Clock gene expression in peripheral leucocytes of patients with type 2 diabetes.
OBJECTIVE
Recent studies have demonstrated relationships between circadian clock function and the development of metabolic diseases such as type 2 diabetes. We investigated whether the peripheral circadian clock is impaired in patients with type 2 diabetes.


METHODS
Peripheral leucocytes were obtained from eight patients with diabetes and six comparatively young non-diabetic volunteers at 09:00, 15:00, 21:00 and 03:00 hours (study 1) and from 12 male patients with diabetes and 14 age-matched men at 09:00 hours (study 2). Transcript levels of clock genes (CLOCK, BMAL1 [also known as ARNTL], PER1, PER2, PER3 and CRY1) were determined by real-time quantitative PCR.


RESULTS
In study 1, mRNA expression patterns of BMAL1, PER1, PER2 and PER3 exhibited 24 h rhythmicity in the leucocytes of all 14 individuals. The expression levels of these mRNAs were significantly (p < 0.05) lower in patients with diabetes than in non-diabetic individuals at one or more time points. Moreover, the amplitudes of mRNA expression rhythms of PER1 and PER3 genes tended to diminish in patients with diabetes. In study 2, leucocytes obtained from patients with diabetes expressed significantly (p < 0.05) lower transcript levels of BMAL1, PER1 and PER3 compared with leucocytes from control individuals, and transcript expression was inversely correlated with HbA(1c) levels (rho = -0.47 to -0.55, p < 0.05).


CONCLUSIONS
These results suggest that rhythmic mRNA expression of clock genes is dampened in peripheral leucocytes of patients with type 2 diabetes. The impairment of the circadian clock appears to be closely associated with the pathophysiology of type 2 diabetes in humans.
Ando
H
H
Division of Clinical Pharmacology, Department of Pharmacology, School of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan. h-ando@jichi.ac.jp
Takamura
T
T
Matsuzawa-Nagata
N
N
Shima
K R
KR
Eto
T
T
Misu
H
H
Shiramoto
M
M
Tsuru
T
T
Irie
S
S
Fujimura
A
A
Kaneko
S
S
D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000032:analysis; D056926:CLOCK Proteins; D002940:Circadian Rhythm / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000503:physiopathology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000097:blood; D007962:Leukocytes / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D010507:Periodicity; D012333:RNA, Messenger / Q000235:genetics; D012016:Reference Values; D015534:Trans-Activators / Q000235:genetics*; D014158:Transcription, Genetic; D055815:Young Adult
D001786:Blood Glucose; D007328:Insulin; D012333:RNA, Messenger; D015534:Trans-Activators; D056926:CLOCK Proteins; C538943:CLOCK protein, human