NIHRDataInsights/HRCSData huggingface dataset:
Title: Identifying genetic factors at the 6q24 TND1 locus that impact on short and longer-term glycaemic control
Funder: Diabetes UK

Abstract: Transient neonatal diabetes (TND1) is a rare, inherited form of diabetes, caused not by changes in DNA sequence but DNA regulation of the candidate TND1 gene PLAGL1. The Wessex Imprinting Group is an acknowledged international research leader in TND1, with the largest cohort of TND1 patients in the world. Our studies show that when the normal tight regulation of PLAGL1 function fails, euglycaemia is lost. We hypothesise that by identifying genetic factors in TND1 we will better understand not only TND but more common glycaemic disorders. Therefore we have two main aims: (i). Clinical Aim: to support diagnosis and management of TND1 globally, aiming to expand our current disease registry for formal characterisation of TND1, and full genotype-phenotype correlation including growth and developmental parameters, features of diabetes relapse, and best management practice. We will link these factors to the genetics of the disease. (ii) Molecular Aim: to investigate TND1 patients, seeking genetic mutations that predispose to TND1, and also to the subsequent hyperinsulinism that develops in a subset of TND1 patients. This will reveal genes and gene regulatory factors that are essential for normal control of glycaemia and link gene mutations to specific disease consequences.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Subcellular disposition of fatty acids in β-cells revealed by non-linear microscopy: insights into mechanisms of pancreatic β-cell lipotoxicity
Funder: Diabetes UK

Abstract: Type 2 diabetes is associated with raised circulating free fatty acids (FFAs) leading to pancreatic beta-cell dysfunction and loss. In vivo, the situation is likely to be complex, however, because beta-cells respond differentially to individual FFAs. Under these conditions, the net response will be determined by the relative contributions of long chain saturated molecules (which are frequently lipotoxic) and various long chain mono- and poly-unsaturated FFAs (which are less toxic and can provide cytoprotection). Importantly, the molecular basis of these differential responses to saturated and unsaturated FFAs is unknown but we hypothesize that they are handled differentially within the cells and that one can influence the uptake and intracellular disposition of the other. Surprisingly, the mechanisms controlling FFA uptake and distribution in beta-cells remain largely undefined, principally because these processes are difficult to study in real time. In the present work, we will use a multidisciplinary approach to explore these parameters in single beta cells, using the UK’s only microscope combining three non-linear imaging modalities (multiphoton fluorescence, stimulated Raman and Coherent Anti-Stokes Raman Scattering) in a single instrument. This understanding will then pave the way for improved therapeutic intervention to minimise FFA-induced cytotoxicity in type 2 diabetes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: The role of microRNAs in the developmental programming of Type 2 diabetes, and their value as biomarkers of disease risk
Funder: Diabetes UK

Abstract: There is overwhelming evidence that sub-optimal nutrition in very early life permanently alters metabolism in ways that increase susceptibility to type 2 diabetes in adulthood, but the molecular mechanisms underlying such programming are poorly understood. In studies using a rat model of maternal protein restriction, as well as a cohort of low birth weight humans, we have shown that programmed changes in expression of proteins involved in insulin action in adipose tissue occur without changes in corresponding mRNAs, implicating regulation at a post-transcriptional level. We hypothesised that microRNAs might mediate this regulation, and as proof of principle have shown that expression of miRNA-483-3p and its target GDF-3 is indeed programmed in low protein rat offspring and low birth weight humans. We propose now to elucidate the network of miRNAs and their targets that are similarly programmed in the rat model and human cohort, and to investigate the pathways by which altered expression of these miRNAs and targets influences adipose tissue metabolism and insulin sensitivity.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: METABOLIC AND ENDOCRINE
Title: GPR55, a novel modulator of insulin sensitivity and energy metabolism in skeletal muscle
Funder: Diabetes UK

Abstract: The mechanisms underlying pathophysiology of insulin resistance and diabetes mellitus are not completely understood. Recent studies, however, have provided emerging evidence that the G-protein coupled receptor GPR55 may have a role in energy homeostasis. Building on this idea, we have made several novel observations which, for the first time, implicate this receptor in modulating key metabolic pathways within skeletal muscle - a major site of glucose utilisation and storage. Firstly, we have discovered that ligand-induced activation of GPR55 significantly improves insulin sensitivity in cultured skeletal muscle cells. In addition, treatment with GPR55 agonists increases the activity and/or expression of proteins (AMPK, CREB and PGC-1alpha) involved in promoting mitochondrial biogenesis and function. Furthermore, we have uncovered potential GPR55-mediated regulation of the endocannabinoid system. Endocannabinoids are arachidonic acid-derived lipids which have been implicated in energy balance and metabolism. Interestingly, we observe altered expression of genes which function in the synthesis and/or degradation of endocannabinoids in response to known GPR55 agonists. Importantly, based on these observations, we anticipate that GPR55 activation would result in suppressed endocannabinoid tone thereby potentially improving metabolic status. Therefore, our aim is to understand, both mechanistically and functionally, how direct modulation of GPR55 impacts upon skeletal muscle metabolic capacity.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: The Importance of Autonomic Imbalance in the aetiology of Type II Diabetes mellitus
Funder: Diabetes UK

