title: Defects in β-cell Ca2+ dynamics in age-induced diabetes.
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.
authors.affiliation: The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Luosheng
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Trifunovic
authors.affiliation: The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Köhler
authors.affiliation: The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Yixin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Jelena
authors.initials: J
authors.lastname: Petrovic Berglund
authors.affiliation: The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Christopher
authors.initials: C
authors.lastname: Illies
authors.affiliation: The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Lisa
authors.initials: L
authors.lastname: Juntti-Berggren
authors.affiliation: Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden Max Planck Institute for Biology of Ageing, Cologne, Germany.
authors.forename: Nils-Göran
authors.initials: NG
authors.lastname: Larsson
authors.affiliation: The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden Lee Kong Chian School of Medicine, Nanyang Technological University/Imperial College London, Novena Campus, Singapore per-olof.berggren@ki.se.
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Berggren
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004579:Electron Transport / Q000502:physiology*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D015544:Inositol 1,4,5-Trisphosphate; D010738:Type C Phospholipases; D002118:Calcium