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.
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Abbreviations
- AD:
-
Alzheimer disease
- BACE1:
-
β-Site APP-cleaving enzyme 1
- BACE2:
-
β-Site APP-cleaving enzyme 2
- GSIS:
-
Glucose-stimulated insulin secretion
- GTT:
-
Glucose tolerance test
- IAPP:
-
Islet amyloid polypeptide
- PCR:
-
Polymerase chain reaction
- mRNA:
-
Messenger RNA
- T2D:
-
Type 2 diabetes mellitus
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Acknowledgements
The authors thank Ms. Kimberly Katte for valuable assistance and comments in the preparation of the manuscript. This work was supported by Sardà Farriol Research Programme and by Grants FIS PI11/00679 and PI14/00447, from the Instituto de Salud Carlos III–Subdirección General de Evaluación y Fomento de la Investigación, Fondo Europeo de Desarrollo Regional (FEDER funds), Unión Europea, Una manera de hacer Europa. It also received support from Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) and from the Project 2014_SGR_520 of the Department of Universities, Research and Information Society of the Government of Catalonia. JM is a recipient of an IDIBAPS Postdoctoral Fellowship-BIOTRACK, supported by the European Community’s Seventh Framework Programme (ECFP7/2007–2013) under Grant Agreement Number 229673.
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Alcarraz-Vizán, G., Castaño, C., Visa, M. et al. BACE2 suppression promotes β-cell survival and function in a model of type 2 diabetes induced by human islet amyloid polypeptide overexpression. Cell. Mol. Life Sci. 74, 2827–2838 (2017). https://doi.org/10.1007/s00018-017-2505-1
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DOI: https://doi.org/10.1007/s00018-017-2505-1