Abstract: Diabetes and its co-morbidities such as cardiovascular disease seriously impact on quality of life. Additionally, 10% of the NHS budget is spent on treatment of diabetes alone. Despite the epidemic scale of the problem, clinicians still lack reliable predictors, that help diagnose co-morbidities early,that serve as bench marks for treatment success, and that determine individual patients' prognosis. We hypothesize that changes in the autonomic nervous system, leading to imbalances between sympathetic and parasympathetic drives, promote the development of diabetes and related morbidities. The aim of this research is to develop a pre-clinical model of autonomic imbalance that allows us to systemically investigate its potential deleterious consequences in an otherwise healthy animal. We will use genetic engineering to suppress the outputs of the vagus nerve and artificially produce autonomic imbalance in rats and mice. We will be testing the effects of this treatment on major physiological pathways, such as glucose tolerance, heart rate variability and nociceptive processing. This work will establish the contribution of autonomic imbalance to metabolic disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: A MicroRNA Signature for Risk of Type II Diabetes
Funder: Diabetes UK

Abstract: Recent studies have begun to unveil a powerful and unexpected role of non-coding microRNAs (miRNAs) in numerous forms of cardiovascular disease, providing a unique opportunity to translate this knowledge into the clinical setting in the form of miRNA-based diagnostics. In a large prospective population-based study, we have recently revealed the first signature pattern of plasma miRNAs for type II DM (Zampetaki et al, 2010). The present project shall focus on the prognostic potential of miRNAs for type II DM. First, we will re-measure the miRNAs in the same participants after a 15-year follow-up (Bruneck study) and investigate their cellular origin. Second, we will apply the miRNA expression profiles to a different cohort from which they were derived from. For this purpose, we have established a new collaboration with UK epidemiologists to get access to samples from Whitehall II, a prospective workplace based cohort. DM-associated miRNAs will be measured in a nested case-control design. Understanding how circulating miRNAs could be harnessed for assessing the risk of type II DM is clearly an essential area of researchRecent studies have begun to unveil a powerful and unexpected role of non-coding microRNAs (miRNAs) in numerous forms of cardiovascular disease, providing a unique opportunity to translate this knowledge into the clinical setting in the form of miRNA-based diagnostics. In a large prospective population-based study, we have recently revealed the first signature pattern of plasma miRNAs for type II DM (Zampetaki et al, 2010). The present project shall focus on the prognostic potential of miRNAs for type II DM. First, we will re-measure the miRNAs in the same participants after a 15-year follow-up (Bruneck study) and investigate their cellular origin. Second, we will apply the miRNA expression profiles to a different cohort from which they were derived from. For this purpose, we have established a new collaboration with UK epidemiologists to get access to samples from Whitehall II, a prospective workplace based cohort. DM-associated miRNAs will be measured in a nested case-control design. Understanding how circulating miRNAs could be harnessed for assessing the risk of type II DM is clearly an essential area of research.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: METABOLIC AND ENDOCRINE
Title: Interleukin 6 and hypoglycaemia tolerance in diabetes
Funder: Diabetes UK

Abstract: Impaired awareness of hypoglycaemia (IHA) affects up to 20-25% of people with type 1 and increases risk of severe hypoglycaemia markedly. A major risk factor for IHA is repeated exposure to hypoglycaemia. There are many parallels between how the body responds to repeated hypoglycaemia and a stress response called pre-conditioning. Pre-conditioning is induced when a non-damaging stressful stimulus is presented to cells to promote a transient adaptive response so that injury resulting from subsequent exposure to the harmful stimulus is reduced. Hypoglycaemia has all the characteristic features of a preconditioning response in that the depth, duration, and frequency of antecedent hypoglycaemia correlated with the magnitude of the ensuing counterregulatory deficit, and the defect resolves with hypoglycaemia avoidance. Preliminary data suggest that the cytokine, interleukin-6 (Il-6), may be central to hypoglycaemic pre-conditioning. Pre-exposure of hypothalamic glucosensing neurons to Il-6 increased their threshold for electrical silencing, while pre-exposure of hypothalamic slice preparations to Il-6 significantly reduces their sensitivity to low glucose. The objective of the current proposal is to build on these exciting new data and to determine whether Il-6 plays an important role in the modulation of whole body responses to hypoglycaemia as well as the adaptation to repeated hypoglycaemia.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Does the calcium sensor sorcin protect against glucolipotoxicity and beta cell failure in Type 2 diabetes?
Funder: Diabetes UK

