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Cell Mol Life Sci. 2017 Aug;74(15):2827-2838. doi: 10.1007/s00018-017-2505-1. Epub 2017 Mar 23.

BACE2 suppression promotes β-cell survival and function in a model of type 2 diabetes induced by human islet amyloid polypeptide overexpression.

Author information

1
Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), C/Rosselló 149-153, 5th floor, 08036, Barcelona, Spain.
2
Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), C/Rosselló 149-153, 5th floor, 08036, Barcelona, Spain. servitja@clinic.cat.
3
Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), C/Rosselló 149-153, 5th floor, 08036, Barcelona, Spain. anovials@clinic.cat.

Abstract

BACE2 (β-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 β-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 β-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 β-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 β-cell and promotes β-cell survival. Thus, targeting BACE2 may represent a promising therapeutic strategy to improve β-cell function in T2D.

KEYWORDS:

BACE activity; Glucose tolerance; Islet inflammation; Proliferation; Survival; Type 2 diabetes

PMID:
28337562
DOI:
10.1007/s00018-017-2505-1
[Indexed for MEDLINE]

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