A human antibody against pathologic IAPP aggregates protects beta cells in type 2 diabetes models.
Fabian WirthFabrice D HeitzChristine SeegerIoana CombaluzierKarin BreuHeather C DenrocheJulien ThévenetMelania OstoPaolo ArosioJulie Kerr-ConteC Bruce VerchereFrancois PattouThomas A LutzMarc Y DonathChristoph HockRoger M NitschJan GrimmPublished in: Nature communications (2023)
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.
Keyphrases
- type diabetes
- endothelial cells
- blood glucose
- cell cycle arrest
- glycemic control
- oxidative stress
- induced pluripotent stem cells
- induced apoptosis
- monoclonal antibody
- cell death
- blood pressure
- squamous cell carcinoma
- stem cells
- insulin resistance
- mouse model
- endoplasmic reticulum stress
- cell therapy
- mesenchymal stem cells
- lymph node
- zika virus
- neoadjuvant chemotherapy
- cancer therapy
- combination therapy