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Autonomous and self-sustained circadian oscillators displayed in human islet cells

Pulimeno, P. ; Mannic, T. ; Sage, D. ; Giovannoni, L. ; Salmon, P. ; Lemeille, S. ; Giry-Laterriere, M. ; Unser, M. ; Bosco, D. ; Bauer, C. ; Morf, J. ; Halban, P. ; Philippe, J. ; Dibner, C.

In: Diabetologia, 2013, vol. 56, no. 3, p. 497-507

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    Titre
    • Autonomous and self-sustained circadian oscillators displayed in human islet cells
    Auteur
    • Pulimeno, P.. Division of Endocrinology, Diabetes and Nutrition, University Hospital of Geneva (HUG), Aile Jura 4-771.2, Rue Gabrielle-Perret-Gentil, 4, CH-1211, Geneva, Switzerland
    • Mannic, T.. Division of Endocrinology, Diabetes and Nutrition, University Hospital of Geneva (HUG), Aile Jura 4-771.2, Rue Gabrielle-Perret-Gentil, 4, CH-1211, Geneva, Switzerland
    • Sage, D.. Biomedical Imaging Group, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
    • Giovannoni, L.. Division of Endocrinology, Diabetes and Nutrition, University Hospital of Geneva (HUG), Aile Jura 4-771.2, Rue Gabrielle-Perret-Gentil, 4, CH-1211, Geneva, Switzerland
    • Salmon, P.. Department of Neurosciences, Faculty of Medicine, University of Geneva, Geneva, Switzerland
    • Lemeille, S.. Division of Endocrinology, Diabetes and Nutrition, University Hospital of Geneva (HUG), Aile Jura 4-771.2, Rue Gabrielle-Perret-Gentil, 4, CH-1211, Geneva, Switzerland
    • Giry-Laterriere, M.. Department of Neurosciences, Faculty of Medicine, University of Geneva, Geneva, Switzerland
    • Unser, M.. Biomedical Imaging Group, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
    • Bosco, D.. Cell Isolation and Transplantation Centre, University Hospital, Geneva, Switzerland
    • Bauer, C.. NCCR Frontiers in Genetics, Bioimaging Platform, Sciences II, University of Geneva, Geneva, Switzerland
    • Morf, J.. Department of Molecular Biology, Sciences II, University of Geneva, Geneva, Switzerland
    • Halban, P.. Department of Genetic Medicine and Development, University Medical Centre, University of Geneva, Geneva, Switzerland
    • Philippe, J.. Division of Endocrinology, Diabetes and Nutrition, University Hospital of Geneva (HUG), Aile Jura 4-771.2, Rue Gabrielle-Perret-Gentil, 4, CH-1211, Geneva, Switzerland
    • Dibner, C.. Division of Endocrinology, Diabetes and Nutrition, University Hospital of Geneva (HUG), Aile Jura 4-771.2, Rue Gabrielle-Perret-Gentil, 4, CH-1211, Geneva, Switzerland
    Type de document
    • Postprint
    Identifiant OAI-PMH
    • oai:doc.rero.ch:311179
    Summary
    Aims/hypothesis: Following on from the emerging importance of the pancreas circadian clock on islet function and the development of type 2 diabetes in rodent models, we aimed to examine circadian gene expression in human islets. The oscillator properties were assessed in intact islets as well as in beta cells. Methods: We established a system for long-term bioluminescence recording in cultured human islets, employing lentivector gene delivery of the core clock gene Bmal1 (also known as Arntl)-luciferase reporter. Beta cells were stably labelled using a rat insulin2 promoter fluorescent construct. Single-islet/cell oscillation profiles were measured by combined bioluminescence-fluorescence time-lapse microscopy. Results: Human islets synchronised in vitro exhibited self-sustained circadian oscillations of Bmal1-luciferase expression at both the population and single-islet levels, with period lengths of 23.6 and 23.9h, respectively. Endogenous BMAL1 and CRY1 transcript expression was circadian in synchronised islets over 48h, and antiphasic to REV-ERBα (also known as NR1D1), PER1, PER2, PER3 and DBP transcript circadian profiles. HNF1A and PDX1 exhibited weak circadian oscillations, in phase with the REV-ERBα transcript. Dispersed islet cells were strongly oscillating as well, at population and single-cell levels. Importantly, beta and non-beta cells revealed oscillatory profiles that were well synchronised with each other. Conclusions/interpretation: We provide for the first time compelling evidence for high-amplitude cell-autonomous circadian oscillators displayed in human pancreatic islets and in dispersed human islet cells. Moreover, these clocks are synchronised between beta and non-beta cells in primary human islet cell cultures