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Toxic human islet amyloid polypeptide (h-IAPP) oligomers are intracellular, and vaccination to induce anti-toxic oligomer antibodies does not prevent h-IAPP-induced beta-cell apoptosis in h-IAPP transgenic mice.
- Source :
-
Diabetes [Diabetes] 2007 May; Vol. 56 (5), pp. 1324-32. Date of Electronic Publication: 2007 Mar 12. - Publication Year :
- 2007
-
Abstract
- Objective: Islets in type 2 diabetes are characterized by a deficit in beta-cells, increased beta-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). The toxic form of amyloidogenic protein oligomers are distinct and smaller than amyloid fibrils and act by disrupting membranes. Using antibodies that bind to toxic IAPP oligomers (but not IAPP monomers or fibrils) and a vaccination-based approach, we sought to establish whether IAPP toxic oligomers form intra- or extracellularly and whether vaccination to induce anti-toxic oligomer antibodies prevents IAPP-induced apoptosis in human IAPP (h-IAPP) transgenic mice.<br />Research Design and Methods: Pancreas was sampled from two h-IAPP transgenic mouse models and examined by immunohistochemistry for toxic oligomers. The same murine models were vaccinated with toxic oligomers of Alzheimer beta protein (AbetaP(1-40)) and anti-oligomer titers, and blood glucose and islet pathology were monitored.<br />Results: Toxic oligomers were detected intracellularly in approximately 20-40% of h-IAPP transgenic beta-cells. Vaccine induced high titers of anti-h-IAPP toxic oligomers in both transgenic models, but beta-cell apoptosis was, if anything, further increased in vaccinated mice, so that neither loss of beta-cell mass nor diabetes onset was delayed.<br />Conclusions: IAPP toxic oligomers form in h-IAPP transgenic mouse models, and anti-toxic oligomer antibodies do not prevent h-IAPP-induced beta-cell apoptosis. These data suggest that prevention of h-IAPP oligomer formation may be more useful than a vaccination-based approach in the prevention of type 2 diabetes.
- Subjects :
- Amyloid genetics
Amyloid immunology
Animals
Body Weight
Diabetes Mellitus pathology
Diabetes Mellitus physiopathology
Disease Models, Animal
Glucose Tolerance Test
Humans
Image Processing, Computer-Assisted
Insulin-Secreting Cells drug effects
Insulin-Secreting Cells pathology
Islet Amyloid Polypeptide
Mice
Mice, Transgenic
Microscopy, Confocal
Vaccines
Amyloid toxicity
Apoptosis drug effects
Diabetes Mellitus, Type 2 immunology
Insulin-Secreting Cells cytology
Insulin-Secreting Cells physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1939-327X
- Volume :
- 56
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Diabetes
- Publication Type :
- Academic Journal
- Accession number :
- 17353506
- Full Text :
- https://doi.org/10.2337/db06-1579