproduced by exposing islets from non-diabetic islets to the KATP-channel activator diazoxide at concentrations not affecting insulin secretion. Glucagon secretion in such “T2DM islets” at low glucose was also much lower than in control islets. Thus, both abnormalities of glucagon secretion in diabetes can be induced by pharmacological activation of the KATP-channels. We propose to study the pathophysiological significance of this finding and its causes by a combination of biochemical measurements of glucagon secretion, electrophysiology, Ca2+-imaging and genetics. We will correlate glucagon secretion from human islets to genotype and phenotype of the donors focusing on ‘diabetogenic’ parameters (risk alleles, BMI, age), attempt to mimic these experimentally (in ND human and rodent islets) and explore if they can be corrected by the clinically used sulphonylureas (that block the KATP-channels).


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Why does glucophage (metformin) help some people with diabetes?
Funder: Diabetes UK

Abstract: Much current research is focused on insulin resistance and how it might be reversed where current treatments are ineffective. The best treatment for insulin-resistant T2D is metformin but the target of this drug is still unclear, hampering development of improved agents to replace metformin, which is not effective in all T2DM and loses potency with prolonged use. Previously, we have investigated how metal ions modify the activity of drugs. Copper interaction with biguanides such as metformin has been known for over a century and in our preliminary studies we have gathered strong evidence that copper is required for specific cellular actions of metformin linked to its beneficial clinical effects. In the current study we will elucidate the precise role of copper in metformin action using unique chemical tools and a variety of techniques including western blotting, gene expression analysis, microscopy and animal studies. This research will establish which effects of metformin are copper-dependent, and of these which are sensitive to specific modes of interaction with the metal. This fundamental understanding will provide the platform to enable future testing of compounds that interact with copper for beneficial effects on glucose metabolism and development of the complications of T2DM.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE
Title: Biobank Biomarkers Enhancement funding – Measurement of HbA1c
Funder: Diabetes UK

Abstract: UK Biobank is a major national health resource that, from 2006-2010, recruited 500,000 people aged 40-69 from across the country who provided measurements, blood, urine and saliva samples and detailed information about themselves and who agreed to have their health followed by researchers. Over many years this will build into a powerful resource that will help scientists to discover why some people develop particular diseases and others do not. Ultimately it could improve the prevention, diagnosis and treatment of a wide range of serious and life-threatening illnesses – including diabetes, cancer, heart disease, stroke, arthritis, osteoporosis, eye disorders, depression and forms of dementia. In collaboration with organisations such as the Medical Research Council and the British Heart Foundation, Diabetes UK has awarded £365,000 to UK Biobank so that key ‘biomarkers’ can be measured in the biological samples obtained from all 500,000 participants. The chosen biomarkers, which include HbA1c (a measure of average blood glucose levels), have been selected to provide an accurate indication of participants’ risks of developing health conditions such as Type 2 diabetes. Gathering information related to these biomarkers is a cost-effective way of increasing the value of the UK Biobank for researchers studying many different health conditions, including Type 2 diabetes and related complications (such as problems with the blood vessels and the kidneys).


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: METABOLIC AND ENDOCRINE
Title: Glycation and calcification in diabetes: a new target for prevention?
Funder: Diabetes UK

Abstract: Patients with diabetes, exhibit more vascular calcification (VC) than age- and gender-matched non-diabetic patients with peripheral arterial disease (PAD). VC is a strong independent predictor of cardiovascular disease (CVD) mortality and recent studies suggest that glycation plays a pathogenic role in this process, although, little is known of the molecular mechanisms involved. We aim to 1) modify LDL in vitro using i) a more reactive glucose metabolite and ii) glucose in the presence of free radicals; 2) investigate how LDL isolated from type 2 diabetic patients and in vitro-modified LDL affect the progression of VC in vitro and 3) whether effects can be prevented using an S100P-Derived RAGE Antagonistic Peptide (RAP). We will treat human VSMCs in vitro with a range of doses of glyc-LDL and glycox-LDL in the presence and absence of a RAGE inhibitor, such as RAP and analyse the effects on calcification. Osteogenic signalling pathways will be interrogated using biochemical assays, western blotting and RT-PCR. A better understanding of the pathophysiology of VC may help develop new interventions for prevention or treatment of VC by modulating the glycation pathway, thus improving not only metabolic control in the context of diabetes but mitigate the added complications of calcification.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;3.3 NUTRITION AND CHEMOPREVENTION
Health categories: METABOLIC AND ENDOCRINE
Title: Elucidating the importance of CDA1 in the Glomerular Podocyte in Diabetic Nephropathy
Funder: Diabetes UK

