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A glucose-dependent spatial patterning of exocytosis in human β cells is disrupted in type 2 diabetes
Jianyang Fu, … , Herbert Y. Gaisano, Patrick E. MacDonald
Jianyang Fu, … , Herbert Y. Gaisano, Patrick E. MacDonald
Published May 14, 2019
Citation Information: JCI Insight. 2019;4(12):e127896. https://doi.org/10.1172/jci.insight.127896.
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Research Article Cell biology Endocrinology

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

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Abstract

Impaired insulin secretion in type 2 diabetes (T2D) is linked to reduced insulin granule docking, disorganization of the exocytotic site, and 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 microscopy in 24 of these donors, demonstrated that these events are nonrandom across the surface of β cells from donors with no diabetes. 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, multichannel Kv2.1 clusters contribute to maintaining the density of membrane-resident granules and the number of fusion “hotspots,” 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 T2D.

Authors

Jianyang Fu, John Maringa Githaka, Xiaoqing Dai, Gregory Plummer, Kunimasa Suzuki, Aliya F. Spigelman, Austin Bautista, Ryekjang Kim, Dafna Greitzer-Antes, Jocelyn E. Manning Fox, Herbert Y. Gaisano, Patrick E. MacDonald

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Figure 1

β Cell exocytosis is impaired in T2D.

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β Cell exocytosis is impaired in T2D.
(A) Compared with islets of donors...
(A) Compared with islets of donors with no diabetes (ND; n = 63), glucose-stimulated insulin secretion is impaired from islets of donors with type 2 diabetes (T2D; n = 17). (B) In both sets of donors (average 6.7 years’ duration of T2D) islet insulin content is not different. (C and D) Cumulative distribution of exocytotic responses of β cells from the same donors, measured by patch-clamp electrophysiology. Glucose (10 mM; red) amplifies the (C) exocytotic responses of ND β cells (n = 701 cells) (D) but not T2D β cells (n = 156 cells). (E) Impaired glucose-stimulated insulin secretion observed in the subgroup of ND (n = 17 donors) and T2D (n = 7 donors) subsequently used for TIRF imaging. (F) In individual β cells expressing NPY-EGFP, fusion events (red circles) observed by live-cell TIRF microscopy at 5 mM glucose in ND β cells, a heatmap of fusion event density, and Voronoi diagram used to separate exocytosis sites (scale bar: 5 μm). (G) Representative recordings from the areas indicated in F. (H) The nonrandom nature of fusion events in ND β cells is demonstrated by spatial K-function calculation (red line) greater than the simulated (dashed lines) maximum. (I–K) The same as F–H but in a T2D β cell, where events appear more randomly distributed (scale bar: 5 μm). Significance was determined by (B) Mann-Whitney test or (A and E) Kruskal-Wallis 1-way ANOVA followed by Mann-Whitney posttest. *P < 0.05; ***P < 0.001.

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