Targeting beta-cell GPR56 for maintenance of islet structure and function to improve glucose homeostasis

Prof Shanta Persaud, Prof Peter Jones, Dr Aileen King, Dr Edward Olaniru - Islet beta-cell differentiation is regulated by interactions between islet cells and extracellular matrix (ECM) proteins. We have identified that ECM and collagens improve islet function, most likely through the abundant islet collagen receptor, GPR56. We are identifying the importance of GPR56 in maintaining the functional phenotype of beta-cells using mice in which beta-cell GPR56 has been deleted. This project has the potential to identify novel approaches for improving islet transplantation outcomes by increasing islet viability and function, and to identify GPR56 as a therapeutic target for optimising functional beta-cell mass in type 2 diabetes.

Using mesenchymal stromal cells to improve the functional survival of islet grafts in type 1 diabetes

Prof Peter Jones, Dr Chloe Rackham, Dr Sara Caxaria, Miss Ella Hubber - Mesenchymal stromal cells improve the outcomes of islet transplantation in animal models of diabetes. We are investigating the mechanisms through MSCs interact with beta-cells to develop cell-free treatments of islet grafts and of graft recipients. We have recently identified a cocktail of MSC-derived molecules which has beneficial effects on islet function and we are now testing this cocktail in clinically-relevant human islets. We are using single cell RNAseq analysis to identify the effects of MSCs on islet cell gene expression, and we are exploring mitochondrial transfer as a mechanism through which MSCs improve beta cell function.

Unravelling the role of fluoxetine in the regulation of beta-cell mass and function

Prof Shanta Persaud, Dr Bo Liu, Dr James Bowe, Dr Inma Ruz Maldonado, Dr Lorna Smith, Miss Klaudia Toczyska - Management of depression using Prozac®, which contains the active pharmaceutical ingredient fluoxetine, can lead to reductions in plasma glucose and glycated haemoglobin that are independent of changes in food intake and body weight. We have been investigating whether fluoxetine plays a direct role in regulating beta-cell function by quantifying its effects, at therapeutically relevant concentrations, on insulin secretion and beta-cell mass and its regulation of glucose homeostasis in vivo.

Characterising a new animal model of diabetes

Dr Aileen King, Miss Matilda Kennard, Miss Lydia Daniels Gatward - We have discovered a new mouse model of diabetes in which males spontaneously develop hyperglycaemia at around 5 weeks. This is due to mutation of the insulin molecule, which leads to beta-cell endoplasmic reticulum stress. The females which have the same mutation do not develop diabetes and one part of the project is to try to understand what is protecting the female mice.

C1QL1-derived proteins and peptides for the treatment of type 2 diabetes

Prof Shanta Persaud, Prof Peter Jones, Dr Aileen King, Dr James Bowe, Dr Patricio Atanes - We have demonstrated that C1QL1 and a 101 amino acid N-terminal fragment (C1QL1-delta4) stimulate insulin release, promote beta-cell proliferation and inhibit beta-cell apoptosis. We are now determining the shortest biologically active C1QL1 fragment in mouse and human islets, using PRESTO-Tango screening to identify the receptor through which C1QL1 peptides improve islet function, and quantifying the effects of C1QL1 fragments in improving glucose homeostasis and beta-cell mass in vivo, in mice.

Beta-cell identity during type 2 diabetes and remission

Dr Timothy Pullen, Miss Maya Wilson - The development of type 2 diabetes is accompanied not just by decreased beta-cell function, but by a loss of cell identity. We are seeking to understand the gene expression patterns which maintain the healthy beta-cell phenotype and are responsible for its loss in diabetes. We currently focus on the role of long non-coding RNAs (lncRNA) in regulating cell identity and how beta-cell de-differentiation affects that capacity for remission in type 2 diabetes.

Identifying metabolic cross-talk in the regulation of islet function: roles of islet GPCRs

Prof Shanta Persaud, Dr Patricio Atanes, Ms Tanyel Ashik, Mr Jingzhe Gao - Glucose homeostasis is regulated by intercellular cross-talk through which ligands secreted by different cell types interact with islets to regulate insulin secretion and maintain beta-cell mass. We are characterising peptide ligands of islet G-protein-coupled receptors that are secreted from liver, skeletal muscle and fat under insulin-sensitive and insulin-resistant conditions, and identifying their effects on mouse and human islets in vitro and in vivo.

Extracellular matrix and islet function

Prof Peter Jones, Miss Carolin Heller - Native islets in the pancreas possess a complex network of extracellular matrix (ECM) which acts as a structural support and as a reservoir for biologically active molecules which influence islet cell function. Islet ECM is largely destroyed during islet isolation with deleterious effects on islet survival and function. We have recently shown that ECM laid down by stromal cells grown in 2D monolayers is beneficial for islet survival and function, so we are now exploring ways to replace islet ECM using 3D co-cultures of islets with mesenchymal stromal cells and islet stellate cells.

