Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

The highly expressed calcium-insensitive synaptotagmin-11 and synaptotagmin-13 modulate insulin secretion

Ofori, Jones K LU ; Karagiannopoulos, Alexandros LU orcid ; Barghouth, Mohammad LU ; Nagao, Mototsugu LU ; Andersson, Markus E LU ; Salunkhe, Vishal A LU ; Zhang, Enming LU ; Wendt, Anna LU and Eliasson, Lena LU orcid (2022) In Acta Physiologica 236(1).
Abstract

AIM: SYT11 and SYT13, two calcium-insensitive synaptotagmins, are downregulated in islets from type-2 diabetic donors, but their function in insulin secretion is unknown. To address this, we investigated the physiological role of these two synaptotagmins in insulin secreting cells.

METHODS: Correlations between gene expression levels were performed using previously described RNA-seq data on islets from 188 human donors. SiRNA knockdown was performed in EndoC-βH1 and INS-1 832/13 cells. Insulin secretion was measured with ELISA. Patch clamp was used for single cell electrophysiology. Confocal microscopy was used to determine intra-cellular localization.

RESULTS: Human islet expression of the transcription factor PDX-1 was... (More)

AIM: SYT11 and SYT13, two calcium-insensitive synaptotagmins, are downregulated in islets from type-2 diabetic donors, but their function in insulin secretion is unknown. To address this, we investigated the physiological role of these two synaptotagmins in insulin secreting cells.

METHODS: Correlations between gene expression levels were performed using previously described RNA-seq data on islets from 188 human donors. SiRNA knockdown was performed in EndoC-βH1 and INS-1 832/13 cells. Insulin secretion was measured with ELISA. Patch clamp was used for single cell electrophysiology. Confocal microscopy was used to determine intra-cellular localization.

RESULTS: Human islet expression of the transcription factor PDX-1 was positively correlated with SYT11 (p = 2.4e
-10 ) and SYT13 (p<2.2 e
-16 ). Syt11 and Syt13 both co-localized with insulin, indicating their localization in insulin granules. Downregulation of Syt11 in INS-1 832/13 cells (siSYT11) resulted in increased basal and glucose-induced insulin secretion. Downregulation of Syt13 (siSYT13) decreased insulin secretion induced by glucose and K
+ .Interestingly, the cAMP raising agent forskolin was unable to enhance insulin secretion in siSYT13 cells. There was no difference in insulin content, exocytosis, or voltage-gated Ca
2+ currents in the two models. Double knockdown of Syt11 and Syt13 (DKD) resembled the results in siSYT13 cells.

CONCLUSION: SYT11 and SYT13 have similar localization and transcriptional regulation but they regulate insulin secretion differentially. While downregulation of SYT11 might be a compensatory mechanism in type-2 diabetes, downregulation of SYT13 reduces the insulin secretory response and overrules the compensatory regulation of SYT11 in a way that could aggravate the disease.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Acta Physiologica
volume
236
issue
1
publisher
Wiley-Blackwell
external identifiers
  • scopus:85133212893
  • pmid:35753051
ISSN
1748-1716
DOI
10.1111/apha.13857
language
English
LU publication?
yes
additional info
This article is protected by copyright. All rights reserved.
id
c125c0fd-2ca7-4ef5-8812-8855717dacbf
date added to LUP
2022-06-28 21:02:58
date last changed
2024-06-13 13:45:44
@article{c125c0fd-2ca7-4ef5-8812-8855717dacbf,
  abstract     = {{<p>AIM: SYT11 and SYT13, two calcium-insensitive synaptotagmins, are downregulated in islets from type-2 diabetic donors, but their function in insulin secretion is unknown. To address this, we investigated the physiological role of these two synaptotagmins in insulin secreting cells.</p><p>METHODS: Correlations between gene expression levels were performed using previously described RNA-seq data on islets from 188 human donors. SiRNA knockdown was performed in EndoC-βH1 and INS-1 832/13 cells. Insulin secretion was measured with ELISA. Patch clamp was used for single cell electrophysiology. Confocal microscopy was used to determine intra-cellular localization.</p><p>RESULTS: Human islet expression of the transcription factor PDX-1 was positively correlated with SYT11 (p = 2.4e<br>
 -10 ) and SYT13 (p&lt;2.2 e<br>
 -16 ). Syt11 and Syt13 both co-localized with insulin, indicating their localization in insulin granules. Downregulation of Syt11 in INS-1 832/13 cells (siSYT11) resulted in increased basal and glucose-induced insulin secretion. Downregulation of Syt13 (siSYT13) decreased insulin secretion induced by glucose and K<br>
 + .Interestingly, the cAMP raising agent forskolin was unable to enhance insulin secretion in siSYT13 cells. There was no difference in insulin content, exocytosis, or voltage-gated Ca<br>
 2+ currents in the two models. Double knockdown of Syt11 and Syt13 (DKD) resembled the results in siSYT13 cells.<br>
 </p><p>CONCLUSION: SYT11 and SYT13 have similar localization and transcriptional regulation but they regulate insulin secretion differentially. While downregulation of SYT11 might be a compensatory mechanism in type-2 diabetes, downregulation of SYT13 reduces the insulin secretory response and overrules the compensatory regulation of SYT11 in a way that could aggravate the disease.</p>}},
  author       = {{Ofori, Jones K and Karagiannopoulos, Alexandros and Barghouth, Mohammad and Nagao, Mototsugu and Andersson, Markus E and Salunkhe, Vishal A and Zhang, Enming and Wendt, Anna and Eliasson, Lena}},
  issn         = {{1748-1716}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{Acta Physiologica}},
  title        = {{The highly expressed calcium-insensitive synaptotagmin-11 and synaptotagmin-13 modulate insulin secretion}},
  url          = {{http://dx.doi.org/10.1111/apha.13857}},
  doi          = {{10.1111/apha.13857}},
  volume       = {{236}},
  year         = {{2022}},
}