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Diabetes mellitus affects one in eleven adults worldwide. Most suffer from Type 2 Diabetes mellituswhich features elevated blood glucose levels, an inability to adequately respond to insulin and poor insulin secretion. Insulin producing β-cells have primary cilia and these have recently been implicated in the regulation of glucose metabolism, insulin signaling and islet integrity although their exact role is not clear. To investigate this role, we generated a β-cell-specific, inducible, cilia-less mouse by deleting a key cilia component, Ift88. After β-cell cilia were ablated glucose homeostasis and insulin secretion deteriorated leading to severe glucose intolerance over the course of twelve weeks. We screened 27 receptor protein-tyrosine kinases and found that EphA3 receptor was hyper-phosphorylated in islets from two different mouse models of ciliary dysfunction. Manipulating EphA/EphrinA signaling revealed that EphA hyper-phosphorylation blocks insulin secretion in a β-cell line and primary islets depleted of Ift88.
EphA3 internalization is blocked by altered actin dynamics linked to epithelial-mesenchymal transition. Defects in 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.In conclusion, β-cell primary cilia play a novel role in actin remodeling and endocytosis.