Presynaptic-like mechanisms and the control of insulin secretion in pancreatic β-cells

Abstract

The regulation of insulin secretion from pancreatic β cells is central to the maintenance of blood glucose homeostasis. While the fundamental steps linking glucose uptake to the exocytosis of insulin-containing granules are known, many details around the precise control mechanisms remain unclear, including how insulin exocytosis is spatially regulated to target the delivery of insulin granules to the islet capillaries. In this thesis, I provide evidence supporting presynaptic-like regulation of insulin secretion to target insulin granule fusion to the β cell-capillary interface. Specifically, I demonstrate that ECM-contact and the local activation of integrins and FAK regulate the positioning of presynaptic scaffold proteins and glucose-dependent Ca2+ responses in β cells (Chapter 3), I describe a novel role for the presynaptic scaffold protein liprin-α1 in tethering insulin granules to the β cell-ECM interface (Chapter 4), and I identify a molecular pathway linking β cell presynaptic machinery to the ECM via the focal adhesion-associated protein KANK1 (Chapter 5) to target insulin secretion to the capillaries. Together, these data provide mechanistic insight into the spatial regulation of insulin exocytosis and open up a new layer of complexity for understanding stimulus-secretion coupling in pancreatic β cells.