Amyloid deposits consisting of fibrillar islet amyloid polypeptide (IAPP) in pancreatic islets are associated with beta-cell loss and have been implicated in type 2 diabetes (T2D). Here, we applied cryo-EM to reconstruct densities of three dominant IAPP fibril polymorphs, formed in vitro from synthetic human IAPP. An atomic model of the main polymorph, built from a density map of 4.2-Å resolution, reveals two S-shaped, intertwined protofilaments. The segment 21-NNFGAIL-27, essential for IAPP amyloidogenicity, forms the protofilament interface together with Tyr37 and the amidated C terminus. The S-fold resembles polymorphs of Alzheimer’s disease (AD)-associated amyloid-β (Aβ) fibrils, which might account for the epidemiological link between T2D and AD and reports on IAPP–Aβ cross-seeding in vivo. The results structurally link the early-onset T2D IAPP genetic polymorphism (encoding Ser20Gly) with the AD Arctic mutation (Glu22Gly) of Aβ and support the design of inhibitors and imaging probes for IAPP fibrils.

胰岛中由原纤维化胰岛淀粉样多肽（IAPP）组成的淀粉样沉积物与β细胞丢失有关，并与2型糖尿病（T2D）有关。在这里，我们应用cryo-EM来重建由合成人IAPP体外形成的三种主要IAPP原纤维多态性的密度。由4.2-Å分辨率的密度图构建的主要多晶型物的原子模型，揭示了两个S形交织在一起的原丝。对于IAPP淀粉样变性至关重要的21-NNFGAIL-27区段与Tyr37和酰胺化的C末端一起形成原丝界面。S折叠类似于阿尔茨海默氏病（AD）相关的淀粉样β（Aβ）原纤维的多态性，这可能解释了T2D和AD之间的流行病学联系，并报道了IAPP–Aβ在体内交叉播种的报道。