HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) All Versions of this Article: db06-1579v1 56/5/1324    most recent Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lin, C.-Y. Articles by Butler, P. C. Search for Related Content PubMed PubMed Citation Articles by Lin, C.-Y. Articles by Butler, P. C. Social Bookmarking                What's this?

Toxic Human IAPP Oligomers are Intracellular, and Vaccination to Induce Anti-toxic Oligomer Antibodies Does not Prevent Human IAPP Induced Beta-Cell Apoptosis in Human IAPP Transgenic Mice.

¹ Larry Hillblom Islet Research Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-7345
² Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697

Correspondence: pbutler{at}mednet.ucla.edu

Objective:: The islet in Type 2 diabetes is characterized by 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 if IAPP toxic oligomers form intra- or extracellularly, and if vaccination to induce anti-toxic oligomer antibodies prevents IAPP induced apoptosis in human IAPP transgenic mice.

Methods:: Pancreas was sampled from two human IAPP (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 (Aß P_1-40) and anti-oligomer titers, blood glucose and islet pathology were monitored.

Results:: Toxic oligomers were detected intracellularly in 20-40% 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 approaches that prevent h-IAPP oligomer formation may be more useful in prevention of type 2 diabetes than a vaccination based approach.

CiteULike

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				S. Bonner-Weir and T. D. O'Brien Islets in Type 2 Diabetes: In Honor of Dr. Robert C. Turner Diabetes, November 1, 2008; 57(11): 2899 - 2904. [Full Text] [PDF]

				S. Zhang, H. Liu, H. Yu, and G. J.S. Cooper Fas-Associated Death Receptor Signaling Evoked by Human Amylin in Islet {beta}-Cells Diabetes, February 1, 2008; 57(2): 348 - 356. [Abstract] [Full Text] [PDF]

				C.-j. Huang, C.-y. Lin, L. Haataja, T. Gurlo, A. E. Butler, R. A. Rizza, and P. C. Butler High Expression Rates of Human Islet Amyloid Polypeptide Induce Endoplasmic Reticulum Stress Mediated {beta}-Cell Apoptosis, a Characteristic of Humans With Type 2 but Not Type 1 Diabetes Diabetes, August 1, 2007; 56(8): 2016 - 2027. [Abstract] [Full Text] [PDF]