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In vivo dysregulation of insulin and glucagon secretion : Disturbed mitochonderial VDAC1 expression and localization in pancreatic β-cells convey global insulin secretory defects in diabetic GK rat

Salehi, Albert LU orcid ; Mohammed Al-Amily, Israa LU ; Parandeh, Fariborz LU ; Östenson, Claes Göran and Lundquist, Ingmar LU (2026) In Biochimica et Biophysica Acta - Molecular Basis of Disease 1872(8).
Abstract

The mildly diabetic Goto-Kakizaki (GK) rat is widely used to study type 2 diabetes (T2D), yet the mechanisms underlying defective insulin secretion in this model remain incompletely understood. We therefore investigated the effects of multiple secretagogues on insulin and glucagon secretion as well as on blood glucose in vivo, followed by mechanistic studies assessing insulin secretion, ATP content and mitochondrial VDAC1/VDAC2 expression in isolated islets from young and aged GK rats. The in vivo study revealed severely impaired insulin responses to various secretagogues in GK rats resulting in lack of suppressive effect on glucagon release and elevated blood glucose as compared to Wistar rats. The in vitro experiments showed that... (More)

The mildly diabetic Goto-Kakizaki (GK) rat is widely used to study type 2 diabetes (T2D), yet the mechanisms underlying defective insulin secretion in this model remain incompletely understood. We therefore investigated the effects of multiple secretagogues on insulin and glucagon secretion as well as on blood glucose in vivo, followed by mechanistic studies assessing insulin secretion, ATP content and mitochondrial VDAC1/VDAC2 expression in isolated islets from young and aged GK rats. The in vivo study revealed severely impaired insulin responses to various secretagogues in GK rats resulting in lack of suppressive effect on glucagon release and elevated blood glucose as compared to Wistar rats. The in vitro experiments showed that isolated islets from GK rats exhibited defective insulin secretion, which further deteriorated with age. This was associated with reduced VDAC2 expression at young age followed by increased VDAC1 expression, along with aberrant mistargeting of VDAC1 to the β-cell plasma membrane, leading to ATP loss and further diminished glucose-stimulated insulin secretion at old age. Pharmacological inhibition or antibody targeting of VDAC1 restored insulin secretion. Complementary studies in INS-1832/13 cells showed the chronic hyperglycemia increases VDAC1 expression and reduces cell viability, effects counteracted by activation of the cAMP/PKA pathway. These findings identify dysregulated VDAC1/VDAC2 expression and VDAC1 mistargeting to cell surface as key contributors to β-cell dysfunction in GK rats, particularly with aging, and suggest VDAC1 as a potential therapeutic target in early-stage of T2D.

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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Glucose-stimulated insulin secretion, Goto-Kakizaki rat, Mitochondria, Pancreatic islets, Type 2 diabetes, VDAC1, VDAC2
in
Biochimica et Biophysica Acta - Molecular Basis of Disease
volume
1872
issue
8
article number
168358
publisher
Elsevier
external identifiers
  • pmid:42402267
  • scopus:105044261052
ISSN
0925-4439
DOI
10.1016/j.bbadis.2026.168358
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2026 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license. http://creativecommons.org/licenses/by/4.0/
id
2985409e-b61a-465b-8943-7ec80dda2fe7
date added to LUP
2026-09-14 15:36:29
date last changed
2026-09-14 15:36:51
@article{2985409e-b61a-465b-8943-7ec80dda2fe7,
  abstract     = {{<p>The mildly diabetic Goto-Kakizaki (GK) rat is widely used to study type 2 diabetes (T2D), yet the mechanisms underlying defective insulin secretion in this model remain incompletely understood. We therefore investigated the effects of multiple secretagogues on insulin and glucagon secretion as well as on blood glucose in vivo, followed by mechanistic studies assessing insulin secretion, ATP content and mitochondrial VDAC1/VDAC2 expression in isolated islets from young and aged GK rats. The in vivo study revealed severely impaired insulin responses to various secretagogues in GK rats resulting in lack of suppressive effect on glucagon release and elevated blood glucose as compared to Wistar rats. The in vitro experiments showed that isolated islets from GK rats exhibited defective insulin secretion, which further deteriorated with age. This was associated with reduced VDAC2 expression at young age followed by increased VDAC1 expression, along with aberrant mistargeting of VDAC1 to the β-cell plasma membrane, leading to ATP loss and further diminished glucose-stimulated insulin secretion at old age. Pharmacological inhibition or antibody targeting of VDAC1 restored insulin secretion. Complementary studies in INS-1832/13 cells showed the chronic hyperglycemia increases VDAC1 expression and reduces cell viability, effects counteracted by activation of the cAMP/PKA pathway. These findings identify dysregulated VDAC1/VDAC2 expression and VDAC1 mistargeting to cell surface as key contributors to β-cell dysfunction in GK rats, particularly with aging, and suggest VDAC1 as a potential therapeutic target in early-stage of T2D.</p>}},
  author       = {{Salehi, Albert and Mohammed Al-Amily, Israa and Parandeh, Fariborz and Östenson, Claes Göran and Lundquist, Ingmar}},
  issn         = {{0925-4439}},
  keywords     = {{Glucose-stimulated insulin secretion; Goto-Kakizaki rat; Mitochondria; Pancreatic islets; Type 2 diabetes; VDAC1; VDAC2}},
  language     = {{eng}},
  number       = {{8}},
  publisher    = {{Elsevier}},
  series       = {{Biochimica et Biophysica Acta - Molecular Basis of Disease}},
  title        = {{In vivo dysregulation of insulin and glucagon secretion : Disturbed mitochonderial VDAC1 expression and localization in pancreatic β-cells convey global insulin secretory defects in diabetic GK rat}},
  url          = {{http://dx.doi.org/10.1016/j.bbadis.2026.168358}},
  doi          = {{10.1016/j.bbadis.2026.168358}},
  volume       = {{1872}},
  year         = {{2026}},
}