TY - JOUR
T1 - Defects in β-cell Ca2+ dynamics in age-induced diabetes
AU - Li, Luosheng
AU - Trifunovic, Aleksandra
AU - Köhler, Martin
AU - Wang, Yixin
AU - Berglund, Jelena Petrovic
AU - Illies, Christopher
AU - Juntti-Berggren, Lisa
AU - Larsson, Nils Göran
AU - Berggren, Per Olof
N1 - Publisher Copyright:
© 2014 by the American Diabetes Association.
PY - 2014/12/1
Y1 - 2014/12/1
N2 - Little is known about the molecular mechanisms underlying age-dependent deterioration in b-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 phospholipase C/inositol 1,4,5-trisphosphate- 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 aging phenotype, a mature aging phenotype, and an aging-resistant phenotype. Premature aging is studied in a genetically modified mouse model with an agedependent 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 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.
AB - Little is known about the molecular mechanisms underlying age-dependent deterioration in b-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 phospholipase C/inositol 1,4,5-trisphosphate- 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 aging phenotype, a mature aging phenotype, and an aging-resistant phenotype. Premature aging is studied in a genetically modified mouse model with an agedependent 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 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.
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U2 - 10.2337/db13-1855
DO - 10.2337/db13-1855
M3 - Article
C2 - 24985350
AN - SCOPUS:84911878131
VL - 63
SP - 4100
EP - 4114
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 12
ER -