Intercellular communication in pseudoislets: shaping the dynamics of insulin secretion

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Glucose is the primary source of energy for the human body. When we eat, food is ultimately broken down into the necessary glucose and so, over the course of a full day, the amount of glucose in the blood varies. Both too high and too low blood glucose levels can cause potentially life threatening conditions. Blood glucose levels are regulated by two key chemicals: insulin, which lowers the level, and glucagon, which raises it. Both of these are produced naturally in the body in structures known as the islets of Langerhans, which are located in the pancreas.Within the islets, the beta cells are responsible for the production and secretion of insulin. Insulin secretion is dependent on the synchronised electrical activity of all beta cells within an islet, which is achieved through communication between them. This communication arises primarily due to physical connections between neighbouring cells. If these connections are disrupted, the ability of the islets to secrete enough insulin to properly regulate blood glucose may become compromised.Both forms of diabetes are associated with a loss of proper functioning of the islets. In type 1 diabetes, the beta cells are destroyed by the body's own immune cells. Below a critical beta cell mass, the body can no longer regulate blood glucose levels and patients become reliant on the administration of externally produced insulin. In type 2 diabetes, the functional changes are more subtle but may be caused by disruptions to the synchronised electrical response across an islet. One potential new therapy for type 1 diabetes involves the transplantation of beta cells into patients to compensate for the loss of their own cells.We now have the capability to grow human beta cells in structures that mimic the islets of Langerhans in laboratories. This allows us to study the exact coupling between cells and observe the synchronisation of activity across the islet. We can also alter the laboratory grown islets in terms of their size, shape and the coupling between cells within them. In doing so, we can rigorously examine how how the connections between the cells quantitatively affect the secretion of insulin within an islet.Mathematical models of biological networks provide powerful tools to simplify the analysis of large networks of cells. These models are constructed by considering mathematical descriptions of key biophysical processes that occur within and between the beta cells. Once developed, they can be used to investigate the mechanisms behind observed behaviours and, more importantly, they offer predictions about how changes to the communication between cells that occur during type 1 and 2 diabetes affect the secretion of insulin from the islet. Importantly, the connections between cells have been recently been highlighted as potential target for treatment of both forms of the disease. The predictions from the model will then be tested by performing similar alterations in the lab-grown islet.Using the mathematical model, this project will investigate the prognoses of type 1 diabetes by considering how cellular communication is disrupted as the beta cells are destroyed, and how this impacts upon the secretory properties of the islets. It will also identify optimal sizes and configurations of islets with respect to insulin secretion to aid in the development of transplantation therapies for type 1 diabetes.