Pseudoislets as a model system to study beta cell dysfunction in diabetes

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Insulin is an essential hormone made by islet beta-cells and reductions in its release cause diabetes. The importance of beta-cells in the development of diabetes means that much research is focused on studying their function, or on using islets/beta-cells to test new diabetes therapies. This is valuable and has led to new drug development and to novel transplantation methods to treat diabetes. The most common source of islets for these studies is laboratory animals, particularly rats and mice, and we estimate that this accounts for the use of tens of thousands of these animals each year. This project proposes to allow a substantial reduction in the numbers of animals required by developing alternatives to islets taken from animals. We already have a variety of animal-derived hormone-producing cells that have been modified so that they grow continuously in tissue culture without the need for using more animals. However, islets are complicated organs in which interactions between cells are very important for their function ? when the cells are grown in isolation they no longer behave normally, and so their usefulness for experiments is limited. We have spent several years investigating interactions between islet cells to find out how to put the cells together to form islet-like structures (pseudoislets) so they perform like normal islets: our current pseudoislet model is much better than the original cell lines, but it is not yet as good as a real islet. We now propose to improve pseudoislet function further through a defined series of experiments and the impact of this model to the 3Rs will be in replacement of animals that would otherwise be used as a source of primary pancreatic islets. Since the development of our current pseudoislet model we have routinely used pseudoislets, rather than islets taken from animals, in our studies of insulin secretion and we have published these studies in first class, peer-reviewed scientific journals. We have also introduced the pseudoislet model into the laboratories of some of our collaborators, but we acknowledge that the scientific community is inherently conservative so an important part of our application is directed towards a programme of dissemination of the results of the studies to investigators who currently use experimental animals as a source of islets. We propose that this will maximize the impact of our project on the replacement of animals that would otherwise be used for islet isolation.