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Diabetologia

, Volume 62, Issue 8, pp 1453–1462 | Cite as

Cellular circadian period length inversely correlates with HbA1c levels in individuals with type 2 diabetes

  • Flore Sinturel
  • Anne-Marie Makhlouf
  • Patrick Meyer
  • Christel Tran
  • Zoltan Pataky
  • Alain Golay
  • Guillaume Rey
  • Cédric Howald
  • Emmanouil T. Dermitzakis
  • Claude Pichard
  • Jacques Philippe
  • Steven A. Brown
  • Charna DibnerEmail author
Article

Abstract

Aims/hypothesis

The circadian system plays an essential role in regulating the timing of human metabolism. Indeed, circadian misalignment is strongly associated with high rates of metabolic disorders. The properties of the circadian oscillator can be measured in cells cultured in vitro and these cellular rhythms are highly informative of the physiological circadian rhythm in vivo. We aimed to discover whether molecular properties of the circadian oscillator are altered as a result of type 2 diabetes.

Methods

We assessed molecular clock properties in dermal fibroblasts established from skin biopsies taken from nine obese and eight non-obese individuals with type 2 diabetes and 11 non-diabetic control individuals. Following in vitro synchronisation, primary fibroblast cultures were subjected to continuous assessment of circadian bioluminescence profiles based on lentiviral luciferase reporters.

Results

We observed a significant inverse correlation (ρ = −0.592; p < 0.05) between HbA1c values and circadian period length within cells from the type 2 diabetes group. RNA sequencing analysis conducted on samples from this group revealed that ICAM1, encoding the endothelial adhesion protein, was differentially expressed in fibroblasts from individuals with poorly controlled vs well-controlled type 2 diabetes and its levels correlated with cellular period length. Consistent with this circadian link, the ICAM1 gene also displayed rhythmic binding of the circadian locomotor output cycles kaput (CLOCK) protein that correlated with gene expression.

Conclusions/interpretation

We provide for the first time a potential molecular link between glycaemic control in individuals with type 2 diabetes and circadian clock machinery. This paves the way for further mechanistic understanding of circadian oscillator changes upon type 2 diabetes development in humans.

Data availability

RNA sequencing data and clinical phenotypic data have been deposited at the European Genome-phenome Archive (EGA), which is hosted by the European Bioinformatics Institute (EBI) and the Centre for Genomic Regulation (CRG), ega-box-1210, under accession no. EGAS00001003622.

Keywords

Circadian bioluminescence recording Circadian clock HbA1c Humans ICAM1 Type 2 diabetes 

Abbreviations

ChIP

Chromatin immunoprecipitation

CLOCK

Circadian locomotor output cycles kaput

CT

Circadian time

MCTQ

Munich Chronotype Questionnaire

O-GlcNAc

O-linked β-N-acetylglucosamine

qRT-PCR

Quantitative real-time PCR

RNAseq

RNA sequencing

SCN

Suprachiasmatic nuclei

Notes

Acknowledgements

The authors thank I. Wagner, L. Perrin (the Dibner lab), G. Sinyavsky (Florida University, USA), K. Tsutsumi and K. Tamura (Yamaguchi University, Japan) for assistance with the experiments and thank J. M. De Abreu Nunes (Department of Genetics and Evolution, University of Geneva) for help with statistical analyses.

Contribution statement

FS, A-MM and CD collected the data and drafted the manuscript. PM, CT and JP recruited and enrolled the volunteers. ZP and AG recruited the volunteers. CH, GR and ETD conducted and analysed RNA sequencing. SAB, CP, JP and CD designed the study. All the authors participated in conception and design of the study and in the drafting and approval of the manuscript. CD is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Funding

This work was funded by the Novartis Foundation for Medical-Biological Research, Jubiläumsstiftung Swiss Life Foundation, Vontobel Foundation and Olga Mayenfisch Foundation (CD) and by SNSF Sinergia grant CRSII3_160741 (SAB, JP, ETD).

Compliance with ethical standards

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Supplementary material

125_2019_4907_MOESM1_ESM.pdf (481 kb)
ESM 1 (PDF 481 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Flore Sinturel
    • 1
    • 2
    • 3
    • 4
  • Anne-Marie Makhlouf
    • 1
    • 2
    • 3
    • 4
  • Patrick Meyer
    • 1
  • Christel Tran
    • 1
    • 5
  • Zoltan Pataky
    • 6
  • Alain Golay
    • 6
  • Guillaume Rey
    • 3
    • 4
    • 7
  • Cédric Howald
    • 4
    • 7
  • Emmanouil T. Dermitzakis
    • 3
    • 4
    • 7
  • Claude Pichard
    • 1
  • Jacques Philippe
    • 1
    • 3
  • Steven A. Brown
    • 8
  • Charna Dibner
    • 1
    • 2
    • 3
    • 4
    Email author
  1. 1.Department of Medicine, Division of Endocrinology, Diabetes, Hypertension and Nutrition, Faculty of MedicineUniversity of GenevaGenevaSwitzerland
  2. 2.Department of Cell Physiology and Metabolism, Faculty of MedicineUniversity of GenevaGenevaSwitzerland
  3. 3.Diabetes Center, Faculty of MedicineUniversity of GenevaGenevaSwitzerland
  4. 4.Institute of Genetics and Genomics of Geneva (iGE3)University of GenevaGenevaSwitzerland
  5. 5.Center for Molecular Diseases, Division of Genetic MedicineLausanne University HospitalLausanneSwitzerland
  6. 6.Division for Therapeutic Patient Education for Chronic DiseasesUniversity Hospital of GenevaGenevaSwitzerland
  7. 7.Department of Genetic Medicine and Development, Faculty of MedicineUniversity of GenevaGenevaSwitzerland
  8. 8.Institute of Pharmacology and ToxicologyUniversity of ZurichZurichSwitzerland

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