Local Integrin Activation in Pancreatic β Cells Targets Insulin Secretion to the Vasculature

Abstract

The extracellular matrix (ECM) critically affects β cell functions via integrin activation. But whether these ECM actions drive the spatial organization of β cells, as they do in epithelial cells, is unknown. Here, we show that within islets of Langerhans, focal adhesion activation in β cells occurs exclusively where they contact the capillary ECM (vascular face). In cultured β cells, 3D mapping shows enriched insulin granule fusion where the cells contact ECM-coated coverslips, which depends on β1 integrin receptor activation. Culture on micro-contact printed stripes of E-cadherin and fibronectin shows that β cell contact at the fibronectin stripe selectively activates focal adhesions and enriches exocytic machinery and insulin granule fusion. Culture of cells in high glucose, as a model of glucotoxicity, abolishes granule targeting. We conclude that local integrin activation targets insulin secretion to the islet capillaries. This mechanism might be important for islet function and may change in disease.

A glucose-dependent spatial patterning of exocytosis in human β cells is disrupted in type 2 diabetes

“…Focal adhesion activation may contribute to this (52), resulting from ECM-dependent interactions that drive cell polarity in situ (17). Although it seems likely that the additional signals, such as integrin activation by the ECM interactions (16), would provide an additional layer of organization, we observed a glucose-dependent spatial patterning of fusion events across the surface of isolated β cells that were defined by the presence of previously or concurrently docked granules. The observation that membrane-docked granules mark hotspots in β cells suggests that the reduced organization of fusion events in T2D β cells could be secondary to impaired glucose-dependent granule docking.…”

“…Recently, the glucose-dependent recruitment of granules to docking sites was shown to be a limiting step in insulin secretion, which is disturbed in T2D (12). The spatial organization of events at the plasma membrane, such as the localization of integrin signals (16) or the clustering of Ca 2+ channels (28), is an important determinant of regulated insulin secretion. However, little is understood about the control of the spatial patterning of fusion events in human health and T2D.…”

“…Although β cells lack ultrastructurally identifiable active zones, glucose stimulation in situ triggers fusion events that are progressively localized to preferential release sites (13). These appear directed toward the islet vasculature (13)(14)(15) and are regulated by extracellular matrix (ECM) interactions with integrin receptors (16), which likely play an important role defining the polarity that defines β cell organization in situ (17). Fusion events in vitro also appear nonrandom in insulinoma cells and rodent β cells, where exocytosis may occur at sites of recently fused vesicles (18)(19)(20)(21)(22).…”

A glucose-dependent spatial patterning of exocytosis in human β-cells is disrupted in type 2 diabetes

“…Recently, the glucose-dependent recruitment of granules to docking sites was shown to be a limiting step in insulin secretion which is disturbed in T2D (12). The spatial organization of events at the plasma membrane, such as the localization of integrin signals (16) or the clustering of Ca 2+ channels (28), are important determinants of regulated insulin secretion. However, little is understood about the control of the spatial patterning of fusion events in human health and T2D.…”

“…While b-cells lack ultra-structurally identifiable active zones, glucose-stimulation in situ triggers fusion events that are progressively localized to preferential release sites (13). These appear directed towards the islet vasculature (13)(14)(15) and are regulated by extracellular matrix (ECM) interactions with integrin receptors (16), which likely play an important role defining the polarity which defines b-cell organization in situ (17). Fusion events in vitro also appear nonrandom in insulinoma cells and rodent b-cells, where exocytosis may occur at sites of recently fused vesicles (18)(19)(20)(21)(22).…”