Funded Research

When people with type 1 diabetes exercise, some experience hypoglycaemia, while others do not; in some HbA1c gets worse while in others it improves. Exercise is known to increase glucose variability leading to more time with high and low levels. It is now known that many people with long-standing type 1 diabetes can produce small amounts of insulin. It is unknown if this is important for limiting blood glucose variability at rest and around exercise. It is also unknown whether this low level of insulin impacts on important health markers such as how well blood vessels expand and shrink and how well the body can repair these vessels. We will examine the relationships between residual insulin production, glucose variability, blood vessel function and repair, inflammation and hypoglycaemia fear and incidence, at rest and after exercise. This will provide a foundation for larger studies which will look at how amount of residual insulin production could be used to predict the level of support people wishing to exercise may need.

Type 1 diabetes is caused when the immune system makes a mistake and destroys the insulin-secreting beta cells in the pancreas. We know that genes play an important role in causing the condition but factors in our environment such as viral infections, pre-natal environment, and early nutrition are also thought to be important. Over recent decades, the incidence of type 1 diabetes has increased rapidly (~3% annually especially in children under 5 years of age). In addition, more people with less type 1 diabetes associated genes develop the condition today compared with previous generations. This suggests the increasing importance of environmental effects in type 1 diabetes. Unlike genes that are usually inherited unchanged from parents, DNA itself can be chemically modified, a phenomenon called DNA methylation. This process has been shown to be changed by environmental exposures and can be different in one individual to another. My collaborator, Professor Yaron Tomer and his team at Albert Einstein College of Medicine in New York has already shown that methylation differences can be found in identical twins where one twin was affected by type 1 diabetes while the other was not. In my three-year fellowship, I will travel to Professor Tomer’s laboratory to study multi-generation type 1 diabetes families from the Bart’s Oxford (BOX) family study of type 1 diabetes which has been running for over 30 years. I am going to investigate whether DNA methylation has changed in children with type 1 diabetes compared with their parents and grandparents. This study will allow us to find out whether the changing environment over time is associated with the increasing incidence of diabetes by modifying our DNA. We hope that this research will identify new markers that can be used in clinical trials to more accurately assign disease risk. In addition, we will dissect the underlying molecular mechanisms to uncover why environmental exposures trigger changes to the immune system leading to beta cell death. In the longer term, if we can understand why type 1 diabetes is becoming more common we may be able to intervene to delay or prevent the condition.

More people with type 2 diabetes have fatty liver disease than people without diabetes. Liver fat accumulation (steatosis) consists of either a large number of small (microsteatosis) or one large (macrosteatosis) fat (lipid) droplet within liver cells (hepatocytes). Large lipid droplets are thought to interfere with the part of the cell that produces energy (mitochondria) so that they don’t work efficiently. We will investigate the relationship between lipid droplets and mitochondrial function in human liver cells. Liver tissue will be obtained from patients undergoing surgery and from this hepatocytes will be isolated. We will then measure the size and number of the lipid droplets and their localisation to mitochondria, using a state-of-the-art automated imaging machine. We will also assess the health and function of the mitochondria by determining their ability to produce energy. This work will help us to understand the relationship between fat in the liver and mitochondrial function and also provide information about pathways that new drugs could be developed for to help to keep the liver healthy.