Regulation of core clock genes in human islets.
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.
Department of Clinical Sciences in Malmö, Units of Molecular Metabolism, Lund University Diabetes Centre, Scania University Hospital, SE-205 02, Malmö, Sweden. Jelena.Stamenkovic@med.lu.se
Jelena A
JA
Stamenkovic
Anders H
AH
Olsson
Cecilia L
CL
Nagorny
Siri
S
Malmgren
Marloes
M
Dekker-Nitert
Charlotte
C
Ling
Hindrik
H
Mulder
D000328:Adult; D000368:Aged; D015992:Body Mass Index; D056926:CLOCK Proteins / Q000235:genetics*; D056931:Cryptochromes / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D005786:Gene Expression Regulation; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007328:Insulin / Q000032:analysis / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D056950:Period Circadian Proteins / Q000032:analysis
D056926:CLOCK Proteins; D056931:Cryptochromes; D006442:Glycated Hemoglobin; D007328:Insulin; D056950:Period Circadian Proteins; C538966:CRY2 protein, human; C421902:PER2 protein, human; C512644:PER3 protein, human; C517652:hemoglobin A1c protein, human