TY - JOUR
T1 - β-Cell Ca2+ dynamics and function are compromised in aging
AU - Barker, Christopher J.
AU - Li, Luosheng
AU - Köhler, Martin
AU - Berggren, Per Olof
N1 - Funding Information:
This study was supported by the Swedish Research Council ( K242-54x-14303 ), the Novo Nordisk Foundation , Karolinska Institutet , the Swedish Diabetes Association , The Family Knut and Alice Wallenberg Foundation , Diabetes Research and Wellness Foundation , Berth von Kantzow's Foundation , The Skandia Insurance Company Ltd. , Lee Kong Chian School of Medicine, Nanyang Technological University, Imperial College London, Singapore , Strategic Research Programme in Diabetes at Karolinska Institutet , ERC-2013-AdG 338936-BetaImage, the Stichting af Jochnick Foundation and the Family Erling Persson Foundation .
Publisher Copyright:
© 2014 Elsevier Ltd.
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2015/1/1
Y1 - 2015/1/1
N2 - Defects in pancreatic β-cell function and survival are key components in type 2 diabetes (T2D). An age-dependent deterioration in β-cell function has also been observed, but little is known about the molecular mechanisms behind this phenomenon. Our previous studies indicate that the regulation of cytoplasmic free Ca2+ concentration ([Ca2+]i) may be critical and that this is dependent on the proper function of the mitochondria. The [Ca2+]i dynamics of the pancreatic β-cell are driven by an interplay between glucose-induced influx of extracellular Ca2+ via voltage-dependent Ca2+ channels and the inositol 1,4,5-trisphosphate (Ins(1,4,5)P3)-mediated liberation of Ca2+ from intracellular stores. Our previous workhas indicated a direct relationship between disruption of Ins(1,4,5)P3-mediated Ca2+ regulation and loss of β-cell function, including disturbed [Ca2+]i dynamics and compromised insulin secretion. To investigate these processes in aging we used three mouse models, a premature aging mitochondrial mutator mouse, a mature aging phenotype (C57BL/6) and an aging-resistant phenotype (129). Our data suggest that age-dependent impairment in mitochondrial function leads to modest changes in [Ca2+]i dynamics in mouse β-cells, particularly in the pattern of [Ca2+]i oscillations. These changes are driven by modifications in both PLC/Ins(1,4,5)P3-mediated Ca2+ mobilization from intracellular stores and decreased β-cell Ca2+ influx over the plasma membrane. Our findings underscore an important concept, namely that even relatively small, time-dependent changes in β-cell signal-transduction result in compromised insulin release and in a diabetic phenotype.
AB - Defects in pancreatic β-cell function and survival are key components in type 2 diabetes (T2D). An age-dependent deterioration in β-cell function has also been observed, but little is known about the molecular mechanisms behind this phenomenon. Our previous studies indicate that the regulation of cytoplasmic free Ca2+ concentration ([Ca2+]i) may be critical and that this is dependent on the proper function of the mitochondria. The [Ca2+]i dynamics of the pancreatic β-cell are driven by an interplay between glucose-induced influx of extracellular Ca2+ via voltage-dependent Ca2+ channels and the inositol 1,4,5-trisphosphate (Ins(1,4,5)P3)-mediated liberation of Ca2+ from intracellular stores. Our previous workhas indicated a direct relationship between disruption of Ins(1,4,5)P3-mediated Ca2+ regulation and loss of β-cell function, including disturbed [Ca2+]i dynamics and compromised insulin secretion. To investigate these processes in aging we used three mouse models, a premature aging mitochondrial mutator mouse, a mature aging phenotype (C57BL/6) and an aging-resistant phenotype (129). Our data suggest that age-dependent impairment in mitochondrial function leads to modest changes in [Ca2+]i dynamics in mouse β-cells, particularly in the pattern of [Ca2+]i oscillations. These changes are driven by modifications in both PLC/Ins(1,4,5)P3-mediated Ca2+ mobilization from intracellular stores and decreased β-cell Ca2+ influx over the plasma membrane. Our findings underscore an important concept, namely that even relatively small, time-dependent changes in β-cell signal-transduction result in compromised insulin release and in a diabetic phenotype.
KW - Aging
KW - Calcium
KW - Calcium oscillations
KW - Diabetes
KW - Insulin secretion
KW - Pancreatic beta cell
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U2 - 10.1016/j.jbior.2014.09.005
DO - 10.1016/j.jbior.2014.09.005
M3 - Review article
C2 - 25282681
AN - SCOPUS:84920828550
VL - 57
SP - 112
EP - 119
JO - Advances in Biological Regulation
JF - Advances in Biological Regulation
SN - 2212-4926
ER -