Primary cilia control glucose homeostasis via islet paracrine interactions

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 16; pp. 8912 - 8923
• Main Authors: Hughes, Jing W., Cho, Jung Hoon, Conway, Hannah E., DiGruccio, Michael R., Ng, Xue Wen, Roseman, Henry F., Abreu, Damien, Urano, Fumihiko, Piston, David W.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 21.04.2020
• Subjects: Animals; Beta cells; Biological Sciences; Calcium - metabolism; Calcium influx; Cell Communication - physiology; Cellular structure; Chemoreception; Cilia; Cilia - genetics; Cilia - metabolism; Cilia - pathology; Clonal deletion; Crosstalk; Diabetes; Diabetes mellitus; Diabetes Mellitus - genetics; Diabetes Mellitus - pathology; Disease Models, Animal; Energy Metabolism - physiology; Female; Glucagon-Secreting Cells - metabolism; Glucose; Glucose - metabolism; Homeostasis; Humans; Insulin; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Male; Mice; Mice, Knockout; Pancreas; Paracrine signalling; Perturbation; Secretion; Signal Transduction - physiology
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2001936117

Pancreatic islets regulate glucose homeostasis through coordinated actions of hormone-secreting cells. What underlies the function of the islet as a unit is the close approximation and communication among heterogeneous cell populations, but the structural mediators of islet cellular cross talk remain incompletely characterized. We generated mice specifically lacking β-cell primary cilia, a cellular organelle that has been implicated in regulating insulin secretion, and found that the β-cell cilia are required for glucose sensing, calcium influx, insulin secretion, and cross regulation of α- and δ-cells. Protein expression profiling in islets confirms perturbation in these cellular processes and reveals additional targets of cilia-dependent signaling. At the organism level, the deletion of β-cell cilia disrupts circulating hormone levels, impairs glucose homeostasis and fuel usage, and leads to the development of diabetes. Together, these findings demonstrate that primary cilia not only orchestrate β-cell–intrinsic activity but also mediate cross talk both within the islet and from islets to other metabolic tissues, thus providing a unique role of cilia in nutrient metabolism and insight into the pathophysiology of diabetes.