Abstract: Podocyte cell injury plays a pivotal role in the pathogenesis of proteinuric kidney diseases, including diabetic nephropathy. The characteristic podocyte response to injury or stress is actin cytoskeleton reorganisation, leading to foot process effacement, proteinuria and irreversible podocyte depletion due to their inability to proliferate and regenerate. The Cell division autoantigen 1 (CDA1) pathway is shown to modulate TGF- signalling. Podocytes contain both CDA1 and its receptor CDA1BP1, with TGF-β identified as a key mediator of podocyte injury. An in vitro podocyte injury model will be employed, utilising both immortalised human podocytes cultured at physiological (5mM) or high glucose concentrations (20mM), alongside primary podocytes isolated from wild-type (WT) and CDA1 knockout (KO) mice, with or without diabetes. TGF-β will be employed as the injurious stimuli and has been reported to produce podocyte apoptosis, de-differentiation and an EMT-like response resulting in increased collagen deposition. These responses to TGF-β will be used as end-points in the presence and absence of CDA1 knockdown to determine if CDA1 is involved in causing podocyte injury in response to TGF-β. In addition the pro-fibrotic effect of CDA1 will be targeted pharmacologically by disrupting the interaction of CDA1 and CDA1BP1.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Immunogenetic regulation of progression to type 1 diabetes
Funder: Diabetes UK

Abstract: One therapeutic strategy to prevent type 1 diabetes is to delay progression from islet autoantibody positivity to clinical onset. This appears to have occurred naturally in a cohort of first degree relatives who have been multiple islet autoantibody positive for more than 10 years but remain diabetes free (slow progressors). We postulate that these individuals are protected by increased CD4+ regulatory T cell function compared to those who progress rapidly. This travelling fellowship will involve a novel approach – I will spend the first two years at the Benaroya Research Institute in Seattle learning state-of–the-art assays to measure regulatory T cell function, RNA signatures and activation of downstream signalling pathways. Initially, building on recent preliminary data from the Benaroya, I will focus on proliferative differences in CD4+ T cells between antibody positive and negative first degree relatives that appear to be genetically determined. I will then return to Bristol to utilise the strategies learned in Seattle to investigate transcriptomic and functional differences in the CD4+ T cell compartment in slow progressors compared with those who progress rapidly. These novel studies have the potential to identify previously unrecognised mediators that may be modulated to prevent or delay type 1 diabetes for decades.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: The influence of diabetes on the rehabilitation outcome of patients following lower limb amputation.
Funder: Diabetes UK

Abstract: The aim is to investigate the factors which affect rehabilitation outcome following lower extremity amputation (LEA) in people with diabetes and to use this information to propose a disease specific rehabilitation model to improve outcomes for this patient group. The study will be undertaken in three work programmes (WP). In WP1 all patients in the Glasgow area who undergo a LEA in one year will be followed up prospectively for 18 months. Preoperative data on the factors associated with the LEA e.g. age, level of amputation, co-morbidity, previous limb salvaging surgery will be recorded and then at 3 monthly intervals information relating to outcome will be recorded e.g. complications, Limb fitted, functional impairment. Those with diabetes and those without diabetes will be compared and statistical analysis performed to investigate the causal relationships between predefined LEA factors and functional outcome. WP2 will involve interviewing people with diabetes who have had a LEA. The interviews will consider the patient’s views on the barriers to limb fitting and obstacles faced during rehabilitation. WP3 will be a survey of physiotherapists who specialise in amputee rehabilitation to ascertain their views on what influences the decision making processes in terms of limb fitting and rehabilitation.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: METABOLIC AND ENDOCRINE
Title: Regulation of the renin-angiotensin-aldosterone system in adipose tissue by AMP-activated protein kinase
Funder: Diabetes UK

Abstract: Type 2 diabetes and obesity are metabolic disorders with high prevalence that burden health services significantly. Improved understanding of the pathophysiology is required to ensure targeted therapeutic interventions. Angiotensin II and aldosterone have been implicated in the adipose tissue inflammation that underlies insulin resistance associated with type 2 diabetes. AMP-activated protein kinase (AMPK) is a key regulator of glucose and lipid metabolism that has independent anti-inflammatory actions and has therefore been proposed to be a therapeutic target to treat obesity and type 2 diabetes. We hypothesise that AMPK will attenuate the detrimental inflammatory and metabolic effects of angiotensin II and aldosterone in adipose tissue. We will determine the effect of AMPK on angiotensin II and aldosterone-mediated pro-inflammatory signalling in adipocytes and macrophages, evaluate whether angiotensin II- and aldosterone-mediated insulin resistance in adipocytes is regulated by AMPK and assess the role of AMPK on adipose-derived angiotensin II and aldosterone synthesis. Our experimental work will include studies using cultured adipocytes and macrophages accompanied by experiments using an AMPKalpha1 knock out mouse model. This research will improve understanding of adipose biology in the context of obesity-related type 2 diabetes and guide future research regarding AMPK as a potential therapeutic target.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Understanding cerebral responses to hypoglycaemia: a pathway to effective strategies to treat hypoglycaemia unawareness in type 1 diabetes
Funder: Diabetes UK

