Funded Research

Damage to the endothelial cells that form the blood vessels is a key step in many of diabetes-related pathologies. This damage is associated with removal of a protective layer (glycocalyx) that lines the inside of blood vessels. The kidney glomerulus is a convoluted ball of small blood vessels which is also susceptible to loss of the glycocalyx in diabetes, leading to endothelial dysfunction and diabetic kidney disease. Glomerular endothelial damage can be measured by small amounts of protein escaping into the urine and reflects generalised endothelial damage. We have identified a growth factor that is produced naturally within the body, which maintains the glycocalyx on glomerular endothelial cells and stops passage of protein in culture conditions. We aim to assess the therapeutic potential of this growth factor on rescuing damaged glomerular endothelial cells in an experimental mouse model of diabetic kidney disease.

People with cystic fibrosis (CF) inherit a genetic defect that significantly shortens life-span. At present, approximately 9,000 people in the UK suffer from CF, and on average, do not live beyond their mid-30s. The genetic defect causes a build-up of thick and sticky secretions (for example, mucus in the lung), which affects the lungs and digestive tracts in particular. In the digestive tract, this causes high blood sugar levels and CF patients often develop diabetes (50% of patients over the age of 30 have diabetes). We do not know the cause, but the development of diabetes accelerates lung disease, which is the primary cause of death among CF patients. This study aims to find out what causes CF-related diabetes (CFRD) by examining the cells which regulate blood sugar levels. The study will not use animal or human tissue, but will create the first artificial CFRD cell model which will be used to study how the genetic defect increases blood sugar levels. This will be the first step in understanding how CFRD develops. By building on this initial investigation, we hope to identify how best to treat these patients to prevent the development of diabetes and increase life-expectancy.

The kidney is often severely damaged by diabetes. Current tests only diagnose kidney problems when a lot of damage has already occurred. We need new tests that identify early damage and tell doctors something about the mechanism of injury. In urine there are particles called exosomes, packets of information released by kidney cells that change when the cells are injured. With DRWF funding we will develop a new method for counting human urinary exosomes and define their cargo. Armed with these crucial pilot data we can go forward and determine what exosomes tell us about diabetic kidney disease.

Gestational diabetes (GDM) is raised blood glucose (sugar) levels occurring for the first time during pregnancy. GDM is associated with increased risk of adverse outcomes for mother and baby. We don’t really know why GDM occurs in some women. During pregnancy the body becomes more resistant to the effects of insulin (the hormone that controls blood glucose levels). During normal pregnancy the mother’s pancreas produces more insulin to compensate and blood glucose remains normal. The increase in insulin production occurs because the insulin-secreting β-cells in the islets of Langerhans in the pancreas both increase in number and release more insulin. GDM occurs when these processes are not enough to overcome the insulin resistance of pregnancy. Kisspeptin is a recently-discovered molecule that is found, along with its receptor, in the placenta and the pancreas. Kisspeptin increases in the blood during normal pregnancy due to massive release from the placenta. The function(s) of kisspeptin in the placenta and the pancreas are unknown. In my research in mice I showed that the kisspeptin receptor, GPR54, is found on β-cells and I demonstrated that kisspeptin increases insulin secretion. My research has suggested that, in pregnant mice, circulating kisspeptin is involved in β-cell responses to pregnancy, supporting islet function. These animal studies continue, but it is now important to examine whether these results translate to humans, as finding a role for kisspeptin in the function of human β-cells may lead to novel therapies for human diabetes. The proposed project is a translational pilot study to see if pregnant women with higher blood glucose levels have lower kisspeptin levels.