2024-03-29T09:31:32Zhttp://uvadoc.uva.es/oai/requestoai:uvadoc.uva.es:10324/392082021-06-23T14:06:54Zcom_10324_30605com_10324_894col_10324_41
Cózar Castellano, Irene
f824327c12bc3895
500
0000-0002-6065-5362
Perdomo Hernández, Germán
18c9aa65-be74-4791-acc9-816c8922cc07
500
Fernández Díaz, Cristina María
d08855beaec139f1
500
0000-0003-0539-7636
Universidad de Valladolid. Instituto de Biología y Genética Molecular (IBGM)
EDUVA63
500
2019-11-15T11:16:17Z
2019-11-15T11:16:17Z
2019
http://uvadoc.uva.es/handle/10324/39208
10.35376/10324/39208
Insulin-degrading enzyme (IDE) is a zinc metalloprotease proposed as the main responsible for degrading insulin, in addition to degrading other peptides such as glucagon, amylin, and amyloid peptide. The association of genetic polymorphisms within the Ide locus and susceptibility to suffer type 2 diabetes (T2DM) is well known, but its therapeutic potential remains unclear. Some investigations have spurred the notion that transient and/or partial inhibition of IDE may help to develop a new pharmacological treatment for T2DM. However, there is a paucity of data in the literature regarding IDE role in insulin producing cells (pancreatic beta-cells) and its potential relationship with pathophysiological conditions, such as T2DM. The aim of the present study is to understand the physiological role of IDE in pancreatic beta-cells. For this purpose, we have performed a wide variety of in vivo and in vitro studies. To determine IDE protein expression in physiological and pathophysiological conditions in pancreatic islets, we have performed histological studies and protein analysis techniques in T2DM patient’s pancreas and in several T2DM preclinical models. To elucidate the role of IDE in pancreatic beta-cells, we have performed IDE activity inhibition both in vitro, by using of pharmacological inhibitors and shRNA silencing; and in vivo, by generating a mouse colony with specific Ide ablation in pancreatic beta-cells: B-IDE-KO mouse line. In these models, we have analyzed beta-cell function, as well as the metabolic impact of IDE ablation on pancreatic beta-cells in the B-IDE-KO mouse. Our studies show that IDE is expressed in beta- and alpha-cells of the pancreatic islet, both in humans and rodents, with increased expression in alpha- than in beta-cells. Additionally, in pathophysiological conditions that are accompanied by hyperinsulinemia, IDE is increased in pancreatic beta-cells, pointing out that IDE is involved in adaptive cellular mechanisms of beta-cells to the hyperinsulinemic environment.
Regarding the role of IDE in pancreatic beta-cells, we observe that both acute and chronic inhibition of IDE in mature beta-cells leads to impaired glucose-stimulated insulin secretion, revealing that IDE plays a key role in beta-cell function. Surprisingly, genetic ablation of Ide in beta-cells in embryonic life leads to constitutive insulin secretion and beta-cell immaturity, suggesting a new role of IDE in beta-cell development. In light of our results, we can conclude that IDE has an important role on beta-cell function, thus, IDE inhibition is not a good therapeutic approach for the T2DM treatment.
Departamento de Bioquímica y Biología Molecular y Fisiología
Doctorado en Investigación Biomédica
application/pdf
eng
info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by-nc-nd/4.0/
Attribution-NonCommercial-NoDerivatives 4.0 Internacional
Type 2 diabetes - Treatment
Diabetes tipo 2 - Tratamiento
Insulin-degrading enzime
Encima degradante de insulina
2302.04 Genética Bioquímica
Role of insulin-degrading enzyme (IDE) in pancreatic beta-cell function: relevance in health and diabetes mellitus
info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
THUMBNAIL
Tesis1576-191115.pdf.jpg
Tesis1576-191115.pdf.jpg
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LICENSE
license.txt
license.txt
text/plain
3926
https://uvadoc.uva.es/bitstream/10324/39208/3/license.txt
017313583e37a1e4d1253e1ef6c66c6c
MD5
3
CC-LICENSE
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https://uvadoc.uva.es/bitstream/10324/39208/2/license_rdf
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ORIGINAL
Tesis1576-191115.pdf
Tesis1576-191115.pdf
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10324/39208
oai:uvadoc.uva.es:10324/39208
2021-06-23 16:06:54.232
UVaDOC
repositorio@uva.es
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