Defects in β-Cell Ca2+ Dynamics in Age-Induced Diabetes

  1. Per-Olof Berggren1,6
  1. 1The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, SE-171 76 Stockholm, Sweden.
  2. 2Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, SE-141 86 Stockholm, Sweden.
  3. 3Present address: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, D-50674 Cologne, Germany.
  4. 4Present address: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
  5. 5Max Planck Institute for Biology of Ageing, D-50931 Cologne, Germany.
  6. 6Lee Kong Chian School of Medicine, Nangyang Technological University, Imperial College London, Novena Campus, Singapore 637 553.
  1. Corresponding Author: Per-Olof Berggren, E-mail: Per-Olof.Berggren{at}ki.se.

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 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.

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