Abstract
Nearly all mammalian cells express a set of genes known as clock genes. These regulate the circadian rhythm of cellular processes by means of negative and
positive autoregulatory feedback loops of transcription and translation. Recent genomewide
association studies have demonstrated an association between a polymorphism near the
circadian clock gene CRY2 and elevated fasting glucose. To determine whether clock genes could play a pathogenetic
role in the disease, we examined messenger RNA (mRNA) expression of core clock genes
in human islets from donors with or without type 2 diabetes mellitus. Microarray and
quantitative real-time polymerase chain reaction analyses were used to assess expression
of the core clock genes CLOCK, BMAL-1, PER1 to 3, and CRY1 and 2 in human islets. Insulin secretion and insulin content in human islets were measured
by radioimmunoassay. The mRNA levels of PER2, PER3, and CRY2 were significantly lower in islets from donors with type 2 diabetes mellitus. To
investigate the functional relevance of these clock genes, we correlated their expression
to insulin content and glycated hemoglobin levels: mRNA levels of PER2 (ρ = 0.33, P = .012), PER3 (ρ = 0.30, P = .023), and CRY2 (ρ = 0.37, P = .0047) correlated positively with insulin content. Of these genes, expression of
PER3 and CRY2 correlated negatively with glycated hemoglobin levels (ρ = −0.44, P = .0012; ρ = −0.28, P = .042). Furthermore, in an in vitro model mimicking pathogenetic conditions, the
PER3 mRNA level was reduced in human islets exposed to 16.7 mmol/L glucose per 1 mmol/L
palmitate for 48 hours (P = .003). Core clock genes are regulated in human islets. The data suggest that perturbations
of circadian clock components may contribute to islet pathophysiology in human type
2 diabetes mellitus.
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Article info
Publication history
Published online: February 10, 2012
Accepted:
November 29,
2011
Received:
June 20,
2011
Footnotes
JS performed and analyzed most of the experiments in this study, with assistance from CN and SM. AHO performed statistical analysis and analysis of the microarray data. MDN conducted the glucolipotoxicity experiments. HM and CL provided critical intellectual input in the preparation of the manuscript. JS, AHO, CL, and HM wrote the paper.
Identification
Copyright
© 2012 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
