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Glucagon secretion by pancreatic alpha-cells requires an intact tubulin-cytoskeleton-primary cilium axis.
Mol. Med. 32:35 (2026)
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 the molecular mechanisms downstream of IDE in the alpha-TC cell model. Knock-down studies of relevant genes involved in the functional pathways identified in the proteomic study, and its impact on glucagon secretion were performed. Primary cilium was stained and detected using confocal and STORM microscopies in alpha-TC cells and mouse pancreas. Results Based on proteomic studies we focus our efforts on the relationship between IDE, tubulin cytoskeleton, and the primary cilium. Although IDE was not localized to the primary cilium of alpha-cells using confocal microscopy and STORM, its absence resulted in impaired ciliogenesis. Consistent with lower protein levels of the insulin receptor, 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, tubulin, ciliary markers (AcTubulin, ARL13B) and insulin receptor levels were diminished in glucose conditions of physiological glucagon repression. Conclusions IDE acts as a mechanistic link between glucose levels, tubulin, and the primary cilium, regulating glucagon secretion in alpha-cells. The dysregulation of the tubulin-primary cilium axis induces glucagon secretion impairment.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Diabetes Mellitus ; Endocrine Pancreas ; Glucagon ; Insulin-degrading Enzyme ; Pancreatic Alpha-cell ; Primary Cilium ; Tubulin; Glucose-homeostasis; Insulin; Transport
ISSN (print) / ISBN
1076-1551
e-ISSN
1435-8123
Journal
Molecular Medicine
Quellenangaben
Volume: 32,
Issue: 1,
Article Number: 35
Publisher
Springer
Publishing Place
One New York Plaza, Suite 4600, New York, Ny, United States
Reviewing status
Peer reviewed
Institute(s)
Institute of Diabetes Research (IDF)
Grants
Juvenile Diabetes Research Foundation International
Agencia Estatal de Investigacin
Junta de Castilla y Len
Agencia Estatal de Investigacin
Junta de Castilla y Len