Insulin-degrading enzyme ablation in mouse pancreatic alpha cells triggers cell proliferation, hyperplasia and glucagon secretion dysregulation – published online 02/06/2022

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

Hyperglucagonaemia is a hallmark of type 2 diabetes, although its underlying mechanisms are poorly elucidated. Insulin-degrading enzyme (IDE) is a protease of insulin and glucagon which is highly expressed in human and mouse pancreatic alpha cells, although its expression levels are decreased in the pancreatic islet cells of individuals with type 2 diabetes. In this issue, Merino et al (https://doi.org/10.1007/s00125-022-05729-y) report that deletion of IDE in adult mouse alpha cells leads to increased proliferation, hyperplasia and constitutively elevated glucagon secretion, with lack of inhibition by insulin or high-glucose levels, leading to hyperglucagonaemia. Furthermore, they demonstrate that IDE deficiency triggers cytoskeletal perturbations, including increased α-synuclein aggregation and decreased tubulin levels, in parallel to impaired ciliogenesis in alpha cells. The authors conclude that these findings highlight novel molecular mechanisms of glucagon secretion regulation in pancreatic alpha cells, which may represent a future therapeutic target to treat hyperglucagonaemia in type 2 diabetes.

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