Disrupted Endoplasmic Reticulum Ca²⁺ Handling: A Harβinger of β-Cell Failure

The β-cell workload increases in the setting of insulin resistance and reduced β-cell mass, which occurs in type 2 and type 1 diabetes, respectively. The prolonged elevation of insulin production and secretion during the pathogenesis of diabetes results in β-cell ER stress. The depletion of β-cell Ca²⁺_ER during ER stress activates the unfolded protein response, leading to β-cell dysfunction. Ca²⁺_ER is involved in many pathways that are critical to β-cell function, such as protein processing, tuning organelle and cytosolic Ca²⁺ handling, and modulating lipid homeostasis. Mutations that promote β-cell ER stress and deplete Ca²⁺_ER stores are associated with or cause diabetes (e.g., mutations in ryanodine receptors and insulin). Thus, improving β-cell Ca²⁺_ER handling and reducing ER stress under diabetogenic conditions could preserve β-cell function and delay or prevent the onset of diabetes. This review focuses on how mechanisms that control β-cell Ca²⁺_ER are perturbed during the pathogenesis of diabetes and contribute to β-cell failure.