Approximately 55% of the energy needs of the average human are met by the metabolism of carbohydrates, of which the major component is glucose. The glucose concentration in the blood is maintained at 4–8 mmol/L (glucose homeostasis) largely by the action of hormones such as insulin and glucagon (Figure 12.1 and Chapter 46). The majority of carbohydrates in the diet are polysaccharides, which are digested in the gastrointestinal tract to mono- and disaccharides by amylases and other enzymes.
Glucose uptake
Glucose is transported into the enterocytes of the gastrointestinal tract by an energy-requiring process against a concentration gradient and then passes down a concentration gradient into the plasma (Chapter 43). Uptake of glucose from the plasma into tissues is mediated by a family of glucose transporters (GLUTs). GLUT4 in adipose and skeletal muscle is dependent on insulin for activity, while GLUT 1 and 3 (brain, erythrocytes) are not. GLUT2 in liver and kidney is insulin independent and can also transport glucose out to the plasma. On entry into the cell, glucose is phosphorylated by hexokinase (all tissues) or glucokinase (liver) to glucose-6-phosphate, which traps it in the cell. Glucokinase is only active at high glucose concentrations.
Glucose metabolism (Figure 12.2)
Glycolysis
All cells are capable of glycolysis. The first stage of glycolysis consumes ATP due to glucose phosphorylation, and then as glucose-6-phosphate is converted to fructose-6-phosphate and then phosphorylated by the regulatory enzyme of glycolysis, phosphofructokinase-1 (PFK-1), to fructose-1,6-bisphosphate. PFK-1 is activated by low ATP concentrations and high ADP and AMP concentrations, as the purpose of glycolysis is to produce ATP. Fructose-1,6-bisphosphate is cleaved to two three-carbon glyceraldehyde-3-phosphate, which is subject to oxidation, generating two molecules of NADH in total, and phosphorylation (not requiring ATP) before 4 ATP is generated for every glucose molecule in energy-yielding steps, leading to the formation of the end product pyruvate. The net yield is 2 ATP for each molecule of glucose, but a further 6 ATP can be generated from the oxidation by the electron transport chain of the 2 NADH produced, and in aerobic conditions the pyruvate can be converted to acetylCoA, which enters the TCA cycle (Chapter 10) to generate more ATP. Under anaerobic conditions, e.g. in skeletal muscle or in erythrocytes (without mitochondria), NADH cannot be oxidised in this way, but instead pyruvate is reduced to lactate to regenerate NAD+ to allow glycolysis to continue. Lactate from these tissues is released to the plasma and converted back to pyruvate in the heart, which respires aerobically, or the liver, where the pyruvate is used to synthesise glucose (gluconeogenesis), which is released back to the circulation (the Cori cycle).
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