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Signal Transduction

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

  1. Luosheng Li1,
  2. Aleksandra Trifunovic2,
  3. Martin Köhler1,
  4. Yixin Wang1,
  5. Jelena Petrovic Berglund1,
  6. Christopher Illies1,
  7. Lisa Juntti-Berggren1,
  8. Nils-Göran Larsson2,3 and
  9. Per-Olof Berggren1,4⇑
  1. 1The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
  2. 2Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
  3. 3Max Planck Institute for Biology of Ageing, Cologne, Germany
  4. 4Lee Kong Chian School of Medicine, Nanyang Technological University/Imperial College London, Novena Campus, Singapore
  1. Corresponding author: Per-Olof Berggren, per-olof.berggren{at}ki.se.
Diabetes 2014 Dec; 63(12): 4100-4114. https://doi.org/10.2337/db13-1855
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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 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 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 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.

Footnotes

  • This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-1855/-/DC1.

  • A.T. is currently affiliated with Cluster of Excellence in Cellular Stress Responses in Aging-Associated Diseases and Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, Cologne, Germany.

  • J.P.B. is currently affiliated with the Department of Cell Biology, Duke University Medical Center, Durham, NC.

  • Received December 6, 2013.
  • Accepted June 25, 2014.
  • © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
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Diabetes: 63 (12)

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December 2014, 63(12)
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Defects in β-Cell Ca2+ Dynamics in Age-Induced Diabetes
Luosheng Li, Aleksandra Trifunovic, Martin Köhler, Yixin Wang, Jelena Petrovic Berglund, Christopher Illies, Lisa Juntti-Berggren, Nils-Göran Larsson, Per-Olof Berggren
Diabetes Dec 2014, 63 (12) 4100-4114; DOI: 10.2337/db13-1855

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Defects in β-Cell Ca2+ Dynamics in Age-Induced Diabetes
Luosheng Li, Aleksandra Trifunovic, Martin Köhler, Yixin Wang, Jelena Petrovic Berglund, Christopher Illies, Lisa Juntti-Berggren, Nils-Göran Larsson, Per-Olof Berggren
Diabetes Dec 2014, 63 (12) 4100-4114; DOI: 10.2337/db13-1855
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