Glucagon secretion requires IDE cilium axis

Hyglucagonemia is a hallmark of diabetes caused by dysregulation of glucagon secretion by pancreatic alpha-cells. Although glucose sensing and insulin signaling are well-established regulators, the pathways governing glucagon secretion are not fully understood. Recent evidences suggest that insulin-degrading enzyme (IDE) regulates glucagon secretion through an unknown pathway. We aimed to ascertain the molecular mechanisms downstream of IDE, directing our efforts toward the relationship between IDE and the primary cilium. IDE was not localized to primary cilium of alpha-cells, but IDE deficiency resulted in impaired ciliogenesis. Consistent with lower levels of the insulin receptor (IR), the counterregulatory effect of insulin on glucagon secretion was reduced in IDE-deficient alpha-cells. Two cellular models of ciliary dysfunction (ARL13B-KD and IFT88-KD) resulted in impaired glucagon secretion, as well as a failure of insulin to suppress glucagon secretion in alpha-cells. Importantly, IDE, ciliary markers (AcTubulin, ARL13B) and IR levels were diminished in conditions of physiological glucagon repression. In conclusion, IDE is a mechanistic link between glucose levels and the primary cilium, which regulates glucagon secretion in alpha-cells.