Project ID CM-HD2023_04

ThemeCM-HD

Co Supervisor 1A Diabetes and Obesity, SCMMSWebsite

Co Supervisor 1B Diabetes, School of Cardiovascular and Metabolic Medicine & Sciences, Faculty of Life Sciences & MedicineWebsite

Identifying new targets to treat Type 1 Diabetes

Autoimmune destruction of insulin-producing β-cells of the pancreas results in Type 1 Diabetes (T1D), with an incidence rate of 25.4 out of 100,000 (0-14 years) in the UK. Despite improvement of care, to-date, there is no cure for T1D, presenting an urgent need for new clinical strategies.

Current knowledge of what connects the adaptive immune system to the beta-cells is limited. Pancreatic islets are complex micro-organs, where in addition to hormone releasing cells (Fig 1), antigen presenting cells of the myeloid lineage are also present. We recently identified the neuropeptide Y (NPY) receptors, NPYR 1, 4 and 5, as novel targets for promoting human beta-cell survival. Using selective ligands, we revealed NPY Y1, 4 and 5 engage a powerful anti-apoptotic pathway, protecting mouse and human islets from damage, helping to preserve beta-cell mass and functionality. This demonstrates proof of concept for targeting these receptors to treat Type 1 diabetes.

Our flow cytometry analysis of murine islet cells identified the Y5 receptor to be present on a CD45+ cell population (Fig 2), suggesting action at this receptor in this population of resident islet immune cells is beneficial for the health of the beta-cell. This project proposes to examine the role of Y5 receptor in protecting pancreatic islets from auto-immune mediated damage and thereby identify a lead target strategy to enable the translation of a new therapy for T1D.

Objectives:
1. Explore the role of Y5 activation on murine and human native islets.
2. To determine whether Y5 is the missing link between distressed ß-cells and the adaptive immune system.
3. Determine the clinical utility of Y5 agonist on preserving beta-cell mass functionality in T1D.

One representative publication from each co-supervisor:

Sayers SR, Beavil RL, Fine NHF, Huang GC, Choudhary P, Pacholarz KJ, Barran PE, Butterworth S, Mills CE, Cruickshank JK, Silvestre MP, Poppitt SD, McGill AT, Lavery GG, Hodson DJ, Caton PW.
Structure-functional changes in eNAMPT at high concentrations mediate mouse and human beta cell dysfunction in type 2 diabetes. Diabetologia. 2020 Feb;63(2):313-323

Islet neuropeptide Y receptors are functionally conserved and novel targets for the preservation of beta-cell mass. Diabetes Obes Metab. 2017 Sep 22. doi: 10.1111/dom.13119.