Abstract: During hypoglycaemia, hypoglycaemia unaware patients (HU) show altered activation in brain regions involved with stress, anxiety, aversion, reward and food-seeking, compared to the hypoglycaemia aware (HA). This matches observations of low concern for hypoglycaemia in HU and reduced compliance with therapeutic recommendations to avoid hypoglycaemia. We will determine if characteristic brain responses to hypoglycaemia in HU are reversible on hypoglycaemia avoidance. We will study regional brain activation to controlled hypoglycaemia [2.6mmol/l] in 10 HA and 30 HU patients using arterial spin labelling functional magnetic resonance imaging [ASLfMRI]. HU patients will be re-studied after 6 months’ rigorous hypoglycaemia avoidance using education and continuous glucose monitoring, demonstrated to restore awareness in at least 50% of people with HU. We will: 1. Compare regional brain responses to hypoglycaemia between HU and HA 2. Compare baseline and 6-month scans in those with restored awareness to evaluate areas associated with reversibility 3. Compare baseline scans between those who do and do not restore awareness for structural and functional predictors of ability to restore awareness. These studies will help us better understand underlying mechanisms of HU and target interventions for HU more effectively. Longer-term, this may help develop potential psychological and pharmacological interventions for resistant HU.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Increasing skeletal muscle carnitine content to improve glycaemic control in individuals recently diagnosed with Type 2 diabetes
Funder: Diabetes UK

Abstract: Skeletal muscle insulin resistance causes hyperglycaemia and is a major risk factor for the development of Type 2 diabetes (T2D). The accumulation of lipid within muscle cells (IMCL), and the associated lipid metabolites, is a major cause of insulin resistance and is due to an imbalance between muscle fatty acid uptake and oxidation. Dietary controlled weight loss can reduce IMCL accumulation in insulin resistant individuals and improve glycaemia, but it is difficult to achieve in the general population. Furthermore, weight loss via caloric restriction does not always restore the ability to increase fat oxidation and thus reduce IMCL. Therefore, nutritional strategies to increase muscle fat oxidation and reduce IMCL in individuals with T2D are warranted. Carnitine translocates fatty acids into mitochondria for oxidation. We have demonstrated that increasing muscle total carnitine (TC) content by >15% in young men improved muscle glucose disposal at rest, and increased fat oxidation during low intensity exercise. Reduced muscle TC and insulin resistance are reversed with L-carnitine feeding in obese rats. We aim to determine for the first time whether increasing muscle TC during 6 months of L-carnitine supplementation can ameliorate IMCL and insulin resistance, and improve glycaemia in individuals with T2D compared to control.


Research activity codes: 6.7 PHYSICAL
Health categories: METABOLIC AND ENDOCRINE
Title: The role of PAS domain containing protein kinase in pancreatic alpha cell function
Funder: Diabetes UK

Abstract: PAS-domain containing protein kinase (PASK), which possesses a “druggable” PAS domain, represents a potential therapeutic target for the treatment of both dysregulated α- and β-cell function in diabetes. We have shown that islets of Langerhans from individuals with Type 2 diabetes exhibit decreased PASK expression. Moreover, PASK null mice (PASK-/-) have higher blood glucose levels, and decreased pancreatic insulin content, than control littermates. Finally, whereas PASK-/- islets secrete glucagon in response to normally inhibitory glucose concentrations, over-expression of PASK suppresses glucagon release at low glucose. Thus, activation of PASK in α-cells may exert beneficial effects on glucagon levels, which complement those resulting from increased insulin expression in β-cells. In this project, we will determine the role of PASK signalling in pancreatic α-cells. We have two overall aims: 1. To test the hypothesis that forced changes in PASK expression selectively in the α-cell affect glucagon secretion in vivo. 2. To explore the molecular mechanisms acting downstream of PASK to control glucagon release.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Developmental origins of brown and white adipose tissue: implications for type 2 diabetes.
Funder: Diabetes UK

