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, College of Medicine, University of Florida, Gainesville, FL 32610, USA; J. Crayton Pruitt Family Department of Biomedical Engineering, Herbert Wertheim College of Engineering, University of Florida, Gainesville, FL 32611, USA.
J. Crayton Pruitt Family Department of Biomedical Engineering, Herbert Wertheim College of Engineering, University of Florida, Gainesville, FL 32611, USA.
Cell Rep. 2025 Aug 26;44(9):116174. doi: 10.1016/j.celrep.2025.116174.
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 retain a substantial beta cell mass, and T cell infiltration of pancreatic islets is typically sporadic. Here, we investigate the hypothesis that the remaining beta cells in T1D are dysfunctional, using live pancreas slices from organ donors recently diagnosed with T1D. Beta cells in slices from donors with T1D have significantly diminished Ca mobilization and insulin secretion in response to glucose. Beta cell function is equally impaired in T-cell-infiltrated and non-infiltrated islets. Fixed tissue staining and gene expression profiling of laser-capture microdissected islets reveal significant reductions in proteins and genes involved in the glucose stimulus secretion coupling pathway. These findings support the notion that molecular changes evolve in beta cells during prediabetes and worsen to functional defects at human T1D diagnosis.
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，患者通常仍保留大量的β细胞群，并且胰岛的T细胞浸润通常是散在性的。在此，我们使用来自最近被诊断为T1D的器官捐献者的新鲜胰腺切片，研究T1D中剩余β细胞功能失调的假说。来自T1D捐献者的切片中的β细胞对葡萄糖刺激的钙动员和胰岛素分泌显著减少。在有T细胞浸润和无T细胞浸润的胰岛中，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，参与葡萄糖刺激-分泌偶联途径的蛋白质和基因显著减少。这些发现支持了这样一种观点，即在糖尿病前期β细胞中就会发生分子变化，并在人类T1D诊断时恶化为功能缺陷。
