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Multicellular regulation of insulin secretion from pancreatic islets

Periodic Reporting for period 3 - OptoBETA (Multicellular regulation of insulin secretion from pancreatic islets)

Reporting period: 2020-06-01 to 2021-11-30

Type 2 diabetes mellitus (T2DM) occurs when pancreatic beta-cells are unable to release enough insulin to combat resistance to the hormone. The resulting increase in blood glucose levels drives a range of severe complications including cardiovascular disease, renal and liver failure, retinal degeneration and cancer. As such, T2DM is considered an immediate healthcare crisis, affecting 1 in 10 adults in the EU and consuming healthcare budgets. To have any hope of halting this trend, we urgently need to open up new research avenues to identify mechanisms and therapeutic targets. Here, by combining novel optogenetic, photopharmacological and innovative imaging approaches, we seek to unravel the complexity underlying the multicellular regulation of insulin secretion from islets of Langerhans during health and disease. The specific aims of OptoBETA are to:

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.
The overarching objective of OptoBETA is to understand how subtle differences between pancreatic beta cells may contribute to insulin release and therefore type 2 diabetes mellitus (T2DM) risk. During the previous 18 months of the project we have:

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.
OptoBETA has already advanced knowledge beyond state-of-the-art by providing a revised blueprint for islet architecture. Specifically, OptoBETA has shown that immature and plastic beta cell subpopulations play a disproportionate role in dictating insulin release. Over the next three years, OptoBETA will further advance the field by showing how beta cell subpopulations operate in vivo through interactions with neurons, as well as how the islets themselves communicate their activity to one another.
OptoBETA- combining chemical biology and genetics to probe beta cell subpopulations