Abstract
Several investigations have shown a relation between diabetes and alterations of the
liver circadian clock. We investigated the diurnal expression of clock genes and clock-controlled
genes (CCGs) in 3-hour intervals for a 24-h period in the livers of male streptozotocin
(STZ)-treated rats, male spontaneous type 1 diabetic LEW.1AR1-iddm (Iddm) rats, and Iddm rats treated for 10 days with insulin. Hepatic mRNA was extracted,
and the relative expression of clock genes (Per1, Per2, Bmal1, Clock, Cry1), as well as CCGs (Dbp, E4bp4, RevErbα, Rorα, Pparγ), was analyzed by reverse transcription followed by real-time polymerase chain reaction.
Diabetic STZ and Iddm rats, as well as insulin-substituted Iddm rats, exhibited a
significant diurnal expression pattern of clock genes as determined by Cosinor analysis;
however, the MESOR (midline estimating statistic of rhythm) of Bmal1, Per2, and Clock transcript expression was altered in Iddm and insulin-substituted Iddm rats. The
hepatic expression of the CCGs Dbp and RevErbα revealed a diurnal rhythm in all investigated groups. Insulin administration to Iddm
rats normalized the enhanced MESOR in the expression of Dbp, RevErbα, and E4bp4 to the levels of normoglycemic controls. Cosinor analysis indicated no diurnal rhythm
of Pparγ expression in the livers of diabetic STZ or Iddm rats or in those of insulin-substituted
Iddm rats. Also, insulin substitution could not reverse the decreased MESOR of Pparγ expression in Iddm rats. In consequence of the diabetic disease, changes in the expression
of clock genes and CCGs suggest alterations in the hepatic peripheral clock mechanism.
Key words
diabetes mellitus type 1 - diurnal rhythm - hepatic gene expression - clock gene -
clock-controlled genes - rat
