**2. Energy needs of the erythrocyte**

Energy needs of the erythrocyte are fulfilled by ATP generated from glycolysis, which comprises several magnesium-dependent enzymes [3]. Magnesium is also necessary as enzyme cofactor or as part of enzyme substrate or product for more than 600 enzymes in the body, although not all these occur in the erythrocyte.

Among the enzymes of glycolysis, or the Embden-Meyerhof pathway, hexokinase, phosphofructokinase, phosphoglycerate kinase, and pyruvate kinase need magnesium as part of the ADP/ATP substrate or product. Aldolase and enolase need magnesium as a fundamental enzyme cofactor for stability and activity. The remaining glycolysis enzymes, glucose-phosphate isomerase, triosephosphate isomerase, glyceraldehyde 3-phosphate dehydrogenase, monophosphoglycerate kinase, and lactate dehydrogenase are not magnesium-dependent. Hexokinase, the first enzyme of glycolysis, increases reaction rate by at least 10 orders of magnitude compared to the uncatalyzed reaction, as an example of the very high catalytic demands on glycolytic enzymes [4]. Along with glycolysis, there is also the Rapoport-Luebering shunt producing 2,3-diphosphoglycerate, which is necessary for hemoglobin regulation. Magnesium level within erythrocytes is around 0.3 mM, which is three times higher than in plasma. The necessary levels of magnesium for glycolytic enzyme function are about an order of magnitude less than intra-erythrocyte magnesium concentration, suggesting that magnesium, while necessary for glycolysis, would not have a direct regulatory function in glycolysis [5]. Extracellular glucose can induce

#### *Erythrocytes as Messengers for Information and Energy Exchange between Cells DOI: http://dx.doi.org/10.5772/intechopen.108321*

magnesium efflux in erythrocytes [6]. Erythrocytes of type II diabetes patients also have lower magnesium levels as compared to healthy individuals. Glycolysis is sometimes described as two competing mechanisms, the pentose-phosphate pathway and the Embden-Meyerhof pathway. The pentose-phosphate pathway, also called the hexose monophosphate shunt, is used by erythrocytes to generate reducing power in the form of NADPH and is not known to require magnesium. Glycolysis is regulated by positive or negative feed-back or feed-forward loops [7] and by the availability of oxygen. The pentose-phosphate shunt is favored when oxygen is abundant, whereas the Embden-Meyerhof pathway is favored in oxygen-limiting conditions. Erythrocyte glycolysis is also regulated by sphingosine-1-phosphate (S1P), at least in high altitudes [8], and by a circadian rhythm coupled to redox regulations [9].

Erythrocytes also contain insulin receptors at a copy number of about 1000–2000 per erythrocyte, depending on age and health status [10]. Erythrocyte insulin receptors respond to insulin and may regulate glycolysis, probably through phosphorylation of phosphofructokinase and intracellular redistribution of the enzyme [11]. This could be through a magnesium-dependent process, since insulin induces magnesium efflux from erythrocytes [12]. Signaling from the erythrocyte insulin receptor seems to be through the phospho-inositide pathway, since magnesium efflux was inhibited by wortmannin, a known inhibitor of phosphinositide-3-kinase [12]. Insulin receptor signaling also involves magnesium-dependent autophosphorylation of the tyrosine kinase part of the receptor. Erythrocytes are not dependent on insulin for glucose uptake, since they import glucose through the non-insulin-dependent glucose transporter GLUT-1. Insulin in synergism with the insulin C-peptide has been shown to inhibit the release of ATP from erythrocytes that occur as a result of low oxygen levels [13, 14]. This effect could be reversed by a phosphodiesterase 3 inhibitor [15]. Insulin and insulin receptors are also known to regulate the potassium balance of cells. This regulation is thought to mainly be at the expression of the genes encoding the voltage-gated potassium channels [16]. If so, then insulin and the insulin receptor are mainly at work in erythroid precursors for regulating potassium channels, rather than in the mature erythrocyte. High glucose concentration in plasma, also called hyperglycemia, as can be observed in diabetes, can have many effects on erythrocytes [17]. For instance, glucose can be metabolized in the erythrocyte by aldose reductase leading to sorbitol or fructose production through the polyol pathway, which can lead to complications like diabetic neuropathy [18]. Hyperglycemia also leads to glycation of hemoglobin. Glycated hemoglobin has an increased affinity for oxygen and could be expected to be less prone to release its oxygen in a normal way. However, the total oxygen delivery capacity of blood containing glycated hemoglobin is essentially unchanged [19]. Hyperglycemia can on the other hand cause cellular hypoxia by other mechanisms [20].
