Periodic Reporting for period 2 - OptoBETA (Multicellular regulation of insulin secretion from pancreatic islets)
Reporting period: 2018-12-01 to 2020-05-31
1) Understand how immature beta cell subpopulations such as hubs influence islet function and insulin release under normal and stressed conditions.
2) Address whether beta cell subpopulations contribute to the regulation of insulin secretion in vivo, focusing on interactions with neurons and the vasculature.
3) Elucidate how islets may communicate with each other to ensure robust insulin release from the intact pancreas in living mice.
The major objective of OptoBETA is to unveil a new route for restoration of insulin secretion in humans, as well as provide the foundation for the de novo construction of islets for transplantation.
1) Developed and published a number of novel chemical biological tools to functionally dissect beta cell heterogeneity. These include photoswitchable fatty acids, drugs that conditionally target certain cell types via enzyme self-labels and far red fluorescent probes for visualising glucagon-like peptide 1 receptors in live cells.
2) With collaborators in the USA and Germany, generated and studied a beta cell loss-of-immaturity model, which allows functional interrogation of beta cell subpopulations such as hubs. Using this model, we have uncovered an hitherto unknown role for immature beta cells in controlling insulin release- the studies are currently under consideration for publication.
3) Deployed chemogenetic mouse models to determine how the islet signalling network influences beta cell heterogeneity and maturity. Unexpectedly, we were able to show that electrical activity between beta cells is important for encoding their molecular identity.
4) Developed a new range of enzyme self-labels, which are restricted solely to the membrane. We have used these probes to understand GPCR trafficking in beta cell subsets.
Together, these studies show that immature beta cells, generally considered to be poorly functional, play a major role in driving islet performance. As such, drug screening programmes and stem cell engineering efforts should focus on preserving immature beta cells to maintain optimal insulin secretion.