Huber Mollie K, Widener Adrienne E, Cuaycal Alexandra E, Smurlick Dylan, Butterworth Elizabeth A, Lenchik Nataliya I, Chen Jing, Beery Maria, Hiller Helmut, Verney Ellen, Kusmartseva Irina, Rupnik Marjan Slak, Campbell-Thompson Martha, Gerling Ivan C, Atkinson Mark A, Mathews Clayton E, Phelps Edward A
Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, United States.
J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, United States.
bioRxiv. 2025 Mar 1:2024.12.29.630665. doi: 10.1101/2024.12.29.630665.
The loss of insulin secretory function associated with type 1 diabetes (T1D) is attributed to the immune-mediated destruction of beta cells. Yet, at onset of T1D, patients often have a significant beta cell mass remaining while T cell infiltration of pancreatic islets is sporadic. Thus, we investigated the hypothesis that the remaining beta cells in T1D are largely dysfunctional using live human pancreas tissue slices prepared from organ donors with recently diagnosed T1D. Beta cells in slices from donors with T1D had significantly diminished Ca mobilization and insulin secretion responses to glucose. Beta cell function was equally impaired in T cell-infiltrated and non-infiltrated islets. Fixed tissue staining and gene expression profiling of laser-capture microdissected islets revealed significant decreases of proteins and genes in the glucose stimulus secretion coupling pathway. From these data, we posit that functional defects occur in the remaining mass of beta cells during human T1D pathogenesis.
1型糖尿病（T1D）相关的胰岛素分泌功能丧失归因于β细胞的免疫介导性破坏。然而，在T1D发病时，患者通常仍有大量的β细胞，而胰岛的T细胞浸润是散在的。因此，我们使用从近期诊断为T1D的器官捐献者获取的新鲜人类胰腺组织切片，研究了T1D中剩余β细胞在很大程度上功能失调的假说。来自T1D捐献者的切片中的β细胞对葡萄糖的钙动员和胰岛素分泌反应显著减弱。在T细胞浸润和未浸润的胰岛中，β细胞功能同样受损。激光捕获显微切割胰岛的固定组织染色和基因表达谱分析显示，葡萄糖刺激分泌偶联途径中的蛋白质和基因显著减少。根据这些数据，我们认为在人类T1D发病过程中，剩余的β细胞团会出现功能缺陷。
