Toxic Human Islet Amyloid Polypeptide (h-IAPP) Oligomers Are Intracellular, and Vaccination to Induce Anti-Toxic Oligomer Antibodies Does Not Prevent h-IAPP–Induced β-Cell Apoptosis in h-IAPP Transgenic Mice

Abstract

OBJECTIVE—Islets in type 2 diabetes are characterized by a deficit in β-cells, increased β-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. 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 β protein (AβP1–40) and anti-oligomer titers, and blood glucose and islet pathology were monitored. RESULTS—Toxic oligomers were detected intracellularly in ∼20–40% of h-IAPP transgenic β-cells. Vaccine induced high titers of anti–h-IAPP toxic oligomers in both transgenic models, but β-cell apoptosis was, if anything, further increased in vaccinated mice, so that neither loss of β-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 β-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.