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dc.contributor.authorFernández Díaz, Cristina M. .
dc.contributor.authorMerino, Beatriz
dc.contributor.authorLópez Acosta, J.F.
dc.contributor.authorCidad, Pilar
dc.contributor.authorFuente, Miguel A. de la
dc.contributor.authorLobatón, Carmen D.
dc.contributor.authorMoreno, Alfredo
dc.contributor.authorLeissring, Malcolm A.
dc.contributor.authorPerdomo Hernández, Germán M. 
dc.contributor.authorCózar Castellano, Irene
dc.date.accessioned2020-03-28T19:34:50Z
dc.date.available2020-03-28T19:34:50Z
dc.date.issued2019-11
dc.identifier.issn0193-1849
dc.identifier.urihttp://hdl.handle.net/10259/5244
dc.description.abstractInhibition 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.es
dc.format.mimetypeapplication/pdf
dc.language.isoenges
dc.publisherAmerican Physiological Societyes
dc.relation.ispartofAmerican Journal of Physiology-Endocrinology and Metabolism. 2019, V. 317, n. 5, p. E805-E819es
dc.titlePancreatic β-cell-specific deletion of insulin-degrading enzyme leads to dysregulated insulin secretion and β-cell functional immaturityes
dc.typeinfo:eu-repo/semantics/articlees
dc.rights.accessRightsinfo:eu-repo/semantics/embargoedAccesses
dc.relation.publisherversionhttps://doi.org/10.1152/ajpendo.00040.2019es
dc.identifier.doi10.1152/ajpendo.00040.2019
dc.identifier.essn1522-1555
dc.journal.titleAmerican Journal of Physiology-Endocrinology and Metabolismes
dc.volume.number317es
dc.issue.number5es
dc.page.initialE805es
dc.page.finalE819es
dc.type.hasVersioninfo:eu-repo/semantics/acceptedVersiones


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