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Pathophysiology/Complications
Inner ear is a target for insulin signaling and insulin resistance: evidence from mice and auditory HEI-OC1 cells
  1. Ann-Ki Pålbrink1,
  2. Franziska Kopietz1,
  3. Björn Morén1,
  4. René In 't Zandt2,
  5. Federico Kalinec3,
  6. Karin Stenkula1,
  7. Olga Göransson1,
  8. Cecilia Holm1,
  9. Måns Magnusson4,
  10. Eva Degerman1
  1. 1Experimental Medical Science, Section for Diabetes, Metabolism and Endocrinology, Lund University Diabetes Centre, Lund University, Lund, Sweden
  2. 2Lund University Bioimaging Center, Lund University, Lund, Sweden
  3. 3Department of Head and Neck Surgery, Laboratory of Auditory Cell Biology, David Geffen Schoolof Medicin, UCLA, Los Angeles, California, USA
  4. 4Department of Clinical Science, Section for Otorhinolaryngology, Lund University & Skåne University Hospital, Lund, Sweden
  1. Correspondence to Dr Eva Degerman; eva.degerman{at}med.lu.se

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 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.

  • complication(s)
  • ears
  • effects of insulin
  • insulin resistance
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/bmjdrc-2019-000820

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    Footnotes

    • Contributors ED, MM, CH, A-KP conceived the study and designed the experiments. A-KP, FK, BM, RIZ conducted the experiments. A-KP, FK, ED, CH analyzed the data. ED drafted and FK helped to edit the manuscript. All authors interpreted the data, contributed to discussion and critically revised the manuscript and figures. All authors approved the final version of this manuscript. ED is responsible for the integrity of the work as a whole.

    • Funding The work was supported by grants from the Swedish Medical Research Council Dnr 2019-01246, the Swedish Diabetes Foundation, the Swedish Foundation for Strategic Research Dnr IRC 15-0067, the Albert Påhlsson Foundation, Sweden, the Crafoord Foundation, Sweden, Diabetes Wellness Sweden, Skane County Council’s Research and Development Foundation, Sweden and the Faculty of Medicin, Lund University, Sweden. The authors alone are responsible for the content and writing the paper.

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Ethics approval All animal procedures were approved by the Regional Ethical Committee for Animal Experiments in Malmö/Lund.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. To obtain MR raw data contact the corresponding author ED (eva.degerman@med.lu.se) to obtain images as zipped dicoms. All other data relevant for the study are included in the article.