Beta cell dysfunction occurs independently of insulitis in type 1 diabetes pathogenesis

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 Ca²⁺ 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.