β-Cell Ca²⁺ dynamics and function are compromised in aging

Defects in pancreatic β-cell function and survival are key components in type 2 diabetes (T2D). An age-dependent deterioration in β-cell function has also been observed, but little is known about the molecular mechanisms behind this phenomenon. Our previous studies indicate that the regulation of cytoplasmic free Ca²⁺ concentration ([Ca²⁺]_i) may be critical and that this is dependent on the proper function of the mitochondria. The [Ca²⁺]_i dynamics of the pancreatic β-cell are driven by an interplay between glucose-induced influx of extracellular Ca²⁺ via voltage-dependent Ca²⁺ channels and the inositol 1,4,5-trisphosphate (Ins(1,4,5)P₃)-mediated liberation of Ca²⁺ from intracellular stores. Our previous workhas indicated a direct relationship between disruption of Ins(1,4,5)P₃-mediated Ca²⁺ regulation and loss of β-cell function, including disturbed [Ca²⁺]_i dynamics and compromised insulin secretion. To investigate these processes in aging we used three mouse models, a premature aging mitochondrial mutator mouse, a mature aging phenotype (C57BL/6) and an aging-resistant phenotype (129). Our data suggest that age-dependent impairment in mitochondrial function leads to modest changes in [Ca²⁺]_i dynamics in mouse β-cells, particularly in the pattern of [Ca²⁺]_i oscillations. These changes are driven by modifications in both PLC/Ins(1,4,5)P₃-mediated Ca²⁺ mobilization from intracellular stores and decreased β-cell Ca²⁺ influx over the plasma membrane. Our findings underscore an important concept, namely that even relatively small, time-dependent changes in β-cell signal-transduction result in compromised insulin release and in a diabetic phenotype.