LAUSR

Loss of functional β-cell mass is the key mechanism leading to the two main forms of diabetes mellitus — type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Understanding the mechanisms behind β-cell failure is critical to prevent or revert disease. Basic pathogenic differences exist in the two forms of diabetes mellitus; T1DM is immune mediated and T2DM is mediated by metabolic mechanisms. These mechanisms differentially affect early β-cell dysfunction and eventual fate. Over the past decade, major advances have been made in the field, mostly delivered by studies on β-cells in human disease. These advances include studies of islet morphology and human β-cell gene expression in T1DM and T2DM, the identification and characterization of the role of T1DM and T2DM candidate genes at the β-cell level and the endoplasmic reticulum stress signalling that contributes to β-cell failure in T1DM (mostly IRE1 driven) and T2DM (mostly PERK–eIF2α dependent). Here, we review these new findings, focusing on studies performed on human β-cells or on samples obtained from patients with diabetes mellitus. Understanding the mechanisms behind β-cell failure in diabetes mellitus is critical to prevent or revert disease. This Review highlights new findings from studies performed on human β-cells or on samples obtained from patients with type 1 or type 2 diabetes mellitus. Pancreatic β-cell dysfunction and cell death are key processes in the development of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). The pathogenesis of T1DM and T2DM is fundamentally distinct, differentially impacting early β-cell dysfunction (immune mediated versus metabolic in T1DM and T2DM, respectively) and cell fate (massive versus mild-to-moderate β-cell loss). Pancreatic islet cells have unexpected plasticity; however, the magnitude and clinical relevance of this phenomenon in humans remains to be determined. A substantial fraction of T1DM-associated genetic variants act at the β-cell level but only become manifest upon immune-mediated islet cell perturbations, whereas T2DM genetic signals largely regulate β-cell development and function. In T1DM (and potentially in other autoimmune diseases), enhancers pre-bound by tissue-specific transcription factors seemingly facilitate cell type-specific responses to ubiquitous pro-inflammatory signals, which could explain the tissue selectivity in autoimmune attack. Endoplasmic reticulum stress affects β-cells in both T1DM and T2DM; however, the signalling differs, with predominantly IRE1-mediated β-cell damage in T1DM and PERK–eIF2α-mediated β-cell damage in T2DM.