RT info:eu-repo/semantics/article
T1 Pancreatic β-cell-specific deletion of insulin-degrading enzyme leads to dysregulated insulin secretion and β-cell functional immaturity
A1 Fernández Díaz, Cristina M. .
A1 Merino, Beatriz
A1 López Acosta, J.F.
A1 Cidad, Pilar
A1 Fuente, Miguel A. de la
A1 Lobatón, Carmen D.
A1 Moreno, Alfredo
A1 Leissring, Malcolm A.
A1 Perdomo Hernández, Germán M.
A1 Cózar Castellano, Irene
K1 Endocrinología
K1 Endocrinology
AB Inhibition of insulin-degrading enzyme (IDE) has been proposed as a possible therapeutic target for type 2 diabetes treatment. However, many aspects of IDE's role in glucose homeostasis need to be clarified. In light of this, new preclinical models are required to elucidate the specific role of this protease in the main tissues related to insulin handling. To address this, here we generated a novel line of mice with selective deletion of the Ide gene within pancreatic beta-cells, B-IDE-KO mice, which have been characterized in terms of multiple metabolic end points, including blood glucose, plasma C-peptide, and intraperitoneal glucose tolerance tests. In addition, glucose-stimulated insulin secretion was quantified in isolated pancreatic islets and beta-cell differentiation markers and insulin secretion machinery were characterized by RT-PCR. Additionally, IDE was genetically and pharmacologically inhibited in INS-1E cells and rodent and human islets, and insulin secretion was assessed. Our results show that, in vivo, life-long deletion of IDE from beta-cells results in increased plasma C-peptide levels. Corroborating these findings, isolated islets from B-IDE-KO mice showed constitutive insulin secretion, a hallmark of beta-cell functional immaturity. Unexpectedly, we found 60% increase in Glut1 (a high-affinity/low-Km glucose transporter), suggesting increased glucose transport into the beta-cell at low glucose levels, which may be related to constitutive insulin secretion. In parallel, IDE inhibition in INS-1E and islet cells resulted in impaired insulin secretion after glucose challenge. We conclude that IDE is required for glucose-stimulated insulin secretion. When IDE is inhibited, insulin secretion machinery is perturbed, causing either inhibition of insulin release at high glucose concentrations or constitutive secretion.
PB American Physiological Society
SN 0193-1849
YR 2019
FD 2019-11
LK http://hdl.handle.net/10259/5244
UL http://hdl.handle.net/10259/5244
LA eng
DS Repositorio Institucional de la Universidad de Burgos
RD 23-nov-2024