Dataset Information

Glucagon secretion requires IDE cilium axis

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Ciliary Processes

DISEASE(S): Type 2 Diabetes Mellitus

SUBMITTER: Carmen Duran

LAB HEAD: MªCarmen Durán-Ruiz

PROVIDER: PXD065342 | Pride | 2026-03-23

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	Inmunoprecipitado_AlphaTC_Irene_280525.zip	Other
	report_Inmunoprecipitado_AlphaTC_Irene__15cm_MS15_280525.pg_matrix.tsv	Tabular
	report_Inmunoprecipitado_AlphaTC_Irene__15cm_MS15_280525.pr_matrix.tsv	Tabular
	report_Inmunoprecipitado_AlphaTC_Irene__15cm_MS15_280525.stats.tsv	Tabular

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Publications

Glucagon secretion by pancreatic alpha-cells requires an intact tubulin-cytoskeleton-primary cilium axis.

Casanueva-Álvarez Elena E Sanz-González Alba A Vilas Alicia A Cámara-Torres Patricia P Ravier Magalie A MA Eslava-Alcon Sara S Duran-Ruiz M Carmen MC Ramírez Cristina M CM Petropoulou Peristera-Ioanna PI Rodriguez-Calvo Teresa T Merino Beatriz B Perdomo Germán G Cozar-Castellano Irene I

Molecular medicine (Cambridge, Mass.) 20260210 1

BACKGROUND: Hyperglucagonemia is a hallmark of diabetes mellitus, resulting from the dysregulation of glucagon secretion by pancreatic alpha-cells. Although glucose sensing and insulin signaling are well-established regulatory processes, the pathways that govern glucagon secretion remain unclear. Recent evidences suggest that insulin-degrading enzyme (IDE) regulates glucagon secretion via an unknown pathway. METHODS: Using IDE-immunoprecipitation proteomic data as a basis, we aimed to ascertain ...[more]

PMID: 41667949

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Project description:Appropriate glucagon secretion from pancreatic alpha cells in response to hypoglycemia is an important component of maintaining glucose homeostasis. Dysregulated glucagon secretion leads to the delayed recovery from a hypoglycemic attack in type 1 diabetes patients which can be lethal. Although elucidating the precise mechanism of glucagon secretion in hypoglycemia is warranted, the underlying mechanism remains poorly understood.The present study provides evidence of the role of autophagy in glucagon secretion in hypoglycemia by demonstrating that autophagy regulates adrenergic stimulation of glucagon secretion downstream of beta2 adrenergic receptor. First, from the analyses of T1D human islets and the published database of scRNA-seq of T1D human alpha cells, we described autophagy pathways altered in T1D alpha cells. Second, we generated alpha cell-specific Atg7KO mice (alphaAtg7KO) and clarified that the lack of autophagy in alpha cells impairs the reactive glucagon secretion in acute hypoglycemia. Third, to interrogate the molecular mechanism of autophagy-mediated glucagon regulation, we analyzed top genes downregulated inT1D and T2D alpha cells and found the expression of beta2 adrenergic receptor showed significant down-regulation in T1D alpha cells. We confirmed the decreased expression of beta2 adrenergic receptor in alpha cells of the T1D pancreas section, the islets of alphaAtg7KO mice, and a murine alpha cell line with stable knockdown of Atg7. Furthermore, in vivo and ex vivo studies of alphaAtg7KO mice exhibited that lack of autophagy led to the loss of stimulatory effect of beta2-adrenergic signaling on glucagon secretion. Finally, we established the Atg7 knockdown model in sorted human alpha cells and confirmed the effect of autophagy on the expression of the beta2 adrenergic receptor. Together, our study provides novel insights into the regulatory role of autophagy in glucagon secretion in response to hypoglycemia and provides therapeutic options to achieve stable glycemic control in T1D patients.