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 Ca2+ 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 Ca2+ mobilization from intracellular stores as well as decreased β-cell Ca2+ 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 Ca2+ 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.
- Received December 6, 2013.
- Accepted June 23, 2014.
- © 2014 by the American Diabetes Association.
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