Abstract:
: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 phospholipase C/inositol 1,4,5-trisphosphate-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 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 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.
journal_name
Diabetesjournal_title
Diabetesauthors
Li L,Trifunovic A,Köhler M,Wang Y,Petrovic Berglund J,Illies C,Juntti-Berggren L,Larsson NG,Berggren POdoi
10.2337/db13-1855subject
Has Abstractpub_date
2014-12-01 00:00:00pages
4100-14issue
12eissn
0012-1797issn
1939-327Xpii
db13-1855journal_volume
63pub_type
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