一种针对病理性 IAPP 聚集物的人源抗体可保护 2 型糖尿病模型中的β细胞。
A human antibody against pathologic IAPP aggregates protects beta cells in type 2 diabetes models.
机构信息
Neurimmune AG, Wagistrasse 18, 8952, Schlieren, Switzerland.
BC Children's Hospital Research Institute and Centre for Molecular Medicine and Therapeutics, Departments of Surgery and Pathology & Laboratory Medicine, University of British Columbia, A4-151 950 W 28 Ave, Vancouver, BC, Canada.
出版信息
Nat Commun. 2023 Oct 9;14(1):6294. doi: 10.1038/s41467-023-41986-0.
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.
在 2 型糖尿病患者中，胰岛β细胞逐渐退化，逐渐丧失产生胰岛素和调节血糖的能力。β细胞功能障碍和丧失与胰岛淀粉样多肽（IAPP）聚集形式的积累有关，这些聚集形式由可溶性原纤维前 IAPP 寡聚物以及胰岛中的不溶性 IAPP 纤维组成。在这里，我们描述了一种人源单克隆抗体，该抗体选择性靶向 IAPP 寡聚物，并通过防止体外膜破裂和细胞凋亡来中和 IAPP 聚集毒性。在雄性大鼠和人 IAPP 转基因小鼠以及 2 型糖尿病的人胰岛移植小鼠模型中进行抗体治疗可触发 IAPP 寡聚物的清除，从而导致β细胞保护和改善葡萄糖控制。这些结果为 IAPP 寡聚物的病理作用提供了新的证据，并表明抗体介导的 IAPP 寡聚物清除可能是一种支持 2 型糖尿病中β细胞功能的药物策略。
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