The hydrogen ion in normal metabolism: a review

The production of hydrogen ions (H+) by metabolic processes is described, with particular emphasis on glycolysis and ketogenesis. Total metabolic production of H+ is approximately 150 g day-1 but utilization closely balances production, so that intracellular and extracellular H+ production is maintained within narrow limits. H+ is generated at several sites in glycolysis but no net H+ production occurs unless the ATP formed is hydrolysed. The other main source of metabolic H+ production is ketogenesis. Here H+ accumulation depends on both the relative dominance of ketone body production over utilization and the loss of base in urine. The H+ is produced during the synthesis of 3-hydroxy-3-methylglutaryl-CoA and not because of dissociation of acetoacetic acid. Lipolysis and re-esterification of fats are additional major producers of H+, while net H+ production also occurs with pathological accumulation and incomplete combustion of other organic acids. Many metabolic systems are sensitive to the changes in pH. These effects have been examined in vivo using an ammonium chloride acidaemia model in the rat. Severe insulin resistance and impaired glucose metabolism in liver and muscle were found. One mechanism involved inhibition, by H+, of the binding of insulin to its receptors. Further mechanisms include inhibition of key glycolytic enzymes including phosphofructokinase. It is concluded that too little attention is paid to metabolic production of hydrogen ions and to their effects, in turn, on metabolism.