Spatial organization and paracrine control of exocytosis in islet cells

Pancreatic islets act as micro-organs whose coordinated output of insulin and glucagon regulates blood glucose.

While islet hormones are released into islet-traversing capillaries to act systemically, transmitter molecules that are co-released by the same granules exert paracrine effects onto neighboring cells.

The aim of this project is to understand the architecture and cell physiology that make this diverse signaling possible, and how it may fail in diabetes, with the central hypothesis that islets are spatially organized to facilitate both hormone release and paracrine signaling with their neighbors, and that this is reflected in the subcellular organization and functional variability of exocytosis.

High-resolution imaging in combination with electrophysiology will be used to understand 1) the spatio-temporal organization of the insulin granule release site, and how it affects release probability and subcellular location of exocytosis; 2) mechanisms of fusion pore regulation and its role for paracrine signaling; and 3) paracrine signaling in human islets, with focus on paracrine resistance in T2D.

The work is immedeately relevant to our understanding of islet function in health and diabetes, and of general interest for cell- and neurobiologists.

We expect that insight in release site and fusion pore regulation will contribute to the identification of novel targets for drug development and a better understanding of currently used antidiabetic therapeutics.