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

Francesco Volta, M. Julia Scerbo, Anett Seelig, Robert Wagner, Nils O’Brien, Felicia Gerst, Andreas Fritsche, Hans-Ulrich Häring, Anja Zeigerer, Susanne Ullrich and Jantje M. Gerdes ()
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Francesco Volta: Institute for Diabetes and Regeneration Research, Helmholtz Zentrum München
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
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
Andreas Fritsche: Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, University Hospital of Tübingen
Hans-Ulrich Häring: Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, University Hospital of Tübingen
Anja Zeigerer: Deutsches Zentrum für Diabetesforschung, DZD
Susanne Ullrich: Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, University Hospital of Tübingen
Jantje M. Gerdes: Institute for Diabetes and Regeneration Research, Helmholtz Zentrum München

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12953-5

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