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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 5

Kv2.1 regulates the density of membrane-resident granules and clustered fusion sites.

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Kv2.1 regulates the density of membrane-resident granules and clustered ...
(A) Knock down of Kv2.1 expression by siRNA in human islet cells confirmed by quantitative PCR of Kv2.1 (KCNB1) and the related Kv2.2 (KCNB2). (B) The initial density of membrane-resident granules marked by NPY-EGFP is reduced by Kv2.1 knock down, as is (C) the frequency of exocytotic events. (D) This occurs without a change in the overall proportion of fusion events occurring at sites marked by membrane-resident granules (n = 30 and 30 cells from 3 donors). (E) The spatial organization of these events is only modestly decreased. (F) Examination of a subset of cells (dashed box) (G) with similar event frequency (H) demonstrates that the proportion of events occurring in spatially clustered regions is unchanged by Kv2.1 knock down (I) while the density of these sites is decreased. Significance was determined by (A) ANOVA and Bonferroni’s posttest, (B–D and G–I) by Student’s t test, or (E) by Kruskal-Wallis 1-way ANOVA followed by Mann-Whitney posttest. **P < 0.01; ***P < 0.005.

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