RT info:eu-repo/semantics/article
T1 Insulin-degrading enzyme ablation in mouse pancreatic alpha cells triggers cell proliferation, hyperplasia and glucagon secretion dysregulation
A1 Merino Antolín, Beatriz
A1 Casanueva Álvarez, Elena
A1 Quesada, Iván
A1 González Casimiro, Carlos Manuel
A1 Fernández Díaz, Cristina María
A1 Postigo Casado, Tamara
A1 Leissring, Malcolm A.
A1 Kaestner, Klaus H.
A1 Perdomo Hernández, Germán
A1 Cózar Castellano, Irene
K1 Alpha cells
K1 Cytoskeleton
K1 Hyperglucagonaemia
K1 Insulin-degrading enzyme
K1 Primary cilia
K1 Proliferation
K1 Type 2 diabetes
K1 32 Ciencias Médicas
AB 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-degradingenzyme (IDE) is present within all islet cells, mostly in alpha cells, in both mice and humans. Furthermore, IDE can degradeglucagon 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-KOmouse line. Glucose metabolism and glucagon secretion in vivo was characterised; isolated islets were tested for glucagon andinsulin secretion; alpha cell mass, alpha cell proliferation and α-synuclein levels were determined in pancreas sections byimmunostaining.Results Targeted deletion of Ide exclusively in alpha cells triggers hyperglucagonaemia and alpha cell hyperplasia, resulting inelevated 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 orinsulin. IDE deficiency also leads to α-synuclein aggregation in alpha cells, which may contribute to impaired glucagon secretionvia cytoskeletal dysfunction. We showed further that IDE deficiency triggers impairments in cilia formation, inducing alpha cellhyperplasia 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 2diabetes
PB Springer
SN 0012-186X
YR 2022
FD 2022
LK https://uvadoc.uva.es/handle/10324/53866
UL https://uvadoc.uva.es/handle/10324/53866
LA eng
NO Diabetologia volume 65, 2022, pages 1375–1389
NO Producción Científica
DS UVaDOC
RD 26-dic-2024