Primary cilia control glucose homeostasis via islet paracrine interactions

Abstract

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.

Primary Cilia and Calcium Signaling Interactions

“…β-cells control insulin secretion through a wide variety of interacting factors including the aforementioned autocrine and paracrine signaling, as well as cell–cell communication and neuronal, cellular, and vascular regulation [ 117 ]. β-cells contain primary cilia which regulate these processes though several different pathways; Ca 2+ signaling mainly occurs in the autocrine insulin secretion pathway and will therefore be the focus of this section [ 117 , 118 ]. Because primary cilia regulate insulin secretion, a high incidence of diabetes is observed in certain ciliopathies, such as Bardet–Biedl and Alström syndromes [ 118 ].…”

“…β-cells contain primary cilia which regulate these processes though several different pathways; Ca 2+ signaling mainly occurs in the autocrine insulin secretion pathway and will therefore be the focus of this section [ 117 , 118 ]. Because primary cilia regulate insulin secretion, a high incidence of diabetes is observed in certain ciliopathies, such as Bardet–Biedl and Alström syndromes [ 118 ].…”

“…The sequence of insulin secretion occurs as follows; an initial influx of Ca 2+ triggers the first-phase insulin secretion, then a period of continuous Ca 2+ oscillations triggers the second-phase insulin secretion [ 119 , 120 ]. Experiments done in mice with cilia-less β-cells (βCKO) show a complete failure of this sequence due to a loss of normal islet Ca 2+ dynamics [ 118 ]. The cascading Ca 2+ currents typically observed after glucose stimulation were abolished in the cilia-less βCKO line, leading to impaired insulin secretion, which established that glucose-mediated Ca 2+ oscillations are cilia-dependent [ 118 ].…”

“…Experiments done in mice with cilia-less β-cells (βCKO) show a complete failure of this sequence due to a loss of normal islet Ca 2+ dynamics [ 118 ]. The cascading Ca 2+ currents typically observed after glucose stimulation were abolished in the cilia-less βCKO line, leading to impaired insulin secretion, which established that glucose-mediated Ca 2+ oscillations are cilia-dependent [ 118 ]. While the exact mechanism of Ca 2+ regulation by β-cell primary cilium is unclear, the existence of Ca 2+ channels on the ciliary membrane, as well as the Ca 2+ -fluxes serving as moderators of cytosolic Ca 2+ levels are strong evidence of its vital role in glucose-mediated insulin secretion [ 11 , 42 , 121 ].…”

Differential effects of voclosporin and tacrolimus on insulin secretion from human islets

“…Indeed, TAC significantly inhibited CREM, a member of the CREB family of transcription factors known as master regulators of b-cell function(53). Previous studies in a b-cell line have shown that TAC inhibits CREB transcriptional activity(54). B9D1 contributes to the biogenesis of the primary cilium, which is required for normal insulin secretion(55).…”