Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.
Institute of Applied Genomic Technologies, Health Sector, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
J Clin Invest. 2023 Apr 17;133(8):e156993. doi: 10.1172/JCI156993.
Peripheral neuropathy is a frequent complication of type 2 diabetes mellitus (T2DM). We investigated whether human islet amyloid polypeptide (hIAPP), which forms pathogenic aggregates that damage pancreatic islet β cells in T2DM, is involved in T2DM-associated peripheral neuropathy. In vitro, hIAPP incubation with sensory neurons reduced neurite outgrowth and increased levels of mitochondrial reactive oxygen species. hIAPP-transgenic mice, which have elevated plasma hIAPP levels without hyperglycemia, developed peripheral neuropathy as evidenced by pain-associated behavior and reduced intraepidermal nerve fiber (IENF) density. Similarly, hIAPP Ob/Ob mice, which have hyperglycemia in combination with elevated plasma hIAPP levels, had signs of neuropathy, although more aggravated. In wild-type mice, intraplantar and intravenous hIAPP injections induced long-lasting allodynia and decreased IENF density. Non-aggregating murine IAPP, mutated hIAPP (pramlintide), or hIAPP with pharmacologically inhibited aggregation did not induce these effects. T2DM patients had reduced IENF density and more hIAPP oligomers in the skin compared with non-T2DM controls. Thus, we provide evidence that hIAPP aggregation is neurotoxic and mediates peripheral neuropathy in mice. The increased abundance of hIAPP aggregates in the skin of T2DM patients supports the notion that hIAPP is a potential contributor to T2DM neuropathy in humans.
周围神经病变是 2 型糖尿病（T2DM）的常见并发症。我们研究了人胰岛淀粉样多肽（hIAPP）是否参与了与 T2DM 相关的周围神经病变，因为它会形成损害胰岛β细胞的致病聚集体。在体外，hIAPP 孵育感觉神经元会减少轴突生长并增加线粒体活性氧的水平。hIAPP 转基因小鼠虽然没有高血糖，但血浆 hIAPP 水平升高，表现出周围神经病变，表现为疼痛相关行为和表皮内神经纤维（IENF）密度降低。同样，hIAPP Ob/Ob 小鼠虽然血糖升高且血浆 hIAPP 水平升高，但也有神经病变的迹象，尽管更为严重。在野生型小鼠中，足底和静脉内注射 hIAPP 会引起持久的痛觉过敏和 IENF 密度降低。非聚集的鼠 hIAPP、突变的 hIAPP（普兰林肽）或聚集受到药理学抑制的 hIAPP 不会引起这些效应。与非 T2DM 对照组相比，T2DM 患者的 IENF 密度降低，皮肤中的 hIAPP 寡聚物增多。因此，我们提供了证据表明 hIAPP 聚集具有神经毒性，并介导了小鼠的周围神经病变。T2DM 患者皮肤中 hIAPP 聚集体的增加支持了 hIAPP 是人类 T2DM 神经病变潜在贡献者的观点。
