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Poor Sleep Quality Is Associated with Dawn Phenomenon and Impaired Circadian Clock Gene Expression in Subjects with Type 2 Diabetes Mellitus.

ABSTRACT: Aims. We investigated whether poor sleep quality is associated with both dawn phenomenon and impaired circadian clock gene expression in subjects with diabetes. Methods. 81 subjects with diabetes on continuous glucose monitoring were divided into two groups according to the Pittsburgh Sleep Quality Index. The magnitude of dawn phenomenon was quantified by its increment from nocturnal nadir to prebreakfast. Peripheral leucocytes were sampled from 81 subjects with diabetes and 28 normal controls at 09:00. Transcript levels of circadian clock genes (BMAL1, PER1, PER2, and PER3) were determined by real-time quantitative polymerase chain reaction. Results. The levels of HbA1c and fasting glucose and the magnitude of dawn phenomenon were significantly higher in the diabetes group with poor sleep quality than that with good sleep quality. Peripheral leucocytes from subjects with poor sleep quality expressed significantly lower transcript levels of BMAL1 and PER1 compared with those with good sleep quality. Poor sleep quality was significantly correlated with magnitude of dawn phenomenon. Multiple linear regression showed that sleep quality and PER1 were significantly independently correlated with dawn phenomenon. Conclusions. Dawn phenomenon is associated with sleep quality. Furthermore, mRNA expression of circadian clock genes is dampened in peripheral leucocytes of subjects with poor sleep quality.

SUBMITTER: Huang Y

PROVIDER: S-EPMC5352967 | biostudies-other | 2017

REPOSITORIES: biostudies-other

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Poor Sleep Quality Is Associated with Dawn Phenomenon and Impaired Circadian Clock Gene Expression in Subjects with Type 2 Diabetes Mellitus.

Huang Yuxin Y Wang Haidong H Li Yuan Y Tao Xiaoming X Sun Jiao J

International journal of endocrinology 20170302

<i>Aims</i>. We investigated whether poor sleep quality is associated with both dawn phenomenon and impaired circadian clock gene expression in subjects with diabetes. <i>Methods</i>. 81 subjects with diabetes on continuous glucose monitoring were divided into two groups according to the Pittsburgh Sleep Quality Index. The magnitude of dawn phenomenon was quantified by its increment from nocturnal nadir to prebreakfast. Peripheral leucocytes were sampled from 81 subjects with diabetes and 28 nor ...[more]

PMID: 28352282

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Project description:BACKGROUND: Recent mapping of eukaryotic transcriptomes and spliceomes using massively parallel RNA sequencing (RNA-seq) has revealed that the extent of alternative splicing has been considerably underestimated. Evidence also suggests that many pre-mRNAs undergo unproductive alternative splicing resulting in incorporation of in-frame premature termination codons (PTCs). The destinies and potential functions of the PTC-harboring mRNAs remain poorly understood. Unproductive alternative splicing in circadian clock genes presents a special case study because the daily oscillations of protein expression levels require rapid and steep adjustments in mRNA levels. RESULTS: We conducted a systematic survey of alternative splicing of plant circadian clock genes using RNA-seq and found that many Arabidopsis thaliana circadian clock-associated genes are alternatively spliced. Results were confirmed using reverse transcription polymerase chain reaction (RT-PCR), quantitative RT-PCR (qRT-PCR), and/or Sanger sequencing. Intron retention events were frequently observed in mRNAs of the CCA1/LHY-like subfamily of MYB transcription factors. In contrast, the REVEILLE2 (RVE2) transcript was alternatively spliced via inclusion of a "poison cassette exon" (PCE). The PCE type events introducing in-frame PTCs are conserved in some mammalian and plant serine/arginine-rich splicing factors. For some circadian genes such as CCA1 the ratio of the productive isoform (i.e., a representative splice variant encoding the full-length protein) to its PTC counterpart shifted sharply under specific environmental stress conditions. CONCLUSIONS: Our results demonstrate that unproductive alternative splicing is a widespread phenomenon among plant circadian clock genes that frequently generates mRNA isoforms harboring in-frame PTCs. Because LHY and CCA1 are core components of the plant central circadian oscillator, the conservation of alternatively spliced variants between CCA1 and LHY and for CCA1 across phyla [2] indicates a potential role of nonsense transcripts in regulation of circadian rhythms. Most of the alternatively spliced isoforms harbor in-frame PTCs that arise from full or partial intron retention events. However, a PTC in the RVE2 transcript is introduced through a PCE event. The conservation of AS events and modulation of the relative abundance of nonsense isoforms by environmental and diurnal conditions suggests possible regulatory roles for these alternatively spliced transcripts in circadian clock function. The temperature-dependent expression of the PTC transcripts among members of CCA1/LHY subfamily indicates that alternative splicing may be involved in regulation of the clock temperature compensation mechanism.

Project description:The human circadian timing system is most sensitive to the phase-shifting effects of light during the biological nighttime, a time at which humans are most typically asleep. The overlap of sleep with peak sensitivity to the phase-shifting effects of light minimizes the effectiveness of using light as a countermeasure to circadian misalignment in humans. Most current light exposure treatments for such misalignment are mostly ineffective due to poor compliance and secondary changes that cause sleep deprivation. Using a 16-day, parallel group design, we examined whether a novel sequence of light flashes delivered during sleep could evoke phase changes in the circadian system without disrupting sleep. Healthy volunteers participated in a 2-week circadian stabilization protocol followed by a 2-night laboratory stay. During the laboratory session, they were exposed during sleep to either darkness (n = 7) or a sequence of 2-msec light flashes given every 30 sec (n = 6) from hours 2 to 3 after habitual bedtime. Changes in circadian timing (phase) and micro- and macroarchitecture of sleep were assessed. Subjects exposed to the flash sequence during sleep exhibited a delay in the timing of their circadian salivary melatonin rhythm compared with the control dark condition (p < 0.05). Confirmation that the flashes penetrated the eyelids is presented by the occurrence of an evoked response in the EEG. Despite the robust effect on circadian timing, there were no large changes in either the amount or spectral content of sleep (p values > 0.30) during the flash stimulus. Exposing sleeping individuals to 0.24 sec of light spread over an hour shifted the timing of the circadian clock and did so without major alterations to sleep itself. While a greater number of matched subjects and more research will be necessary to ascertain whether these light flashes affect sleep, our data suggest that this type of passive phototherapy might be developed as a useful treatment for circadian misalignment in humans.

Dataset Information

Poor Sleep Quality Is Associated with Dawn Phenomenon and Impaired Circadian Clock Gene Expression in Subjects with Type 2 Diabetes Mellitus.

Publications

Poor Sleep Quality Is Associated with Dawn Phenomenon and Impaired Circadian Clock Gene Expression in Subjects with Type 2 Diabetes Mellitus.

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