title: β-Cell Ca(2+) dynamics and function are compromised in aging.
abstract: 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 Ca(2+) concentration ([Ca(2+)]i) may be critical and that this is dependent on the proper function of the mitochondria. The [Ca(2+)]i dynamics of the pancreatic β-cell are driven by an interplay between glucose-induced influx of extracellular Ca(2+) via voltage-dependent Ca(2+) channels and the inositol 1,4,5-trisphosphate (Ins(1,4,5)P3)-mediated liberation of Ca(2+) from intracellular stores. Our previous work has indicated a direct relationship between disruption of Ins(1,4,5)P3-mediated Ca(2+) regulation and loss of β-cell function, including disturbed [Ca(2+)]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 [Ca(2+)]i dynamics in mouse β-cells, particularly in the pattern of [Ca(2+)]i oscillations. These changes are driven by modifications in both PLC/Ins(1,4,5)P3-mediated Ca(2+) mobilization from intracellular stores and decreased β-cell Ca(2+) 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.
authors.affiliation: The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, SE-171 76 Stockholm, Sweden.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Barker
authors.affiliation: The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, SE-171 76 Stockholm, Sweden.
authors.forename: Luosheng
authors.initials: L
authors.lastname: Li
authors.affiliation: The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, SE-171 76 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 L1, SE-171 76 Stockholm, Sweden; Lee Kong Chian School of Medicine, Nangyang Technological University, Imperial College London, Novena Campus, Singapore 637 553. Electronic address: per-olof.berggren@ki.se.
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Berggren
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice
chemical_list: D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium
keywords: Aging; Calcium; Calcium oscillations; Diabetes; Insulin secretion; Pancreatic beta cell