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oai:uvadoc.uva.es:10324/538662025-02-20T12:41:52Zcom_10324_32522com_10324_952com_10324_894col_10324_32523

Insulin-degrading enzyme ablation in mouse pancreatic alpha cells triggers cell proliferation, hyperplasia and glucagon secretion dysregulation Merino Antolín, Beatriz Casanueva Álvarez, Elena Quesada, Iván González Casimiro, Carlos Manuel Fernández Díaz, Cristina María Postigo Casado, Tamara Leissring, Malcolm A. Kaestner, Klaus H. Perdomo Hernández, Germán Cózar Castellano, Irene 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 2022-07-06T09:00:40Z 2022-07-06T09:00:40Z 2022-07-06T09:00:40Z 2022 info:eu-repo/semantics/article Diabetologia volume 65, 2022, pages 1375–1389 0012-186X https://uvadoc.uva.es/handle/10324/53866 10.1007/s00125-022-05729-y Diabetologia 1432-0428 eng https://link.springer.com/article/10.1007/s00125-022-05729-y info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/4.0/ © The Author(s) 2022 Atribución 4.0 Internacional Springer