Primary cilia control glucose homeostasis via islet paracrine interactions

Significance The primary cilium is a small subcompartment of the cell but has powerful influence on pancreatic islet function. In this study, we find a critical role for cilia in regulating β-cell function and energy metabolism. Importantly, the deletion of β-cell cilia disrupts intercellular communication and leads to islet dysfunction and diabetes, as seen in a number of human ciliopathy syndromes. These results should help elucidate pathophysiology of human ciliopathy and aid the development of pharmacologic agents targeting primary cilia that may lead to a more effective treatment for human diabetes.
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.