Islet amyloidosis is characterized by the aberrant accumulation of islet amyloid polypeptide (IAPP) in pancreatic islets, resulting in β cell toxicity, which exacerbates type 2 diabetes and islet transplant failure. It is not fully clear how IAPP induces cellular stress or how IAPP-induced toxicity can be prevented or treated. We recently defined the properties of toxic IAPP species. Here, we have identified a receptor-mediated mechanism of islet amyloidosis–induced proteotoxicity. In human diabetic pancreas and in cellular and mouse models of islet amyloidosis, increased expression of the receptor for advanced glycation endproducts (RAGE) correlated with human IAPP–induced (h-IAPP–induced) β cell and islet inflammation, toxicity, and apoptosis. RAGE selectively bound toxic intermediates, but not nontoxic forms of h-IAPP, including amyloid fibrils. The isolated extracellular ligand–binding domains of soluble RAGE (sRAGE) blocked both h-IAPP toxicity and amyloid formation. Inhibition of the interaction between h-IAPP and RAGE by sRAGE, RAGE-blocking antibodies, or genetic RAGE deletion protected pancreatic islets, β cells, and smooth muscle cells from h-IAPP–induced inflammation and metabolic dysfunction. sRAGE-treated h-IAPP Tg mice were protected from amyloid deposition, loss of β cell area, β cell inflammation, stress, apoptosis, and glucose intolerance. These findings establish RAGE as a mediator of IAPP-induced toxicity and suggest that targeting the IAPP/RAGE axis is a potential strategy to mitigate this source of β cell dysfunction in metabolic disease.

中文翻译：

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RAGE结合淀粉样蛋白IAPP中间体并介导胰腺β细胞蛋白毒性

胰岛淀粉样变性病的特征是胰岛淀粉样蛋白多肽（IAPP）在胰腺胰岛中异常积累，导致β细胞毒性，加剧了2型糖尿病和胰岛移植失败。尚不清楚IAPP如何诱导细胞应激或如何预防或治疗IAPP诱导的毒性。我们最近定义了有毒IAPP种类的属性。在这里，我们确定了胰岛淀粉样变性引起的蛋白毒性的受体介导机制。在人类糖尿病胰腺以及胰岛淀粉样变性的细胞和小鼠模型中，晚期糖基化终产物（RAGE）受体的表达增加与人类IAPP诱导（h-IAPP诱导）的β细胞和胰岛炎症，毒性和细胞凋亡有关。RAGE选择性结合有毒的中间体，但不结合h-IAPP的无毒形式，包括淀粉样原纤维。可溶性RAGE（sRAGE）的分离的细胞外配体结合域可阻断h-IAPP毒性和淀粉样蛋白的形成。sRAGE，RAGE阻断抗体或基因RAGE缺失抑制h-IAPP与RAGE之间的相互作用可保护胰岛，β细胞和平滑肌细胞免受h-IAPP引起的炎症和代谢功能障碍。sRAGE处理过的h-IAPP Tg小鼠受到保护，免受淀粉样蛋白沉积，β细胞面积减少，β细胞炎症，压力，细胞凋亡和葡萄糖耐受不良的困扰。这些发现将RAGE确立为IAPP诱导的毒性的介质，并表明靶向IAPP / RAGE轴是减轻代谢疾病中这种β细胞功能障碍来源的潜在策略。sRAGE，RAGE阻断抗体或基因RAGE缺失抑制h-IAPP与RAGE之间的相互作用可保护胰岛，β细胞和平滑肌细胞免受h-IAPP引起的炎症和代谢功能障碍。sRAGE处理过的h-IAPP Tg小鼠受到保护，免受淀粉样蛋白沉积，β细胞面积减少，β细胞炎症，压力，细胞凋亡和葡萄糖耐受不良的困扰。这些发现将RAGE确立为IAPP诱导的毒性的介质，并表明靶向IAPP / RAGE轴是减轻代谢疾病中这种β细胞功能障碍来源的潜在策略。sRAGE，RAGE阻断抗体或基因RAGE缺失抑制h-IAPP与RAGE之间的相互作用可保护胰岛，β细胞和平滑肌细胞免受h-IAPP引起的炎症和代谢功能障碍。sRAGE处理过的h-IAPP Tg小鼠受到保护，免受淀粉样蛋白沉积，β细胞面积减少，β细胞炎症，压力，细胞凋亡和葡萄糖耐受不良的困扰。这些发现将RAGE确立为IAPP诱导的毒性的介质，并表明靶向IAPP / RAGE轴是减轻代谢疾病中这种β细胞功能障碍来源的潜在策略。sRAGE处理过的h-IAPP Tg小鼠受到保护，免受淀粉样蛋白沉积，β细胞面积减少，β细胞炎症，压力，细胞凋亡和葡萄糖耐受不良的困扰。这些发现将RAGE确立为IAPP诱导的毒性的介质，并表明靶向IAPP / RAGE轴是减轻代谢疾病中这种β细胞功能障碍来源的潜在策略。sRAGE处理过的h-IAPP Tg小鼠受到保护，免受淀粉样蛋白沉积，β细胞面积减少，β细胞炎症，压力，细胞凋亡和葡萄糖耐受不良的困扰。这些发现将RAGE确立为IAPP诱导的毒性的介质，并表明靶向IAPP / RAGE轴是减轻代谢疾病中这种β细胞功能障碍来源的潜在策略。