The browser you are using is not supported by this website. All versions of Internet Explorer are no longer supported, either by us or Microsoft (read more here: https://www.microsoft.com/en-us/microsoft-365/windows/end-of-ie-support).

Please use a modern browser to fully experience our website, such as the newest versions of Edge, Chrome, Firefox or Safari etc.

Eva Degerman

Eva Degerman

Professor

Eva Degerman

Insulin regulates Nedd4-2 via a PKB-dependent mechanism in HEI-OC1 auditory cells-crosstalks with sphingolipid and cAMP signaling

Author

  • Ann-Ki Pålbrink
  • Björn Morén
  • Karin G Stenkula
  • Måns Magnusson
  • Eva Degerman

Summary, in English

BACKGROUND: The mechanisms of association between diabetes and inner ear dysfunction are unknown, although endolymphatic hydrops may be involved. We have previously shown that insulin signaling components are expressed in human saccule and that insulin signaling takes place in HEI-OC1 auditory cells.

AIM: To explore Nedd4-2 as a target for insulin signaling.

MATERIALS AND METHODS: Effects of insulin were analyzed using western blot and confocal microscopy in HEI-OC1 auditory cells.

RESULTS: Insulin induced phosphorylation of Nedd4-2 and increased the amount of ENaC at the plasma membrane. Also, protein kinase B (PKB) and NDRG1, a substrate for SGK1 (serum and glucocorticoid stimulated kinase), were phosphorylated in response to insulin. The SGK1 inhibitor GSK650394 prevented insulin-induced phosphorylation of NRDG1, but not of PKB and Nedd4-2, whereas the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin and the PKB inhibitor MK2206 inhibited phosphorylation of all components. Ceramides prevented insulin-induced phosphorylation of PKB and NDRG1, but not of Nedd4-2. The ceramide metabolite sphingosine 1-phosphate induced phosphorylation of Nedd4-2.

CONCLUSIONS: Insulin induces phosphorylation of Nedd4-2, most likely involving PI3K/PKB signaling. Sphingosine 1-phosphate might protect Nedd4-2 against ceramide-induced insulin resistance.

SIGNIFICANCE: Insulin-mediated regulation of Nedd4-2 might impact on inner ear sodium homeostasis with implications for diabetes-induced inner ear damage.

Department/s

  • Insulin Signal Transduction
  • EXODIAB: Excellence of Diabetes Research in Sweden
  • Glucose Transport and Protein Trafficking
  • Otorhinolaryngology (Lund)

Publishing year

2022

Language

English

Pages

6-12

Publication/Series

Acta Oto-Laryngologica

Volume

142

Issue

1

Document type

Journal article

Publisher

Taylor & Francis

Topic

  • Endocrinology and Diabetes
  • Cell and Molecular Biology

Status

Published

Research group

  • Insulin Signal Transduction
  • Glucose Transport and Protein Trafficking
  • LUDC (Lund University Diabetes Centre)

ISBN/ISSN/Other

  • ISSN: 1651-2251