Abstract: The overall aim of this project is to 1) understand the cell determination pathways involved in the generation of human white adipocytes (WA), Myf5+ lineage brown adipocytes (BA) and Myf5- Brown in White Adipose Tissue (BRITE) cells from hESCs, and 2) establish the impact of these different cell populations on glycaemic control, in vivo. Recent studies have successfully derived functional BA from human embryonic stem cells (hESCs) and induced pluripotent stem cells (hIPSCs) but these cells posses the paraxial mesoderm / Myf5+ lineage BA characteristics thought to be only present in human infants, and not the adult human BRITE cells which are responsible for improvements in glycaemic control. We have induced hESCs to differentiate to cells expressing either paraxial (Myf5+) or lateral plate (Myf5-) mesoderm markers. Our hypothesis is that the BRITE cells can be generated from cells expressing lateral plate mesoderm markers via a Myf5- population, and that these differ functionally from the BAs recently generated using a hematopoietic cocktail (HC). We further plan to determine whether WA can be generated from both Myf5+ and Myf5- cells and can be transdifferentiated to BRITE cells. We then aim to determine the in vitro and in vivo functionality and impact on glycaemic control of the different adipose subtypes derived from hECSs.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: Brain Glucokinase and Blood Glucose: A Novel Therapeutic Target for Type 2 diabetes?
Funder: Diabetes UK

Abstract: We will use contemporary molecular techniques to probe how brain glucokinase controls peripheral glucose homeostasis. We will first examine insulin secretion and insulin action in neuronal glucokinase knockout mice anticipating that insulin secretion and/or action may be impaired. This conditional murine knockout line is already established and preliminary data show impaired glucose tolerance. We will also examine how these mice respond to hypoglycaemia. We will then use mice expressing cre-recombinase controlled by the glucokinase promoter to characterise how glucokinase containing cells respond to glucose. Combining these mice with Designer Receptors Exclusively Activated by Designer Drugs (DREADD) techniques, we will examine acute pharmacogenetic activation of glucokinase-containing neurones on glucose homeostasis. Finally we will use both these murine lines in high fat diet fed mice to examine whether acute pharmacogenetic activation of glucokinase-containing cells and/or brain delivery of glucokinase activators improves insulin secretion and/or action in a model of type 2 diabetes. In summary, these studies will use modern molecular genetics to examine whether activating brain glucokinase or indeed glucokinase containing cells offers a potential future treatment option for type 2 diabetes.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE
Title: Optimising islet engraftment for long term function in Type 1 diabetes.
Funder: Diabetes UK

Abstract: Islet transplantation restores awareness of hypoglycaemia but 2 donor pancreases are required and insulin independence is low. Sixty per cent of islets fail to engraft into the liver in the first 3 days following transplantation. Secondly, islet function diminishes over time, but the cause of this is not understood. Hepatocytes stream from zone 1 and 2 (highly oxygenated periportal zone) to zone 3 (central vein) where they undergo apoptosis. Partial hepatectomy induces liver regeneration increasing islet engraftment but is clinically inappropriate. We have shown tri-iodothyronine (T3) and hepatocyte growth factor (HGF) increase liver proliferation in a zone specific manner. Our aim is to develop clinically applicable techniques to optimise human islet engraftment. We will determine if: (i) The use of growth factors/mitogens improve islet engraftment (ii) The zone of engraftment is biased using growth factors/mitogens (iii) The zone of engraftment affects in vivo graft function (iv) The islets migrate from zone 1 to 3 over time with the “streaming liver” (v) The zone of engraftment affects the longevity of the graft Thus following growth factors, islet engraftment in relation to zones of the liver will be assessed serially using immunohistochemical techniques in combination with in vivo metabolic tests of islet function.


Research activity codes: 5.4 SURGERY
Health categories: METABOLIC AND ENDOCRINE
Title: Pre-clinical evaluation of destructive exon skipping of Myostatin mRNA as a potential therapy for type II diabetes and sarcopaenic obesity
Funder: Diabetes UK

Abstract: Skeletal muscle is normally responsible for approximately 80% of post-prandial glucose disposal and a defect in this process is a major component of the insulin resistance that underpins type 2 diabetes. One potential therapeutic strategy to overcome this defect is to increase the capacity of muscle for glucose disposal by encouraging accretion of muscle mass. Myostatin (MSTN) is a potent negative regulator of muscle mass and inactivating gene mutations or its pharmacological inhibition results in a phenotype of hypermuscularity, accompanied by reduced adiposity and increased glucose disposal and insulin sensitivity. We aim to explore the therapeutic potential of inactivating MSTN using a novel approach of destructive exon skipping with clinically relevant antisense oligonucleotide (AO) reagents. We will optimise a phosphorodiamidate morpholino (PMO) AO targeting exon 2 of the MSTN gene for exon skipping. An in vitro screen will identify candidate PMOs that will then be tested in vivo, to establish whether the glucose intolerance and insulin resistance of mice fed a high fat diet is ameliorated. The expected outcome is to develop a PMO reagent that will be put forward for evaluation in further animal studies and subsequently human clinical trials.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE