Figure 1

Overview of glucose metabolism in mammalian cells. Glucose is known to be oxidized through cytoplasmic glycolysis to produce pyruvate. Pyruvate may be reduced into lactate by lactate dehydrogenase or it may enter the mitochondria to participate in the citric acid cycle and the production of ATP by the mitochondrial respiratory chain and ATPase. However, glucose can be involved in other pathways. Glycogen synthesis is a major way to store glucose in muscle and liver. In the polyol pathway, aldose reductase reduces toxic aldehyde to inactive alcohol and glucose to sorbitol and fructose. In reducing NADPH to NADP⁺, this enzyme may be deleterious by consuming the essential cofactor needed to regenerate reduced glutathione, an essential antioxidant factor in cells. The hexosamine pathway originates from glycolysis at the fructose-6-phosphate level. In this pathway, glutamine fructose-6-phosphate amidotransferase is involved in the synthesis of glucosamine-6-phosphate, which is ultimately converted to uridine diphosphate (UDP)-N-acetyl-glucosamine. This glucosamine is able to activate transcription factors such as Sp-1 and to induce the production of pro-inflammatory cytokines. Diacylglycerol, which activates isoforms of protein kinase C (PKC), may be produced from dihydroxyacetone phosphate. The PKC activation can induce several pro-inflammatory patterns, such as activation of the transcription factor NF-κB, and the production of NADPH oxidase or pro-inflammatory cytokines. The pentose phosphate pathway may use glucose-6-phosphate to produce pentoses for nucleic acid production. This pathway is also able to produce NADPH for use in lipid, nitric oxide and reduced glutathione production, and also the synthesis of reactive oxygen species by NADPH oxidase. Advanced glycation end product (AGE) synthesis is linked to high intracellular glucose concentrations. AGEs can induce cell dysfunction by modifying cell proteins, and extracellular matrix proteins, which changes signalling between the matrix and the cell, or by activating receptors for advanced glycation end products (RAGEs), which induce the production of the transcription factors NF-κB and TNF-α or other pro-inflammatory molecules. GLUT, glucose transporter.