Consequences of Altered Glucose Metabolism Oxidative Stress

Oxidative stress is defined as an imbalance between oxidants and antioxidants in favour of the oxidants. The oxidants, also termed ROS, are present as a normal product of aerobic metabolism but can be produced at elevated rates under pathophysiological conditions. They are intermediate compounds derived from the univalent reduction of molecular oxygen (by electrons and protons), characterised by a spared electron in the external orbital, which confers them a particular instability (anion superoxide O2-; hydroxyl radical OH-); or compounds such as hydrogen peroxide (H2O2), which react with oxidable functional groups. Anion superoxide and hydrogen peroxide are poorly reactive but in the presence of the transitional form of some metals, such as Fe3+, they generate the more reactive hydroxyl radical. These compounds are partially useful but potentially toxic, so the body is provided with several systems to counteract their activity. These systems include antioxidants produced in the body, both endogenous and exogenous, supplied from the diet. Endogenous antioxidants include both enzymatic defences, such as Se-GSH peroxidase, catalase and

SOD, as well as non-enzymatic defences, such as GSH, histidine peptides, the iron-binding proteins transferrin and ferritin, dihydrolipoic acid and reduced CoQ10 [50].

Glucose, through the pentose phosphate pathway, plays a key role in the synthesis of reducing compounds such as the reduced GSH, which is required to maintain the normal reduced state of the cells and to counteract all the deleterious effects of oxidative stress. GSH is synthesised inside the cells through a complex biochemical pathway composed of several well-known enzymes. During the reaction of H2O2 scavenging, GSH is oxidised to GSH disulphide (GSSG) by the enzyme GSH peroxidase. The reduction of GSSG to GSH is catalysed by GSSG reductase, which uses NADPH as reducing potential. NADPH is also required for the formation of active catalase tetramers. This latter enzyme catalyses the reduction of H2O2 to H2O and O2. The NADPH required for the production of both GSH and catalase is produced by the pentose phosphate pathway. Glucose-6-phosphate dehydrogenase (G6PD) is the first and rate-limiting enzyme of the pentose phosphate pathway and recent results have demonstrated that this enzyme plays a protective role against ROS [52].

Reactive oxygen species, if not detoxified by the antioxidant systems, exert a toxic action on polyunsaturated fatty acids, circulating proteins, proteins of cell surface, enzymes and nucleic acid (DNA), leading to irreversible damage of cell structure and functions. Thus, an adequate presence and functioning of antioxidant systems is paramount for cell activity. In advanced cancer patients the high levels of ROS are caused by:

1. An increased production due to hypermetabo-lism, increased activation of the immune system and chronic inflammation with the associated release of proinflammatory cytokines, CRP and fibrinogen

2. An inadequate detoxification due to altered glucose metabolism in addition to symptoms such as anorexia/cachexia, nausea, and vomiting, that prevent a normal nutrition and thereby a normal supply of nutrients such as glucose, proteins and vitamins, leading to accumulation of ROS [53]. In a series of our recently published studies

[50, 53, 54] we have demonstrated that patients with cancer at advanced stage showed a condition of oxidative stress characterised by high blood levels of ROS and reduced erythrocyte GSH per-oxidase and SOD activity. Antioxidant activity was significantly reduced in patients with the most advanced stage (IV) and compromised performance status (EGOG PS 2-3). Moreover, oxidative stress was associated with high levels of proin-flammatory cytokines IL-6 and TNF-a, and CRP, and low levels of leptin [51]. The inverse correlation between leptin levels and the parameters of oxidative stress (ROS) strongly suggests that lep-tin is a signal of negative energy balance and low energy reserves and that oxidative stress is a consequence of the metabolic derangements, particularly of glucose metabolism.

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