Luosheng Li, Aleksandra Trifunovic, Martin Köhler, Yixin Wang, Jelena Petrovic Berglund, Christopher Illies, Lisa Juntti-Berggren, Nils-Göran Larsson, Per-Olof Berggren

Little is known about the molecular mechanisms underlying age-dependent deterioration in β-cell function. We now demonstrate that age-dependent impairment in insulin release and thereby glucose homeostasis is associated with subtle changes in Ca(2+) dynamics in mouse β-cells. We show that these changes are likely to be accounted for by impaired mitochondrial function and to involve PLC/InsP3-mediated Ca(2+) mobilization from intracellular stores as well as decreased β-cell Ca(2+) influx over the plasma membrane. We use three mouse models, namely a premature ageing phenotype, a mature ageing phenotype and an ageing-resistant phenotype. Premature ageing is studied in a genetically modified mouse model with an age-dependent accumulation of mtDNA mutations. Mature ageing is studied in the C57BL/6 mouse, whereas the 129 mouse represents a model that is more resistant to age-induced deterioration. Our data suggest that ageing is associated with a progressive decline in β-cell mitochondrial function that negatively impacts on the fine tuning of Ca(2+) dynamics. This is conceptually important since it emphasizes that even relatively modest changes in β-cell signal-transduction over time lead to compromised insulin release and a diabetic phenotype.