Modulation of the sodium-chloride cotransporter by insulin in auditory cells : A potential link to diabetes-related hearing complications
Pålbrink, Ann Ki LU ; Magnusson, Måns LU
and Degerman, Eva
LU
(2025)
In Journal of Diabetes and its Complications
39(9).
- Abstract
Aim: While diabetes mellitus (types 1 and 2) is known to negatively impact vestibular and auditory function, the precise mechanisms underlying this effect are not fully understood. Building on our previous findings, which demonstrated the presence of insulin signaling components within the human saccule and identified the sodium transporter ENaC as a target for insulin signaling in HEI-OC1 auditory cells, this study aimed to investigate the role of the sodium-chloride cotransporter (NCC) in insulin signaling and to identify the upstream signaling pathways involved. Methods: We utilized a combination of kinase inhibitors, ceramide treatments, and western blot analysis to evaluate the effects of insulin and induced insulin resistance on... (More)
Aim: While diabetes mellitus (types 1 and 2) is known to negatively impact vestibular and auditory function, the precise mechanisms underlying this effect are not fully understood. Building on our previous findings, which demonstrated the presence of insulin signaling components within the human saccule and identified the sodium transporter ENaC as a target for insulin signaling in HEI-OC1 auditory cells, this study aimed to investigate the role of the sodium-chloride cotransporter (NCC) in insulin signaling and to identify the upstream signaling pathways involved. Methods: We utilized a combination of kinase inhibitors, ceramide treatments, and western blot analysis to evaluate the effects of insulin and induced insulin resistance on NCC phosphorylation and the related upstream signaling pathways in HEI-OC1 cells. Results: Insulin treatment resulted in a dose-dependent increase in NCC phosphorylation. This phosphorylation was significantly attenuated by the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin, the protein kinase B (PKB) inhibitor MK2206, the protein kinase A (PKA) inhibitor H89, and ceramide. Conversely, the serum/glucocorticoid regulated kinase 1 (SGK1) inhibitor GSK650394 did not affect insulin-induced NCC phosphorylation, although it did block insulin-induced phosphorylation of the SGK1 substrate, NDRG1. Furthermore, WNK1 (With-No-Lysine Kinase 1), a proposed downstream target of PKB and a regulator of NCC, also exhibited insulin-induced phosphorylation, dependent on PI3K, PKB, PKA, and ceramide. Conclusions: These findings indicate that insulin promotes NCC phosphorylation, likely through the PI3K/PKB/WNK1 signaling pathway, with a possible contribution from cAMP/PKA signaling. This suggests that insulin-mediated NCC phosphorylation may influence inner ear sodium homeostasis. This mechanism could potentially contribute to the inner ear dysfunction observed in diabetes.
(Less)
- author
- Pålbrink, Ann Ki
LU
; Magnusson, Måns
LU
and Degerman, Eva
LU
- organization
- publishing date
- 2025-09
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Auditory HE1-OC1 cells, Endolymph homeostasis, Hearing, Inner ear, Insulin signaling, Sodium-chloride cotransporter
- in
- Journal of Diabetes and its Complications
- volume
- 39
- issue
- 9
- article number
- 109111
- publisher
- Elsevier
- external identifiers
-
- pmid:40561788
- scopus:105008769042
- ISSN
- 1056-8727
- DOI
- 10.1016/j.jdiacomp.2025.109111
- language
- English
- LU publication?
- yes
- additional info
- Publisher Copyright: © 2025 The Author(s)
- id
- 688d8fc4-4cfb-4839-b13a-f64ff64e72fc
- date added to LUP
- 2025-07-06 14:24:04
- date last changed
- 2025-07-08 03:01:08
@article{688d8fc4-4cfb-4839-b13a-f64ff64e72fc,
abstract = {{<p>Aim: While diabetes mellitus (types 1 and 2) is known to negatively impact vestibular and auditory function, the precise mechanisms underlying this effect are not fully understood. Building on our previous findings, which demonstrated the presence of insulin signaling components within the human saccule and identified the sodium transporter ENaC as a target for insulin signaling in HEI-OC1 auditory cells, this study aimed to investigate the role of the sodium-chloride cotransporter (NCC) in insulin signaling and to identify the upstream signaling pathways involved. Methods: We utilized a combination of kinase inhibitors, ceramide treatments, and western blot analysis to evaluate the effects of insulin and induced insulin resistance on NCC phosphorylation and the related upstream signaling pathways in HEI-OC1 cells. Results: Insulin treatment resulted in a dose-dependent increase in NCC phosphorylation. This phosphorylation was significantly attenuated by the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin, the protein kinase B (PKB) inhibitor MK2206, the protein kinase A (PKA) inhibitor H89, and ceramide. Conversely, the serum/glucocorticoid regulated kinase 1 (SGK1) inhibitor GSK650394 did not affect insulin-induced NCC phosphorylation, although it did block insulin-induced phosphorylation of the SGK1 substrate, NDRG1. Furthermore, WNK1 (With-No-Lysine Kinase 1), a proposed downstream target of PKB and a regulator of NCC, also exhibited insulin-induced phosphorylation, dependent on PI3K, PKB, PKA, and ceramide. Conclusions: These findings indicate that insulin promotes NCC phosphorylation, likely through the PI3K/PKB/WNK1 signaling pathway, with a possible contribution from cAMP/PKA signaling. This suggests that insulin-mediated NCC phosphorylation may influence inner ear sodium homeostasis. This mechanism could potentially contribute to the inner ear dysfunction observed in diabetes.</p>}},
author = {{Pålbrink, Ann Ki and Magnusson, Måns and Degerman, Eva}},
issn = {{1056-8727}},
keywords = {{Auditory HE1-OC1 cells; Endolymph homeostasis; Hearing; Inner ear; Insulin signaling; Sodium-chloride cotransporter}},
language = {{eng}},
number = {{9}},
publisher = {{Elsevier}},
series = {{Journal of Diabetes and its Complications}},
title = {{Modulation of the sodium-chloride cotransporter by insulin in auditory cells : A potential link to diabetes-related hearing complications}},
url = {{http://dx.doi.org/10.1016/j.jdiacomp.2025.109111}},
doi = {{10.1016/j.jdiacomp.2025.109111}},
volume = {{39}},
year = {{2025}},
}