A human antibody against pathologic IAPP aggregates protects beta cells in type 2 diabetes models.

A human antibody against pathologic IAPP aggregates protects beta cells in type 2 diabetes models.

Nature communications (2023-10-10)

Fabian Wirth, Fabrice D Heitz, Christine Seeger, Ioana Combaluzier, Karin Breu, Heather C Denroche, Julien Thevenet, Melania Osto, Paolo Arosio, Julie Kerr-Conte, C Bruce Verchere, François Pattou, Thomas A Lutz, Marc Y Donath, Christoph Hock, Roger M Nitsch, Jan Grimm

PMID37813862

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.

MATERIALS

Product Number

Brand

Product Description

C2618

Sigma-Aldrich

Cytochalasin D, Ready Made Solution, from Zygosporium mansonii, 5 mg/mL in DMSO

SCC207

Sigma-Aldrich

INS-1 832/13 Rat Insulinoma Cell Line, INS-1 832/13 rat insulinoma cell line is a useful model for insulin secretion regulation and pancreatic islet beta-cell function studies.