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Julia V. Busik, Qi Wang, Svetlana Bozack, Todd A. Lydic, Priyanka R. Padney, Kelly M. McSorley, Matthew S. Faber, Maria B. Grant, Maria Tikhonenko; Differential Effect Of Diabetes On Circadian Rhythmicity In Light-Entrained (Retina) Vs. Feeding Entrained (Liver) Peripheral Tissues: Implications For Pathogenesis Of Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3589.
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There is a growing body of evidence that circadian and metabolic systems are coordinated and loss of circadian regulation plays vital role in the pathogenesis of diabetes and diabetic complications. We have previously demonstrated that diabetic retinopathy is associated with depressed peripheral clock. In this study we explored 24-hour mRNA expression patterns of central and peripheral clock.
STZ-injected male Wistar rat model of Type I diabetes with 6 weeks duration of diabetes was used. All animals were maintained in standard 12/12 light/dark cycle conditions. Three diabetic and three control rats were sacrificed every two hours and retinas, suprachiasmatic nucleus (SCN), liver and total blood were collected. RNA was extracted from retinas, SCN and the liver and Clock, Per1, Per2, BMAL, Cry1, Cry2, RORA and Rev-erb expression measured by qRT-PCR. Rat EPC were enumerated by FACS analysis in each sample. Statistical analysis was performed using two-way ANOVA.
Diabetes induced differential dysregulation of central and peripheral clock with more pronounced effects in the peripheral than in central clock. In the SCN, we found statistically significant difference between control and diabetic groups in circadian expression of Bmal1, Cry2, and RORA. In the retina Clock, Bmal1, Per1, Per2 genes had significantly different chronological patterns of expression in diabetic animals compared to controls. In the liver expression of Per1, Per2, Cry2, RORA and Rev-erb was altered in diabetes compared to control. Control rats demonstrated a biphasic EPC levels pattern in the blood with a clear peak in the beginning of the light cycle. In diabetic rats this peak release of EPC was dramatically reduced.
Diabetes is associated with markedly impaired circadian rhythmicity in peripheral tissues with lesser effect on the central clock. Interestingly, we found very distinct circadian patterns and diabetes-induced circadian dysregulation in light-entrained (retina) vs. feeding entrained (liver) peripheral tissues. Loss of rhythmicity in blood EPC levels in combination with altered retinal circadian patterns is likely to impact the reparative capability in retinal vasculature leading to diabetic retinopathy. Correction of circadian defect is a promising novel target for the treatment of diabetic retinopathy.
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