A human antibody against pathologic IAPP aggregates protects beta cells in type 2 diabetes models
Fabian Wirth, Fabrice D. Heitz, Christine Seeger, Ioana Combaluzier, Karin Breu, Heather C. Denroche, Julien Thévenet, Melania Osto, Paolo Arosio, Julie Kerr‐Conte, C. Bruce Verchere, François Pattou, Thomas A. Lutz, Marc Y. Donath, Christoph Höck, Roger M. Nitsch, Jan Grimm
Abstract
In patients with type 2 diabetes, pancreatic beta cells progressively degenerate and gradually lose their ability to produce insulin and regulate blood glucose. Beta cell dysfunction and loss is associated with an accumulation of aggregated forms of islet amyloid polypeptide (IAPP) consisting of soluble prefibrillar IAPP oligomers as well as insoluble IAPP fibrils in pancreatic islets. Here, we describe a human monoclonal antibody selectively targeting IAPP oligomers and neutralizing IAPP aggregate toxicity by preventing membrane disruption and apoptosis in vitro. Antibody treatment in male rats and mice transgenic for human IAPP, and human islet-engrafted mouse models of type 2 diabetes triggers clearance of IAPP oligomers resulting in beta cell protection and improved glucose control. These results provide new evidence for the pathological role of IAPP oligomers and suggest that antibody-mediated removal of IAPP oligomers could be a pharmaceutical strategy to support beta cell function in type 2 diabetes.