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Single Fusion Pore Analysis via Single Cell Amperometry Uncovers Impaired Pore Expansion That Restricts Insulin Exocytosis in Human Type 2 Diabetes

Hatami, Amir ; Gandasi, Nikhil R. ; Dou, Haiqiang ; Kothegala, Lakshmi ; Eliasson, Lena LU orcid ; Ewing, Andrew and Rorsman, Patrik LU (2025) In Angewandte Chemie International Edition
Abstract
Insulin secretion from vesicles within pancreatic beta cells occurs through the rapid (≤10 ms) process of exocytosis. A crucial final step in this process is the formation of a fusion pore, which connects the insulin vesicle interior to the extracellular space and insulin secretion rate. We employed real-time single-cell amperometry (SCA) with microsensors to quantitatively and dynamically monitor serotonin secretion (used as a proxy for insulin) and alterations in the dynamics of fusion pore formation, including opening, duration, and closing times, during single exocytosis events. Additionally, total internal reflection fluorescence (TIRF) microscopy was used to track docked vesicles and optically measure insulin release. In beta cells... (More)
Insulin secretion from vesicles within pancreatic beta cells occurs through the rapid (≤10 ms) process of exocytosis. A crucial final step in this process is the formation of a fusion pore, which connects the insulin vesicle interior to the extracellular space and insulin secretion rate. We employed real-time single-cell amperometry (SCA) with microsensors to quantitatively and dynamically monitor serotonin secretion (used as a proxy for insulin) and alterations in the dynamics of fusion pore formation, including opening, duration, and closing times, during single exocytosis events. Additionally, total internal reflection fluorescence (TIRF) microscopy was used to track docked vesicles and optically measure insulin release. In beta cells from human organ donors with type 2 diabetes (T2D), the fusion pore opening was prematurely aborted, leading to diminished cargo release. Furthermore, the number of docked vesicles per beta cell differed between healthy donors and individuals with T2D. In conclusion, our combined super-sensitive optical and electrochemical analyses from a new perspective highlight a link between defective fusion pore dynamics and reduced insulin secretion (a hallmark of T2D) that has not been previously reported. These findings reveal the role of impaired fusion pore dynamics in T2D, independent of its underlying etiology, with potential therapeutic implications. (Less)
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author
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organization
publishing date
type
Contribution to journal
publication status
epub
subject
in
Angewandte Chemie International Edition
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:105017861940
ISSN
1521-3773
DOI
10.1002/anie.202509875
language
English
LU publication?
yes
id
775ea54b-978c-4371-aaaf-8cc9d0aab454
date added to LUP
2025-09-26 12:45:09
date last changed
2025-10-25 04:01:05
@article{775ea54b-978c-4371-aaaf-8cc9d0aab454,
  abstract     = {{Insulin secretion from vesicles within pancreatic beta cells occurs through the rapid (≤10 ms) process of exocytosis. A crucial final step in this process is the formation of a fusion pore, which connects the insulin vesicle interior to the extracellular space and insulin secretion rate. We employed real-time single-cell amperometry (SCA) with microsensors to quantitatively and dynamically monitor serotonin secretion (used as a proxy for insulin) and alterations in the dynamics of fusion pore formation, including opening, duration, and closing times, during single exocytosis events. Additionally, total internal reflection fluorescence (TIRF) microscopy was used to track docked vesicles and optically measure insulin release. In beta cells from human organ donors with type 2 diabetes (T2D), the fusion pore opening was prematurely aborted, leading to diminished cargo release. Furthermore, the number of docked vesicles per beta cell differed between healthy donors and individuals with T2D. In conclusion, our combined super-sensitive optical and electrochemical analyses from a new perspective highlight a link between defective fusion pore dynamics and reduced insulin secretion (a hallmark of T2D) that has not been previously reported. These findings reveal the role of impaired fusion pore dynamics in T2D, independent of its underlying etiology, with potential therapeutic implications.}},
  author       = {{Hatami, Amir and Gandasi, Nikhil R. and Dou, Haiqiang and Kothegala, Lakshmi and Eliasson, Lena and Ewing, Andrew and Rorsman, Patrik}},
  issn         = {{1521-3773}},
  language     = {{eng}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Angewandte Chemie International Edition}},
  title        = {{Single Fusion Pore Analysis via Single Cell Amperometry Uncovers Impaired Pore Expansion That Restricts Insulin Exocytosis in Human Type 2 Diabetes}},
  url          = {{http://dx.doi.org/10.1002/anie.202509875}},
  doi          = {{10.1002/anie.202509875}},
  year         = {{2025}},
}