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.
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.


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.


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.


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.
Lin
Chia-Yu
CY
Larry Hillblom Islet Research Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095-7345, USA.
Gurlo
Tatyana
T
Kayed
Rakez
R
Butler
Alexandra E
AE
Haataja
Leena
L
Glabe
Charles G
CG
Butler
Peter C
PC
D000682:Amyloid / Q000235:genetics / Q000276:immunology / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001835:Body Weight; D003920:Diabetes Mellitus / Q000473:pathology / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology*; D004195:Disease Models, Animal; D005951:Glucose Tolerance Test; D006801:Humans; D007091:Image Processing, Computer-Assisted; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D058228:Islet Amyloid Polypeptide; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D014612:Vaccines
D000682:Amyloid; D058228:Islet Amyloid Polypeptide; D014612:Vaccines