The β-cells in type 1 diabetes mellitus: findings from human pancreas studies.

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease characterized by long-term and dynamic interactions between the immune system and pancreatic β-cells, ultimately leading to severe insulin deficiency. A paradigm shift in T1DM research has occurred in the past few years, with research now focusing on the human disease because of access to human pancreatic tissue and pancreas-draining lymph nodes. Advances in high-resolution imaging, single-cell and spatial multi-omics, and histopathology based on artificial intelligence have profoundly reshaped our understanding of disease initiation and progression. These studies revealed that β-cell loss and/or dysfunction might begin earlier than previously appreciated, preferentially affecting small β-cell-rich islets and insulin-positive cell clusters, with larger islets showing transient resistance. Substantial β-cell mass often persists at diagnosis, accompanied by functional impairment rather than immediate cell death. Across disease stages, β-cells exhibit conserved molecular signatures dominated by interferon signalling, enhanced antigen presentation and adaptive immune-evasion programmes, with evidence of heterogeneity linked to age, disease duration and immune context. Parallel analyses of pancreatic lymph nodes show early immune dysregulation, including altered regulatory T cell signatures and expansion of stem-like cytotoxic T cell populations, even before overt hyperglycaemia. Together, these findings support an integrated model of T1DM progression that enables alignment of clinical staging with evolving β-cell and immune phenotypes.