Cellular circadian period length inversely correlates with HbA 1c levels in individuals with type 2 diabetes

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Biopsy
  • Blood Glucose / metabolism
  • CLOCK Proteins / metabolism
  • Circadian Clocks / genetics*
  • Circadian Rhythm*
  • Diabetes Mellitus, Type 2 / blood*
  • Female
  • Fibroblasts / metabolism
  • Glycated Hemoglobin A / analysis*
  • Humans
  • Intercellular Adhesion Molecule-1 / metabolism
  • Lentivirus / metabolism
  • Male
  • Middle Aged
  • Phenotype
  • Sequence Analysis, RNA
  • Skin / metabolism

Substances

  • Blood Glucose
  • Glycated Hemoglobin A
  • ICAM1 protein, human
  • hemoglobin A1c protein, human
  • Intercellular Adhesion Molecule-1
  • CLOCK Proteins
  • CLOCK protein, human