- 2013Pump Priming
Plasma kisspeptin in pregnancy and gestational diabetes: a translational pilot studyRecipient:Dr James BoweInstitution:King’s College LondonCity:LondonAmount:£19,700.00Description: 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.
- 2012The Professor David Matthews Non-Clinical Fellowship
Identifying Genetic Predictors of Graft Function to Enable Pancreas Transplantation to Become a Lifelong Cure for Type 1 DiabetesRecipient:Dr Matthew SimmondsInstitution:OCDEM, Churchill Hospital, OxfordCity:OxfordAmount:£164,230.00Description: In type 1 diabetes (T1D) the cells within the pancreas, which produce the hormone insulin, are destroyed by the immune system. Injecting insulin is the main form of treatment for T1D patients but in some patients giving insulin does not control their diabetes and they can go on to develop severe problems of the eyes, kidneys, nerves, brain and heart. In these patients, a transplant of the pancreas or the cells from a pancreas is currently the only treatment that can restore the patient’s own ability to produce insulin, as well as improving diabetes related complications. At present 85% of pancreas transplant patients regain normal pancreas function one year after transplantation, enabling them to discontinue insulin use. Transplanted pancreas function can, however, decrease over time and in some patients stop completely, with only 68% of transplant patients having a functional pancreas after five years. Decreased or lack of transplanted pancreas function means a return to insulin and potentially further worsening of other diabetic complications. Currently we cannot predict when the transplanted pancreas will start to fail. I want to test the genetic material obtained from both pancreas transplant donors and recipients, from all pancreas transplant centres across Europe and America, to investigate naturally occurring variations within genes influencing transplant rejection and pancreas development/function to help us try to predict when the transplanted pancreas is likely to fail so that we can administer medicines that might extend the pancreas’ lifespan and the benefits to patients of having a functioning pancreas for as long as possible.
- 2012Sutherland-Earl Clinical Fellowship
The identification of maturity onset diabetes of the young (MODY) and characterization of diabetes subtype in a young multi-ethnic population to inform appropriate treatmentRecipient:Dr Shivani MisraInstitution:Imperial College LondonCity:LondonAmount:£180,000.00 (3 years)Description: Maturity onset diabetes of the young (MODY) is a rare but frequently misdiagnosed form of diabetes requiring expert and tailored treatment. Misdiagnosis results in incorrect management, impacting on health, quality of life and complications. Diagnosis is challenging as MODY phenotypes overlap with commoner forms of diabetes and undertaking routine genetic screening is prohibitively expensive. A MODY probability calculator which uses clinical and biochemical data to predict the likelihood of MODY, has been shown to improve detection of MODY. Those scoring highly are stratified to undergo genetic testing. However, this approach has not been developed, studied or evaluated in South Asians (SAs), where subtype assignment poses a greater challenge due to the higher proportion of young-onset type 2 diabetes.
- 2012The Professor David Matthews Non-Clinical Fellowship
The role of long non-coding RNAs in regulating β-cell function and developmentRecipient:Dr Tim PullenInstitution:Imperial College LondonCity:LondonAmount:£165,000.00Description: RNA has long been seen as an intermediate between DNA of the genome and functional proteins, however only around 2% of the different RNA molecules in the cell perform this role. Many of the remaining non-protein-coding RNAs (ncRNA) play a previously underappreciated role in regulating the specific pattern in which the protein-coding genes are turned on and off. This is critical for determining the type of cell produced, and in the case of the β-cell, how well it can perform its role of glucose-regulated insulin secretion. The failure of β-cell function is the critical step in the development of type 2 diabetes (T2D). Understanding the mechanisms which maintain that function provide the opportunity both to help boost β-cell function in patients with T2D, and increase the efficiency and efficacy of producing β-cells from stem cells in vitro for treating diabetes through transplantation. I aim to identify how ncRNAs regulate β-cell function in three areas. Firstly, whether novel ncRNAs keep a group of genes which would interfere with β-cell function specifically turned off in these cells. Secondly, how a ncRNA I have already identified regulates the levels of Pdx1 (a gene known to regulate β-cell function). This may partly control the process in which another type of cell in pancreatic islets can turn into new β-cells, which could help block the progression of diabetes. Finally, whether previously unidentified lncRNAs could explain why mutations in humans which are not close to known genes affect susceptibility to T2D.
- 2011Pump Priming
Development of regulatory B cell assay in type 1 diabetesRecipient:Professor Susan WongInstitution:Cardiff UniversityCity:CardiffAmount:£20,000.00Description: White blood cells called B cells produce antibodies which are very important markers of the immune attack on insulin producing beta cells. Normally B cells protect against infection, but they also help turn off immune responses when no longer needed. We will study if the B cells that can dampen other immune responses (known as regulatory B cells) are defective in patients with diabetes. Our overall aim is to understand how B cells contribute to immune damage in type 1 diabetes (T1DM) and whether alterations in B cell function can be used as markers to monitor disease. Individuals will be asked to provide blood samples. We will study whether the B cells that can dampen down immune responses (regulatory B cells) have abnormal function in people with diabetes, compared with control subjects. This research will be important for understanding why people develop T1DM. In addition, new immune therapies are in trial to protect beta cells and this research may give us a new tool to detect how well these treatments work, vitally important for improvement of design of treatments for T1DM over the next 5-10 years.