Iwaya Keiichi, Nagase Terumasa, Zako Tamotsu, Itoh Yoshiyuki, Yoshiko Takashima, Arai Hisae, Nagami Nobumasa, Ishikawa Takashi, Sugimura Haruhiko
Department of Pathology, Kyoundo Hospital, Sasaki Foundation, Chiyoda-ku, Tokyo, Japan.
Sasaki Institute, Sasaki Foundation, Chiyoda-ku, Tokyo, Japan.
Commun Med (Lond). 2025 May 7;5(1):158. doi: 10.1038/s43856-025-00889-5.
Protein misfolding is a hallmark of aging, resulting in diabetes and neuroendocrine disorders. Insulin preparations also form aggregates known as insulin balls. Aggregated insulin preparations usually form amyloids and are stable in subcutaneous tissue, some specimens are cytotoxic to cultured cells.
A multilayered structural analysis of the detailed morphology of 21 insulin balls was performed by connecting regions of interest along spatial axes. Gross and optical microscopic findings, Raman spectrometric analysis using formalin-fixed paraffin-embedded block specimens, matrix-assisted laser desorption/ionization-time of flight-mass spectrometry, microfocus X-ray computed tomography, scanning electron microscopy-energy dispersive X-ray spectroscopy analysis, and transmission electron microscopy analysis were performed.
Here, we show the presence of 100 µm Cu within an insulin ball removed from a woman in her mid-40s with diabetes. The insulin ball is made of insulin lispro in an insoluble state in the lower abdominal subcutaneous adipose tissue. Transmission electron microscopy reveals fibrous structures. Microfocus X-ray computed tomography detects many spots with strong light contrast in the insulin ball. Scanning electron microscopy-energy dispersive X-ray spectroscopic analysis shows that the largest light spot is elemental metallic copper without an oxidation state (Cu).
The largest amount of Cu found in living things is in a human. Our discovery of 100 µm Cu within the insulin ball supports the idea that insulin preparations from outside can disrupt the balance of metals, including Cu. In 2025, the patient continues to inject subcutaneous insulin preparations, but no new insulin balls appear.
蛋白质错误折叠是衰老的一个标志，会导致糖尿病和神经内分泌紊乱。胰岛素制剂也会形成称为胰岛素球的聚集体。聚集的胰岛素制剂通常会形成淀粉样蛋白，并且在皮下组织中稳定，一些标本对培养细胞具有细胞毒性。
通过沿空间轴连接感兴趣区域，对21个胰岛素球的详细形态进行了多层结构分析。进行了大体和光学显微镜检查、使用福尔马林固定石蜡包埋块标本的拉曼光谱分析、基质辅助激光解吸/电离飞行时间质谱分析、微焦点X射线计算机断层扫描、扫描电子显微镜-能量色散X射线光谱分析和透射电子显微镜分析。
在此，我们展示了从一名40多岁患有糖尿病的女性身上取出的胰岛素球内存在100μm的铜。该胰岛素球由赖脯胰岛素在腹部下侧皮下脂肪组织中以不溶状态构成。透射电子显微镜显示出纤维结构。微焦点X射线计算机断层扫描在胰岛素球中检测到许多具有强光对比度的斑点。扫描电子显微镜-能量色散X射线光谱分析表明，最大的亮点是无氧化态的元素金属铜（Cu）。
生物体内发现的最大量的铜存在于人体中。我们在胰岛素球内发现100μm的铜支持了外部胰岛素制剂会破坏包括铜在内的金属平衡这一观点。到2025年，该患者继续皮下注射胰岛素制剂，但未出现新的胰岛素球。
