BACE2 suppression promotes ß-cell survival and function in a model of type 2 diabetes induced by human islet amyloid polypeptide overexpression.
Cell Mol Life Sci
; 74(15): 2827-2838, 2017 08.
Article
em En
| MEDLINE
| ID: mdl-28337562
ABSTRACT
BACE2 (ß-site APP-cleaving enzyme 2) is a protease expressed in the brain, but also in the pancreas, where it seems to play a physiological role. Amyloidogenic diseases, including Alzheimer's disease and type 2 diabetes (T2D), share the accumulation of abnormally folded and insoluble proteins that interfere with cell function. In T2D, islet amyloid polypeptide (IAPP) deposits have been shown to be a pathogenic key feature of the disease. The aim of the present study was to investigate the effect of BACE2 modulation on ß-cell alterations in a mouse model of T2D induced by IAPP overexpression. Heterozygous mice carrying the human transcript of IAPP (hIAPP-Tg) were used as a model to study the deleterious effects of IAPP upon ß-cell function. These animals showed glucose intolerance and impaired insulin secretion. When crossed with BACE2-deficient mice, the animals presented a significant improvement in glucose tolerance accompanied with an enhanced insulin secretion, as compared to hIAPP-Tg mice. BACE2 deficiency also partially reverted gene expression changes observed in islets from hIAPP-Tg mice, including a set of genes related to inflammation. Moreover, homozygous hIAPP mice presented a severe hyperglycemia and a high lethality rate from 8 weeks onwards due to a massive destruction of ß-cell mass. This process was significantly reduced when crossed with the BACE2-KO model, improving the survival rate of the animals. Altogether, the absence of BACE2 ameliorates glucose tolerance defects induced by IAPP overexpression in the ß-cell and promotes ß-cell survival. Thus, targeting BACE2 may represent a promising therapeutic strategy to improve ß-cell function in T2D.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Regulação para Baixo
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Regulação para Cima
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Ácido Aspártico Endopeptidases
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Diabetes Mellitus Tipo 2
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Células Secretoras de Insulina
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Secretases da Proteína Precursora do Amiloide
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Polipeptídeo Amiloide das Ilhotas Pancreáticas
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article