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

Impaired insulin secretion in type 2 diabetes (T2D) is linked to reduced insulin granule docking, disorganization of the exocytotic site, and an impaired glucose-dependent facilitation of insulin exocytosis. We show in β-cells from 80 human donors that the glucose-dependent amplification of exocytosis is disrupted in T2D. Spatial analyses of granule fusion events, visualized by total internal reflection fluorescence (TIRF) microscopy, demonstrate that these are non-random across the surface of β-cells from donors with no diabetes (ND). The compartmentalization of events occurs within regions defined by concurrent or recent membrane-resident secretory granules. This organization, and the number of membrane-associated granules, is glucose-dependent and notably impaired in T2D β-cells. Mechanistically, multi-channel Kv2.1 clusters contribute to maintaining the density of membrane-resident granules and the number of fusion ‘hot spots’, while SUMOylation sites at the channel N-(K145) and C-terminus (K470) determine the relative proportion of fusion events occurring within these regions. Thus, a glucose-dependent compartmentalization of fusion, regulated in part by a structural role for Kv2.1, is disrupted in β-cells from donors with type 2 diabetes. HIGHLIGHTS Exocytosis of secretory granules is non-random across the surface of human β-cells, and this organization is disrupted in type 2 diabetes. Increasing glucose facilitates the spatial compartmentalization of fusion, independent of an overall increase in event frequency. Compartmentalized ‘hot spots’ occur at sites marked by membrane-associated granules, the density of which is regulated in part by a clustered K+ channel (Kv2.1). SUMOylation status of the channel controls the proportion of events that occur within these local regions.