Primary cilia regulate GLP-1 signaling in pancreatic beta cells

Melena, I.; Jo, J. H.; Townsend, S.; DiGruccio, S. A.; Dong, X.; Zhu, L.; Campbell, J.; Hughes, J. W.

doi:10.64898/2026.02.22.707280

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bioRxiv · 10.64898/2026.02.22.707280

Primary cilia regulate GLP-1 signaling in pancreatic beta cells

Melena, I.·Jo, J. H.·Townsend, S.·DiGruccio, S. A.·Dong, X.·Zhu, L.·Campbell, J.·Hughes, J. W.

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Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are mainstay therapies for diabetes and obesity, acting in part by enhancing glucose-dependent insulin secretion. While the primary cilium is a known signaling compartment for certain G-protein coupled receptors (GPCRs), its role in the {beta}-cell response to incretins remains undefined. Here, we show that primary cilia are essential for GLP-1R signaling. Loss of {beta}-cell cilia in mouse and human islets severely impaired GLP-1-potentiated insulin secretion, an effect preceded by blunted whole-cell cAMP and Ca{superscript 2} responses. Immunofluorescence and immunogold scanning electron microscopy revealed endogenous GLP-1R localized to the primary cilium. Critically, disrupting ciliary GPCR trafficking via Tulp3 knockdown - while preserving cilia structure - recapitulated the signaling and secretory deficits, demonstrating a specific requirement for the ciliary receptor pool. These findings establish the primary cilium as a non-redundant signaling compartment for GLP-1R and uncover a new layer of subcellular organization in incretin action in {beta} cells.

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Melena, I., Jo, J. H., Townsend, S., DiGruccio, S. A., Dong, X., Zhu, L., Campbell, J., Hughes, J. W.. 2026-02-22. Primary cilia regulate GLP-1 signaling in pancreatic beta cells. https://doi.org/10.64898/2026.02.22.707280

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