Glucose as a Major Antioxidant: When, What for and Why It Fails?

Abstract

A human organism depends on stable glucose blood levels in order to maintain its metabolic needs. Glucose is considered to be the most important energy source, and glycolysis is postulated as a backbone pathway. However, when the glucose supply is limited, ketone bodies and amino acids can be used to produce enough ATP. In contrast, for the functioning of the pentose phosphate pathway (PPP) glucose is essential and cannot be substituted by other metabolites. The PPP generates and maintains the levels of nicotinamide adenine dinucleotide phosphate (NADPH) needed for the reduction in oxidized glutathione and protein thiols, the synthesis of lipids and DNA as well as for xenobiotic detoxification, regulatory redox signaling and counteracting infections. The flux of glucose into a PPP-particularly under extreme oxidative and toxic challenges-is critical for survival, whereas the glycolytic pathway is primarily activated when glucose is abundant, and there is lack of NADP⁺ that is required for the activation of glucose-6 phosphate dehydrogenase. An important role of glycogen stores in resistance to oxidative challenges is discussed. Current evidences explain the disruptive metabolic effects and detrimental health consequences of chronic nutritional carbohydrate overload, and provide new insights into the positive metabolic effects of intermittent fasting, caloric restriction, exercise, and ketogenic diet through modulation of redox homeostasis.

Keywords: NADPH; glucose; glycogen; glycolysis; insulin resistance; pentose phosphate pathway; redox balance; stress resistance.

Figure 1

Schematic presentation of the conventional (a) and pentose phosphate pathway-centric (b) views of glucose metabolism. Abbreviations: G1P—glucose 1 phosphate, G6P—glucose 6 phosphate, PPP—pentose phosphate pathway, TCA—tricarboxylic acid cycle, NOX—NADPH oxidase, NOS—nitric oxide synthase.

Figure 2

Glucose availability is a major factor in the maintenance of redox homeostasis through the reduction in oxidized NADP⁺, which is used for the subsequent reduction in oxidized glutathione and thiols. At the same time NADPH is used for synthesis of DNA and fatty acid synthesis and is needed for activities of NADPH oxidases, NO-synthase and other processes. The scheme is simplified and regulatory networks functioning in living systems are much more complex and include other mechanisms and feedback loops. For example, it was recently shown that the deletion of Nrf2 in mice can be—to a large extent—compensated by other adaptive mechanisms in conditions of caloric restriction [23]. This suggests that robust regulatory network beyond Nrf2 and FOXO transcription factors exists in order to maintain redox balance. Abbreviations: PPP—pentose phosphate pathway, NOX—NADPH oxidase, NOS—nitric oxide synthase, GSH—glutathione, GSSG—glutathione disulfide, Pr—protein, PrSSPr—disulfide bonds between/within the proteins and other molecules, ARE—antioxidant response element, InsR—insulin receptor, cAMP—cyclic adenosine monophosphate, FOXO—forheadkbox O transcription factors, Prx3—peroxiredoxin 3, Nrf2—Nuclear factor (erythroid-derived 2)-like 2 transcription factor, MnSOD—manganese superoxide dismutase, NF-kB—nuclear factor kappa-light-chain-enhancer of activated B cells.

Figure 3

The dependence of redox effects of glucose on its concentration (hypothetic relationship suggested by the authors). Hypothetical simplified model describing the influence of the blood concentration of glucose on redox potential in human organisms. Multiple additional factors influencing redox potential such as concentration of oxygen, availability of amino and fatty acids, type of cells and effects of either hormones (insulin, glucagon) or cytokines are not considered. Concentrations of glucose as well as the shape of the curve are roughly estimated and not confirmed by actual experiments and may significantly vary depending on conditions and tissue type.

Figure 4

Role of redox sensors (pancreatic α and β cells), immune system and central nervous system in the regulation of blood glucose concentrations by liver. Glucose release or absorption by the liver integrates signals from nervous and immune systems, and peripheral redox sensors. The system is highly flexible and tunable, providing redox modulation that is dependent on actual needs. The other way around, glucose flows and redox state regulate the function of immune system [121]. Failure of feedback loops and distorted signaling—either from CNS (stress), the immune system (inflammation) or the malfunction of peripheral sensors—lead to excessive, uncontrolled (poorly controlled) glucose release and/or the activation of gluconeogenesis, leading to diabetes.