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Glucose homeostasis is regulated by pancreatic β-cell cilia via endosomal EphA-processing

Author

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  • Francesco Volta

    (Institute for Diabetes and Regeneration Research, Helmholtz Zentrum München
    Technical University of Munich, Medical Faculty)

  • M. Julia Scerbo

    (Institute for Diabetes and Regeneration Research, Helmholtz Zentrum München)

  • Anett Seelig

    (Institute for Diabetes and Regeneration Research, Helmholtz Zentrum München)

  • Robert Wagner

    (Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, University Hospital of Tübingen
    Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (IDM)
    Deutsches Zentrum für Diabetesforschung, DZD)

  • Nils O’Brien

    (Institute for Diabetes and Regeneration Research, Helmholtz Zentrum München)

  • Felicia Gerst

    (Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, University Hospital of Tübingen
    Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (IDM)
    Deutsches Zentrum für Diabetesforschung, DZD)

  • Andreas Fritsche

    (Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, University Hospital of Tübingen
    Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (IDM)
    Deutsches Zentrum für Diabetesforschung, DZD)

  • Hans-Ulrich Häring

    (Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, University Hospital of Tübingen
    Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (IDM)
    Deutsches Zentrum für Diabetesforschung, DZD)

  • Anja Zeigerer

    (Deutsches Zentrum für Diabetesforschung, DZD
    Institute for Diabetes and Cancer, Helmholtz Zentrum München)

  • Susanne Ullrich

    (Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, University Hospital of Tübingen
    Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (IDM)
    Deutsches Zentrum für Diabetesforschung, DZD)

  • Jantje M. Gerdes

    (Institute for Diabetes and Regeneration Research, Helmholtz Zentrum München
    Deutsches Zentrum für Diabetesforschung, DZD)

Abstract

Diabetes mellitus affects one in eleven adults worldwide. Most suffer from Type 2 Diabetes which features elevated blood glucose levels and an inability to adequately secrete or respond to insulin. Insulin producing β-cells have primary cilia which are implicated in the regulation of glucose metabolism, insulin signaling and secretion. To better understand how β-cell cilia affect glucose handling, we ablate cilia from mature β-cells by deleting key cilia component Ift88. Here we report that glucose homeostasis and insulin secretion deteriorate over 12 weeks post-induction. Cilia/basal body components are required to suppress spontaneous auto-activation of EphA3 and hyper-phosphorylation of EphA receptors inhibits insulin secretion. In β-cells, loss of cilia/basal body function leads to polarity defects and epithelial-to-mesenchymal transition. Defective insulin secretion from IFT88-depleted human islets and elevated pEPHA3 in islets from diabetic donors both point to a role for cilia/basal body proteins in human glucose homeostasis.

Suggested Citation

  • Francesco Volta & M. Julia Scerbo & Anett Seelig & Robert Wagner & Nils O’Brien & Felicia Gerst & Andreas Fritsche & Hans-Ulrich Häring & Anja Zeigerer & Susanne Ullrich & Jantje M. Gerdes, 2019. "Glucose homeostasis is regulated by pancreatic β-cell cilia via endosomal EphA-processing," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12953-5
    DOI: 10.1038/s41467-019-12953-5
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    Cited by:

    1. Konxhe Kulaj & Alexandra Harger & Michaela Bauer & Özüm S. Caliskan & Tilak Kumar Gupta & Dapi Menglin Chiang & Edward Milbank & Josefine Reber & Angelos Karlas & Petra Kotzbeck & David N. Sailer & Fr, 2023. "Adipocyte-derived extracellular vesicles increase insulin secretion through transport of insulinotropic protein cargo," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Andreas Müller & Nikolai Klena & Song Pang & Leticia Elizabeth Galicia Garcia & Oleksandra Topcheva & Solange Aurrecoechea Duran & Davud Sulaymankhil & Monika Seliskar & Hassan Mziaut & Eyke Schöniger, 2024. "Structure, interaction and nervous connectivity of beta cell primary cilia," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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