BACE2 suppression promotes β-cell survival and function in a model of type 2 diabetes induced by human islet amyloid polypeptide overexpression.
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.
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.
Gema
G
Alcarraz-Vizán
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.
Carlos
C
Castaño
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.
Montse
M
Visa
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.
Joel
J
Montane
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.
Joan-Marc
JM
Servitja
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.
Anna
A
Novials
D053829:Amyloid Precursor Protein Secretases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D015536:Down-Regulation; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D058228:Islet Amyloid Polypeptide / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D059467:Transcriptome; D015854:Up-Regulation
C509285:Bace2 protein, mouse; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases
BACE activity; Glucose tolerance; Islet inflammation; Proliferation; Survival; Type 2 diabetes