Islet microRNAs and their roles in regulating beta-cell mass and secretory function

Dr Bo Liu - It is known that insulin-secreting beta-cells make adaptative changes during the initial stage of obesity, but progression of obesity and the eventual failure of beta-cell compensatory responses leads to the transition from non-diabetic obesity to type 2 diabetes (T2D). The precise mechanisms involved in beta-cell adaptation during obesity and beta-cell failure in progression to T2D have not been identified. However, I have shown that human islets exhibit a distinct microRNA expression profile during obesity and these microRNAs target a network of genes known to regulate beta-cell mass and/or secretory function. My research therefore aims to characterise the role(s) of several candidate microRNAs in beta-cells using in vitro and in vivo approaches. Results obtained from this study will contribute to the understanding of the physiological role(s) islet microRNAs play in regulating glucose homeostasis and will provide new insights in identifying novel therapeutic targets for the treatment of T2D.

Characterising the origin, heterogeneity and functional maturity of the developing human pancreas

Prof Shanta Persaud, Dr Edward Olaniru - We are generating single cell cDNA libraries from human fetal pancreases at 8, 10, 14, 17 and 20 wpc and identifying the major cell types by unsupervised clustering and subcluster analysis based on their transcriptional similarities. This project will reveal how human islet cells are born, their diversity and the cellular mechanisms that regulate how they mature. We are creating a comprehensive human fetal pancreas cell atlas describing sub-populations of cell types. The identified gene products will be validated by in situ hybridisation and immunohistochemistry in human pancreas sections at the appropriate stages of development.

Exploring the translational potential of the NPY Y4 receptor for treating type 1 diabetes

Dr Gavin Bewick, Dr Naila Haq - Type 1 diabetes (T1D) affects 1 in 300 people by 18 years of age in the USA and its worldwide incidence has been increasing by 2-5% a year. It is characterized by autoimmune destruction of beta-cells, leading to insulin insufficiency and loss of glucose homeostasis. There is no cure for T1DM which presents an urgent need for new clinical strategies. Of high importance are strategies which target the promotion of beta-cell survival, the regeneration of functional residual beta-cell mass and or target diabetic hyperglucagonaemia. The aim of these strategies is to lower, or remove, the exogenous insulin burden. In doing so disease management could be greatly improved and the risk of harmful complications reduced. Our previous work suggests targeting NPY Y4 receptors could address some of these challenges. This project will identify a lead NPY Y4 receptor agonist and validate its translational potential for treating T1D.

Targeting eNAMPT to treat diabetes

Dr Paul Caton, Dr Sophie Sayers, Mr Daniel Egbase - Our previous studies have shown that the circulating protein eNAMPT could play and important role in diabetes pathophysiology, particularly through mediating pancreatic beta-cell failure. We are currently developing and testing compounds which selectively target the protein eNAMPT, for treatment of both type 1 and type 2 diabetes (collaboration with Dr Sam Butterworth, Manchester).

NAD and pancreatic beta-cell function and mass

Dr Paul Caton, Dr Sophie Sayers - Progressive loss of functional beta-cell mass is a key step in the development of type 2 diabetes, yet the underlying mechanisms for this are yet to be fully elucidated. This area of research aims to understand how changes in islet NAD levels can regulate beta-cell differentiation status, leading to alterations in functional beta-cell mass, and whether we can target these pathways to develop novel treatments for type 2 diabetes.

Skin function and metabolic health

Dr Paul Caton - Individuals with psoriasis are at increased risk of developing type 2 diabetes and other metabolic co-morbidities. This project aims to investigate the underlying mechanisms responsible for these links. Specifically, we are investigating whether changes in skin-derived lipids and proteins (the skin secretome) can play a role in inducing insulin resistance and beta-cell dysfunction, leading to increased risk of developing type 2 diabetes.

Laboratory Work Experience Scheme

Every year we hold a work experience week where we invite around ten 16-18 year-old school pupils to join us for a week in the lab to gain insight into what life is like as a diabetes researcher. During the week, the pupils get hands-on experience of a variety of commonly used lab techniques. They also have a chance to interact with researchers at different stages of their career as well as students studying on our BSc programmes at King’s.

• Inspiring the next generation

Interactive islet transplantation

PhD student Ella Hubber has collaborated with computing arts students from Goldsmiths University to create an interactive public engagement activity based on her research project on a treatment for type 1 diabetes. The activity simulates the transplantation of islets into different organs, with sensors detecting the islets transplanted into different tubes then displaying the number of functioning islets on LCD screens. This activity was debuted at New Scientist Live in October 2019 and was a hit with 15-18 year olds who enthusiastically competed to transplant the most islets. Feedback was positive, with most students saying that they enjoyed the activity and that it made them interested in learning more about diabetes research. The activity was also at the Evelina Inspiring Youth Conference and Society for Endocrinology Annual Conference in Brighton in 2019 and it will be featured at the King’s 2020 Festival and STEMRoller 2020, an event where young women interested in science careers play the sport roller derby.