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Título
Insulin-degrading enzyme ablation in mouse pancreatic alpha cells triggers cell proliferation, hyperplasia and glucagon secretion dysregulation
Autor
Año del Documento
2022
Editorial
Springer
Descripción
Producción Científica
Documento Fuente
Diabetologia volume 65, 2022, pages 1375–1389
Zusammenfassung
Aims/hypothesis Type 2 diabetes is characterised by hyperglucagonaemia and perturbed function of pancreatic glucagon secreting alpha cells but the molecular mechanisms contributing to these phenotypes are poorly understood. Insulin-degrading
enzyme (IDE) is present within all islet cells, mostly in alpha cells, in both mice and humans. Furthermore, IDE can degrade
glucagon as well as insulin, suggesting that IDE may play an important role in alpha cell function in vivo.
Methods We have generated and characterised a novel mouse model with alpha cell-specific deletion of Ide, the A-IDE-KO
mouse line. Glucose metabolism and glucagon secretion in vivo was characterised; isolated islets were tested for glucagon and
insulin secretion; alpha cell mass, alpha cell proliferation and α-synuclein levels were determined in pancreas sections by
immunostaining.
Results Targeted deletion of Ide exclusively in alpha cells triggers hyperglucagonaemia and alpha cell hyperplasia, resulting in
elevated constitutive glucagon secretion. The hyperglucagonaemia is attributable in part to dysregulation of glucagon secretion,
specifically an impaired ability of IDE-deficient alpha cells to suppress glucagon release in the presence of high glucose or
insulin. IDE deficiency also leads to α-synuclein aggregation in alpha cells, which may contribute to impaired glucagon secretion
via cytoskeletal dysfunction. We showed further that IDE deficiency triggers impairments in cilia formation, inducing alpha cell
hyperplasia and possibly also contributing to dysregulated glucagon secretion and hyperglucagonaemia.
Conclusions/interpretation We propose that loss of IDE function in alpha cells contributes to hyperglucagonaemia in type 2
diabetes
Materias Unesco
32 Ciencias Médicas
Palabras Clave
Alpha cells
Cytoskeleton
Hyperglucagonaemia
Insulin-degrading enzyme
Primary cilia
Proliferation
Type 2 diabetes
ISSN
0012-186X
Revisión por pares
SI
Patrocinador
Ministerio de Economía, Industria y Competitividad (SAF2016-77871-C2-1-R to IC and BFU2016-77125-R to IQ)
Ministerio de Ciencia, Innovación y Universidades (PID2019-110496RB-C21 to IC and PID2019-110496RB-C22 to GP)
La Caixa Foundation (grant LCF/PR/PR18/51130007 to GP)
National Institutes of Health from USA (GM115617)
Publicación en abierto financiada por el Consorcio de Bibliotecas Universitarias de Castilla y León (BUCLE), con cargo al Programa Operativo 2014ES16RFOP009 FEDER 2014-2020 DE CASTILLA Y LEÓN, Actuación:20007-CL - Apoyo Consorcio BUCLE
Ministerio de Ciencia, Innovación y Universidades (PID2019-110496RB-C21 to IC and PID2019-110496RB-C22 to GP)
La Caixa Foundation (grant LCF/PR/PR18/51130007 to GP)
National Institutes of Health from USA (GM115617)
Publicación en abierto financiada por el Consorcio de Bibliotecas Universitarias de Castilla y León (BUCLE), con cargo al Programa Operativo 2014ES16RFOP009 FEDER 2014-2020 DE CASTILLA Y LEÓN, Actuación:20007-CL - Apoyo Consorcio BUCLE
Version del Editor
Propietario de los Derechos
© The Author(s) 2022
Idioma
eng
Tipo de versión
info:eu-repo/semantics/publishedVersion
Derechos
openAccess
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