Format

Send to

Choose Destination
Diabetologia. 2019 Aug;62(8):1453-1462. doi: 10.1007/s00125-019-4907-0. Epub 2019 May 27.

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

Author information

1
Department of Medicine, Division of Endocrinology, Diabetes, Hypertension and Nutrition, Faculty of Medicine, University of Geneva, Rue Michel-Servet, 1, CH-1211, 14, Geneva, Switzerland.
2
Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
3
Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
4
Institute of Genetics and Genomics of Geneva (iGE3), University of Geneva, Geneva, Switzerland.
5
Center for Molecular Diseases, Division of Genetic Medicine, Lausanne University Hospital, Lausanne, Switzerland.
6
Division for Therapeutic Patient Education for Chronic Diseases, University Hospital of Geneva, Geneva, Switzerland.
7
Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
8
Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.
9
Department of Medicine, Division of Endocrinology, Diabetes, Hypertension and Nutrition, Faculty of Medicine, University of Geneva, Rue Michel-Servet, 1, CH-1211, 14, Geneva, Switzerland. Charna.Dibner@hcuge.ch.
10
Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. Charna.Dibner@hcuge.ch.
11
Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland. Charna.Dibner@hcuge.ch.
12
Institute of Genetics and Genomics of Geneva (iGE3), University of Geneva, Geneva, Switzerland. Charna.Dibner@hcuge.ch.

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

PMID:
31134308
DOI:
10.1007/s00125-019-4907-0

Supplemental Content

Full text links

Icon for Springer
Loading ...
Support Center