Taken together, these data suggest that daily fluctuations in GSH may promote the health of the nervous MLN4924 system more efficiently than if GSH is maintained at constitutively elevated levels. Another important point is that while per01 exhibits constant high GSH levels, the expression of the GSH-conjugating enzyme GstD1 is significantly reduced in this mutant. This suggests that dysregulation between GSH supply and utilization may occur in clock-deficient flies. One important question that remains to be addressed is whether rhythms in GSH-biosynthesis are controlled cell-autonomously or systemically. The circadian system in fly heads consists of several clusters of central pacemaker neurons forming a circuit responsible for circadian rhythms of locomotor activity. In addition, retinal photoreceptors, sensory neurons, glia, and other cells contain a molecular clock mechanism, which can function independently of the central pacemaker. Transcriptional rhythms that are detected in whole heads may be generated in peripheral oscillators. Nevertheless, at least some central pacemaker neurons appear to be among the cells showing transcriptional Gclc and Gclm rhythms, based on microarray analysis of isolated pacemaker cells. While the range of cells displaying rhythmic GSH biosynthesis remains to be determined, it is likely to be broad. A recent genome-wide study suggests that circadian expression of Gclc may occur in isolated fly brains, and our data suggest that Gclc and Gclm expression is also rhythmic in fly bodies. What is the biological advantage of adding a circadian level of regulation to GSH biosynthesis? While excessive ROS levels are detrimental to cell function, some levels of ROS are necessary in the organism, as these molecules are responsible for essential processes including cell signaling cascades and immune response. Thus, GSH acts not only as an antioxidant, but also plays a critical role in a plethora of redox-sensitive cellular functions. While over-expression of GCLc in Drosophila neuronal tissue, and thus increased GSH levels, correlated with protection against oxidative stress and extension of lifespan, recent findings suggests that GSH may rather function via affecting specific metabolic and defense pathways. An array of connections has been recently established between circadian clocks and metabolism in mammals and in flies. Our present study adds an important novel link to this array by demonstrating circadian control of glutathione, a compound that is critically involved in maintaining human health. The pathogenesis of diabetic heart disease is multi-factorial and complex. Putative mechanisms include metabolic disturbances, myocardial fibrosis and small vessel disease. High dietary intake of free fatty acids may result in intracellular accumulation of potentially toxic intermediates of the lipid metabolism, all of which lead to impaired myocardial performance and morphological changes. At the late stage of the disease myocyte loss and replacement fibrosis is increased, indicating cardiac remodeling in patients with type-2 diabetes mellitus. In accordance, assessment of cardiac lipid metabolism by means of magnetic resonance spectroscopy in obese patients with T2DM and non-ischemic cardiomyopathy demonstrated increased intramyocardial lipid content. However, to date contradictive results have been published concerning the short term effects of MYCL accumulation on cardiac function. Growing evidence indicates a potential relationship between chronic hyperinsulinemia in pre-diabetic patients and structural changes of the heart leading to myocardial fibrosis. A crucial role in the pathogenesis of myocardial hypertrophy has been identified for insulin-related cell signaling pathways including the insulin/PI3k/PKB/Akt axis.