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Inner ear is a target for insulin signaling and insulin resistance : evidence from mice and auditory HEI-OC1 cells

Pålbrink, Ann-Ki LU ; Kopietz, Franziska LU orcid ; Morén, Björn LU orcid ; In 't Zandt, René LU orcid ; Kalinec, Federico ; Stenkula, Karin LU ; Göransson, Olga LU orcid ; Holm, Cecilia LU ; Magnusson, Måns LU orcid and Degerman, Eva LU orcid (2020) In BMJ open diabetes research & care 8.
Abstract

OBJECTIVE: The mechanisms underlying the association between diabetes and inner ear dysfunction are not known yet. The aim of the present study is to evaluate the impact of obesity/insulin resistance on inner ear fluid homeostasis in vivo, and to investigate whether the organ of Corti could be a target tissue for insulin signaling using auditory House Ear Institute-Organ of Corti 1 (HEI-OC1) cells as an in vitro model.

METHODS: High fat diet (HFD) fed C57BL/6J mice were used as a model to study the impact of insulin resistance on the inner ear. In one study, 12 C57BL/6J mice were fed either control diet or HFD and the size of the inner ear endolymphatic fluid compartment (EFC) was measured after 30 days using MRI and gadolinium... (More)

OBJECTIVE: The mechanisms underlying the association between diabetes and inner ear dysfunction are not known yet. The aim of the present study is to evaluate the impact of obesity/insulin resistance on inner ear fluid homeostasis in vivo, and to investigate whether the organ of Corti could be a target tissue for insulin signaling using auditory House Ear Institute-Organ of Corti 1 (HEI-OC1) cells as an in vitro model.

METHODS: High fat diet (HFD) fed C57BL/6J mice were used as a model to study the impact of insulin resistance on the inner ear. In one study, 12 C57BL/6J mice were fed either control diet or HFD and the size of the inner ear endolymphatic fluid compartment (EFC) was measured after 30 days using MRI and gadolinium contrast as a read-out. In another study, the size of the inner ear EFC was evaluated in eight C57BL/6J mice both before and after HFD feeding, with the same techniques. HEI-OC1 auditory cells were used as a model to investigate insulin signaling in organ of Corti cells.

RESULTS: HFD feeding induced an expansion of the EFC in C57BL/6J mice, a hallmark of inner ear dysfunction. Insulin also induced phosphorylation of protein kinase B (PKB/Akt) at Ser473, in a PI3-kinase-dependent manner. The phosphorylation of PKB was inhibited by isoproterenol and IBMX, a general phosphodiesterase (PDE) inhibitor. PDE1B, PDE4D and the insulin-sensitive PDE3B were found expressed and catalytically active in HEI-OC1 cells. Insulin decreased and AICAR, an activator of AMP-activated protein kinase, increased the phosphorylation at the inhibitory Ser79 of acetyl-CoA carboxylase, the rate-limiting enzyme in de novo lipogenesis. Furthermore, the activity of hormone-sensitive lipase, the rate-limiting enzyme in lipolysis, was detected in HEI-OC1 cells.

CONCLUSIONS: The organ of Corti could be a target tissue for insulin action, and inner ear insulin resistance might contribute to the association between diabetes and inner ear dysfunction.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
BMJ open diabetes research & care
volume
8
article number
e000820
publisher
BMJ Publishing Group
external identifiers
  • pmid:32238362
  • scopus:85082896846
ISSN
2052-4897
DOI
10.1136/bmjdrc-2019-000820
project
The inner ear as a target organ for insulin action and resistance
language
English
LU publication?
yes
additional info
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
id
2691d57a-52ca-4778-9e3e-63969bd81110
date added to LUP
2020-04-17 11:31:51
date last changed
2024-05-15 09:20:44
@article{2691d57a-52ca-4778-9e3e-63969bd81110,
  abstract     = {{<p>OBJECTIVE: The mechanisms underlying the association between diabetes and inner ear dysfunction are not known yet. The aim of the present study is to evaluate the impact of obesity/insulin resistance on inner ear fluid homeostasis in vivo, and to investigate whether the organ of Corti could be a target tissue for insulin signaling using auditory House Ear Institute-Organ of Corti 1 (HEI-OC1) cells as an in vitro model.</p><p>METHODS: High fat diet (HFD) fed C57BL/6J mice were used as a model to study the impact of insulin resistance on the inner ear. In one study, 12 C57BL/6J mice were fed either control diet or HFD and the size of the inner ear endolymphatic fluid compartment (EFC) was measured after 30 days using MRI and gadolinium contrast as a read-out. In another study, the size of the inner ear EFC was evaluated in eight C57BL/6J mice both before and after HFD feeding, with the same techniques. HEI-OC1 auditory cells were used as a model to investigate insulin signaling in organ of Corti cells.</p><p>RESULTS: HFD feeding induced an expansion of the EFC in C57BL/6J mice, a hallmark of inner ear dysfunction. Insulin also induced phosphorylation of protein kinase B (PKB/Akt) at Ser473, in a PI3-kinase-dependent manner. The phosphorylation of PKB was inhibited by isoproterenol and IBMX, a general phosphodiesterase (PDE) inhibitor. PDE1B, PDE4D and the insulin-sensitive PDE3B were found expressed and catalytically active in HEI-OC1 cells. Insulin decreased and AICAR, an activator of AMP-activated protein kinase, increased the phosphorylation at the inhibitory Ser79 of acetyl-CoA carboxylase, the rate-limiting enzyme in de novo lipogenesis. Furthermore, the activity of hormone-sensitive lipase, the rate-limiting enzyme in lipolysis, was detected in HEI-OC1 cells.</p><p>CONCLUSIONS: The organ of Corti could be a target tissue for insulin action, and inner ear insulin resistance might contribute to the association between diabetes and inner ear dysfunction.</p>}},
  author       = {{Pålbrink, Ann-Ki and Kopietz, Franziska and Morén, Björn and In 't Zandt, René and Kalinec, Federico and Stenkula, Karin and Göransson, Olga and Holm, Cecilia and Magnusson, Måns and Degerman, Eva}},
  issn         = {{2052-4897}},
  language     = {{eng}},
  month        = {{03}},
  publisher    = {{BMJ Publishing Group}},
  series       = {{BMJ open diabetes research & care}},
  title        = {{Inner ear is a target for insulin signaling and insulin resistance : evidence from mice and auditory HEI-OC1 cells}},
  url          = {{http://dx.doi.org/10.1136/bmjdrc-2019-000820}},
  doi          = {{10.1136/bmjdrc-2019-000820}},
  volume       = {{8}},
  year         = {{2020}},
}