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Free keywords:
Aging/*metabolism
Animals
Blood Glucose/*metabolism
Calcium/*metabolism
Diabetes Mellitus, Type 2/*metabolism
Electron Transport/*physiology
Inositol 1,4,5-Trisphosphate/metabolism
Insulin-Secreting Cells/*metabolism
Mice
Mice, Inbred C57BL
Mitochondria/genetics/*metabolism
Type C Phospholipases/metabolism
Abstract:
Little is known about the molecular mechanisms underlying age-dependent deterioration in beta-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 beta-cells. We show that these changes are likely to be accounted for by impaired mitochondrial function and to involve phospholipase C/inositol 1,4,5-trisphosphate-mediated Ca(2+) mobilization from intracellular stores as well as decreased beta-cell Ca(2+) influx over the plasma membrane. We use three mouse models, namely, a premature aging phenotype, a mature aging phenotype, and an aging-resistant phenotype. Premature aging is studied in a genetically modified mouse model with an age-dependent accumulation of mitochondrial DNA mutations. Mature aging 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 aging is associated with a progressive decline in beta-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 beta-cell signal transduction over time lead to compromised insulin release and a diabetic phenotype.
