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Open Access 02-06-2022 | Insulins | Article

Insulin-degrading enzyme ablation in mouse pancreatic alpha cells triggers cell proliferation, hyperplasia and glucagon secretion dysregulation

Authors: Beatriz Merino, Elena Casanueva-Álvarez, Iván Quesada, Carlos M. González-Casimiro, Cristina M. Fernández-Díaz, Tamara Postigo-Casado, Malcolm A. Leissring, Klaus H. Kaestner, Germán Perdomo, Irene Cózar-Castellano

Published in: Diabetologia | Issue 8/2022

Abstract

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.

Graphical abstract

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Title: Insulin-degrading enzyme ablation in mouse pancreatic alpha cells triggers cell proliferation, hyperplasia and glucagon secretion dysregulation
Authors: Beatriz Merino
Elena Casanueva-Álvarez
Iván Quesada
Carlos M. González-Casimiro
Cristina M. Fernández-Díaz
Tamara Postigo-Casado
Malcolm A. Leissring
Klaus H. Kaestner
Germán Perdomo
Irene Cózar-Castellano
Publication date: 02-06-2022
Publisher: Springer Berlin Heidelberg
Keywords: Insulins
Insulins
Published in: Diabetologia / Issue 8/2022
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-022-05729-y

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