Induction of IAPP amyloid deposition and associated diabetic abnormalities by a prion-like mechanism.

In this article, Mukherjee et al. show that the pathologic and clinical alterations of type 2 diabetes can be induced in vitro and in vivo by prion-like transmission of IAPP misfolded aggregates, supporting an important role for IAPP aggregation in the disease. Although a large proportion of patients with type 2 diabetes (T2D) accumulate misfolded aggregates composed of the islet amyloid polypeptide (IAPP), its role in the disease is unknown. Here, we show that pancreatic IAPP aggregates can promote the misfolding and aggregation of endogenous IAPP in islet cultures obtained from transgenic mouse or healthy human pancreas. Islet homogenates immunodepleted with anti-IAPP–specific antibodies were not able to induce IAPP aggregation. Importantly, intraperitoneal inoculation of pancreatic homogenates containing IAPP aggregates into transgenic mice expressing human IAPP dramatically accelerates IAPP amyloid deposition, which was accompanied by clinical abnormalities typical of T2D, including hyperglycemia, impaired glucose tolerance, and a substantial reduction on β cell number and mass. Finally, induction of IAPP deposition and diabetic abnormalities were also induced in vivo by administration of IAPP aggregates prepared in vitro using pure, synthetic IAPP. Our findings suggest that some of the pathologic and clinical alterations of T2D might be transmissible through a similar mechanism by which prions propagate in prion diseases.

在这篇文章中，慕克吉等人表明，通过胰岛淀粉样多肽（IAPP）错误折叠聚集体的类朊病毒传播，可在体外和体内诱导2型糖尿病的病理和临床改变，这支持了IAPP聚集在该疾病中的重要作用。 尽管大部分2型糖尿病（T2D）患者会积累由胰岛淀粉样多肽（IAPP）组成的错误折叠聚集体，但其在该疾病中的作用尚不清楚。在此，我们表明胰腺IAPP聚集体可促进从转基因小鼠或健康人胰腺获取的胰岛培养物中内源性IAPP的错误折叠和聚集。用抗IAPP特异性抗体进行免疫去除的胰岛匀浆不能诱导IAPP聚集。重要的是，将含有IAPP聚集体的胰腺匀浆腹腔接种到表达人IAPP的转基因小鼠中，会显著加速IAPP淀粉样蛋白沉积，同时伴有典型的T2D临床异常，包括高血糖、葡萄糖耐量受损以及β细胞数量和质量大幅减少。最后，通过给予使用纯合成IAPP在体外制备的IAPP聚集体，在体内也诱导了IAPP沉积和糖尿病异常。我们的研究结果表明，T2D的一些病理和临床改变可能通过一种与朊病毒在朊病毒疾病中传播类似的机制传播。