Abstract: The decline in beta cell function in type 2 diabetes is exacerbated by chronic hyperglycaemia and elevated serum free fatty acids, a condition known as glucolipotoxicity. Our recent work has revealed that sorcin, a calcium binding protein, may exert a beneficial action to protect against glucolipotoxicity. This possibility will be further examined here in vivo where sorcin will be inactivated in pancreatic beta cells by conditional knockout. The engineered mice will be subjected to a high fat diet to induce insulin resistance and stress the beta cells and glucose homeostasis will be assessed by glucose and insulin tolerance tests. The impact of sorcin inactivation and overexpression on glucose-induced gene expression, intracellular Ca2+ homeostasis, insulin secretion, cell viability and apoptosis will also be explored in details in vitro using isolated primary and clonal beta cells.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Unveiling the mechanisms by which Glucagon-Like Peptide-1 protects pancreatic beta-cells from programmed cell death.
Funder: Diabetes UK

Abstract: Type 2 diabetes (T2DM) develops once pancreatic beta-cells fail to secrete sufficient insulin to compensate for peripheral insulin resistance. Central to this process is the loss of beta-cell mass due to the toxic effects of glucose and lipid (glucolipotoxicity). Therapies preventing beta-cell loss are therefore attractive targets for treating T2DM. Glucagon-like peptide-1 (GLP-1) improves glycaemic control through multiple actions, including preventing beta-cell loss. Despite intensive development of GLP-1 analogs for the treatment of T2DM, the mechanisms involved in the pro-survival effect of GLP-1 are not well understood. The purpose of the proposed research is to investigate how GLP-1 protects against beta-cell death through evaluation of the relative contributions of apoptosis and autophagy to this pro-survival response. A role for the BH3-protein family member Bad in these processes will be investigated since Bad knock-out protects against high-fat diet induced diabetes. The study will investigate: i) the relative contribution of apoptosis and autophagy in the pro-survival effect of GLP-1 in response to glucolipotoxicity; ii) the signalling pathways involved in these mechanisms with specific focus on Bad. Identifying the signalling pathway(s) that regulate the pro-survival effect of GLP-1 will allow for the development of improved therapies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Increased levels of maternal beta cells in the neonatal pancreas – a trigger for T1D?
Funder: Diabetes UK

Abstract: Maternal cells transfer to her foetus during pregnancy and increased levels of these cells have been associated with different forms of autoimmunity. We demonstrated maternal cells in different cell subsets in the pancreas indicating that some cells that transfer from the mother have stem cell characteristics. We have also shown that levels of maternal cells are increased in type 1 diabetes pancreas and in the periphery. These cells however do not actively destroy pancreatic beta cells in type 1 diabetes. Data from several studies suggest that maternal cells play a role in establishing immune tolerance; in particular inducing development of CD4+CD25highFoxP3+Tregs in foetal lymph nodes that suppress anti-maternal immunity and have persistent effects on tolerance. In this study, we seek evidence to support the hypothesis that failure of this process results in autoimmune diabetes, and that increased frequencies of maternal cells in developing human beta cells is a trigger for autoimmune diabetes early in life. We propose to analyse MMc frequency and phenotype in the developing foetal pancreas and in pre-diabetic (>2 islet autoantibody markers) and diabetic pancreas and pancreatic lymph node. Parallel experiments will be carried out in the NOD mouse to allow the effects of future manipulation of MMc in the pancreas to be observed.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Defining the role of eIF2 phosphorylation in -cell toxicity in type II diabetes
Funder: Diabetes UK

Abstract: A growing body of evidence implicates endoplasmic reticulum (ER) stress in the pathogenesis of diabetes. Pancreatic beta-cells experience ER stress when faced with large swings in pro-insulin synthesis and in peripheral tissues ER dysfunction induces insulin resistance. Defects in ER stress signalling frequently cause diabetes, for example mutations of the kinase Perk cause the Walcott Rallinson syndrome of neonatal diabetes, because failure to respond effectively to ER stress leads to beta-cell death. Crucially, the mechanisms by which ER dysfunction causes cell death remains obscure. To address this, we have examined the signalling pathways triggered by ER stress that regulate protein translation. To date, our work funded by Diabetes UK has focused on immortalised cell lines. It is now crucial that we determine the relevance of these pathways in primary beta-cell cultures and animals. Specific aims 1. We will characterise in isolated beta-cells the consequences on ER stress-induced toxicity of Gadd34 inactivation. 2. We will determine how the phosphorylation status of eIF2alpha affects beta-cell differentiation in cultured isolated islets. 3. We will determine how inactivation of the Gadd34 gene affects beta-cell function, survival and differentiation status in models of type II diabetes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: An investigation into the mechanisms of action of incretin based anti-diabetic therapies in the human vasculature
Funder: Diabetes UK

