Funded Research

During healthy pregnancy insulin sensitivity in the mother decreases and the insulin-secreting beta-cells in the islets of Langerhans release more insulin and increase in number to maintain normal blood glucose levels. Gestational diabetes mellitus (GDM) is a form of diabetes that occurs specifically during pregnancy and occurs when the maternal islets are unable to sufficiently compensate for the increased insulin resistance, though the mechanisms involved are currently poorly understood. Corticotropin releasing hormone (CRH) and growth hormone releasing hormone (GHRH) are two hormones that are primarily released from the hypothalamic area of the brain. They are responsible for controlling stress responses and growth respectively. Both hormones also have beneficial effects on the beta-cells, though the physiological reason for this is unknown. Levels of CRH and GHRH in the blood are low under most circumstances, but increase greatly during pregnancy due to release from the placenta. Thus, this project will investigate whether CRH and/or GHRH regulate beta-cell adaptation to pregnancy, and whether insufficient CRH or GHRH is linked to GDM.

This research aims to define the mechanisms though which Mesenchymal Stromal Cells (MSCs) or the biologically active substances that they produce should be used to improve the efficiency of clinical islet transplantation. Our experiments have shown that MSCs produce Annexin A1 (ANXA1) and that ANXA1 partially mimics the beneficial effects of using MSCs. We aim to define a 'cocktail' of therapeutic factors produced by MSCs, that can be used instead of the MSCs, to fully reproduce the beneficial effects of MSCs in transplantation protocols. Defining MSC-derived biotherapeutics will allow simple modifications to clinical transplantation, that will help to overcome some of the safety concerns of using MSCs directly and allow safe and reproducible modifications to be carried out. The proposed work will help design and start a clinical trial within the next five years. Through improving the efficiency of the transplant procedure, clinical islet transplantation can be offered as a therapeutic option to the greatest possible number of patients with Type 1 Diabetes and improve outcomes for individual transplant recipients.

We need to understand more about how the insulin-producing beta-cell works. One good way to do this is to study patients who get diabetes because they do not make insulin as a result of a single spelling mistake in one word of their whole library of books of genetic information (monogenic diabetes). These patients are likely to develop diabetes when young. We will look for the genetic cause of diabetes in patients diagnosed between 6-12 months using two recently available tools: 1) a test which allows us to select patients likely to have monogenic diabetes, this is called a genetic risk score; 2) whole-genome-sequencing which allows us to analyse the entire human DNA to identify the critical spelling mistakes in the genetic information. Using these tools we will identify the likely cause of diabetes in these children and confirm it in other patients. As we have already excluded the known causes of monogenic diabetes, this will be a new finding which will help us to understand the beta-cell better.