Abstract: Evidence suggests that GLP-1 acts on blood vessels beneficially to either induce or enhance vessel dilatation (relaxation). Indeed, preliminary (unpublished) evidence from our own laboratory has shown that GLP-1 analogues increase skin blood flow. However, the underlying mechanisms are not fully understood. The available data are inconclusive and, since most have been obtained using a variety of animal based models/cells may not be relevant to human responses. Additionally, the cells/vessels used previously have predominately originated from large vessels (macrovasculature). In light of previous research demonstrating that DPP-IV activity is differentially regulated between the macro- and microcirculation (small vessels), and the fact that small vessel disease is common in diabetes, it is important to examine the action of incretins and its associated therapies at both a macro- and microvascular level. Using physiologically relevant cells from both the micro- and macrovasculature we will study the effects of incretin based therapies, GLP-1 analogues and DPP-IV inhibitors, on cellular pathways known to be critical to healthy endothelial function. These will include pathways that control vessel relaxation and contraction and also adhesion of white blood cells to the vessel wall e.g. nitric oxide. We will compliment these studies with myography experiments using mounted isolated human small blood vessels to determine the effects of the incretin-based therapies on whole vessel physiology. Patient


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE
Title: GLP-1-regulated beta cell connectivity in human and rodent islets: molecular mechanisms and role in type 2 diabetes
Funder: Diabetes UK

Abstract: Incretins are released from specialised enteroendocrine cells in response to food intake and bile acid flux. Following circulation to the endocrine pancreas, they act upon their cognate receptors within the Islets of Langerhans to improve glucose-stimulated insulin secretion (GSIS). This incretin-stimulated glucose secretion (ISIS) is essential for counteracting the large postprandial spike in glucose concentrations. Indeed, a hallmark of T2DM pathogenesis is the loss of sensitivity to incretins, resulting in impaired insulin secretion as well as cell survival. Despite this, the mechanisms underlying the islet-wide augmentation of beta cell dynamics by incretins, and how these are targeted by T2DM contributing factors such as diet and genes, remain largely unexplored. Therefore, the aims of the current proposal are to use multicellular calcium imaging in combination with real-time measurement of insulin secretion to decode the beta-cell population responses to incretin stimulation in in vivo and ex vivo models of diet and gene-induced T2DM.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: A Novel Approach for Identifying Human Pancreatic Stem Cells for Diabetes
Funder: Diabetes UK

Abstract: Diabetes is associated with pathophysiology of the islet β-cells, which fail and cannot be replaced through compensatory measures. Despite the fact that islet cell progenitors contribute to increases in islet cell mass in the post-natal period, we have little information on the identity of these cells or why they fail in people with diabetes. Recently we developed a novel panel of human pancreatic stem cell lines - PEndo cells, which can be differentiated to insulin-producing cells using a defined protocol. Here, we will use proteomic profiling of PEndo cells to document the expression profiles of cell surface protein markers associated with stage-specific differentiation of the cells. Through these studies we expect to identify specific proteins associated with distinct stages of differentiation which we will then validate in the developing human pancreas and a model of human pancreas regeneration. This work will provide a greater understanding of the roles of these cells in both the progression of diabetes and therapeutic responses to conventional drugs. Further, by defining specific markers, antibody-based cell sorting techniques could be used to isolate and purify progenitor cells from the human pancreas for drug-discovery purposes and for cell-based treatments of diabetes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Targeting islet inflammation ex vivo and following transplantation
Funder: Diabetes UK

Abstract: Since the introduction of the Edmonton protocol in 2000, islet transplantation has become established as a proven therapy for preventing severe hypoglycaemia in people with type 1 diabetes complicated by recurrent life-threatening events. While optimal overall glycaemic control can also be restored this often requires supplementary insulin injections. True insulin independence at 5 years cannot be reproducibly achieved even after multiple islet infusions. Up to 50% of islets are lost very soon after transplantation through the instant blood mediated inflammatory reaction. Although a number of factors influence this reaction, it is clear that signalling from the islets themselves is a key initiating event. The aims of the proposed research are to characterise the proinflammatory response in stressed islets ex vivo and specifically the role of contaminating ductal cells; to investigate whether this response can be attenuated by filtration to remove contaminating / stressed single cells or by co-culture with Multistem multipotent adult progenitor cells; and determine whether this enhances beta-cell function in vitro and following transplantation into the portal vein in an optimised preclinical model. Successful ex vivo targeting of proinflammatory signalling in donor islets prior to transplantation offers the potential of sustainable insulin independence following a single graft.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: METABOLIC AND ENDOCRINE