CARBOHYDRATE METABOLISM--A REVIEW AZMY R. BOUTROS, M.B., CH.B., D.A., F.F.A.R.C.S. :I' CARBOHYDRATE METABOLISM has been the subject of extensive research during the last decade. 1-6 The possibility that induction of the anaesthetic state may be due to some derangement in cellular metabolism makes the anaesthetist take more than the usual academic interest in the subject. Details of the important achievements in this field are beyond file scope of this review and the reviewer will endeavour to discuss the more salient points of the subject without entering into too much detail. The functions of carbohydrate metabolism are more involved than was previously thought and, in short, they consist of the following: 1. Energy production. The process of glucose oxidation consists of a series of reactions, the large majority of which are exergonic, that is to say, these reactions produce energy, which is made available to the organism for the performance of various functions, thus: (a) Energy in the form of heat may be used to maintain the body temperattire, and is thus lost to the body. (b) Energy may be immediately transferred to another type of chemical bio- logical reaction that requires energy for its completion (endergonic reactions). (c) The most important outlet of the free energy produced in glycolytic re- actions, howeyer, is the use of this energy in the synthesis of high-energy sub- stances, which can subsequently decompose, releasing this locked energy when and where it is required. This is an extremely economical and flexible way of dealing with free energy. Broadly speaking energetic substances are of two types: (i) hydrogenated substances such as reduced diphosphopyridine nucleotide "DPNH"; (ii) phosphorylated compounds such as adenosine triphosphate "ATP" and creatine phosphate. 2. Apart from energy production, carbohydrate metabolism can supply the organism with certain necessary substances that are either unavailable to the body in the diet or present in insufficient amounts; thus some of the substances produced in the process of glycolysis provide intermediates for fatty acid synthesis (glycerophosphates and acetyl carbohydrates) and for synthesis of amino acids (pyruvate, oxalacetate, and alpha-ketoglutarate). PATHWAYS OF CARBOHYDRATE CATABOLISM The first step in the oxidation of blood glucose is the transport of this glucose into the cells. In liver cells, this occurs by simple diffusion of the sugar through the cell membrane, 7 but in other tissues and particularly in muscle cell, evidence has accumulated indicating that insulin plays an important role in facilitating the transfer of sugar through the cell membranes, s'9 *Assistant Professor, Department of Anaesthesia, University of Saskatchewan, Saskatoo~, Saskatchewan. 3fi3 Can. Anaes. Soe. J., vol. 9, no. 4, July, 1962 3154 CANADIAN ANAESTHETISTS' SOCIETY jOURNAL Following entry into the cells, glucose is rapidly incorporated into the cellular metabolic machinery by a process of phosphorylation (Step 1, Fig. 1). Thus, with the aid of the hexokinase enzyme and a phosphate molecule from adenosine triphosphate (ATP), glucose is changed into glucose-6-phosphate and the ATP is changed into ADP (adenosine diphosphate). Some workers I think that insulin has no effect on the hexokinase reaction and the phosphorylation of glucose, while others 1~ feel that insulin facilitates the transport of glucose into the cell, as well as the subsequent phosphorylation process. Glucose-6-phosphate is an important branch point in the subsequent catabolic processes of carbohydrates via the Embden-Meyerhof pathway or the pentose phosphate pathway, the so-called hexose monophosphate shunt. Conversely glucose-6-phosphate may be reconverted into glucose. This reaction occurs only in the liver under the influence of the enzyme glucose-6-phosphatase with energy production, which appears in the form of heat. Glucose-6-phosphate may also form glycogen through a process of assimilation. This review will deal only with the general outlines of these processes, and the interested reader seeking more detailed information is referred to a number of excellent articles and reviews where the subject is discussed in great detail. 1-~ I. Glycolytic Pathways The complete dissimilation of glucose to carbon dioxide and water occurs in two phases: A. The Embden-Meyerhoff phase, which can function tinder anaerobic con- ditions. Through this phase, one molecule of glucose is changed into two molecules of pyruvic acid or two molecules of lactic acid under anaerobic conditions. B. The citric acid or Krebs cycle phase, which is obligatory aerobic and cannot function under anaerobic conditions. Through this phase pyruvic acid is changed into carbon dioxide and water. A. THE EMBDEN-MEYERHOF PATHWAYTM (FIG. 1) This is the main pathway of carbohydrate catabolism and, in the brain and skeletal muscle cells, the only one. In liver, adipose tissue, and red blood cells, however, it accounts for a variable fraction of the glucose catabolized, the rest of the glucose being catabolized through the pentose phosphate pathway, or the hexose monophosphate shunt, which will be discussed later. A summary of the steps involved in the E~nbden-Meyerhof pathway is as follows: 1. Glucose-6-phosphate to fructose-6-phosphate (Step 2). Process: isomeri- zation. Enzyme: phosphohexose isomerase. 2. FructoseZ6-phosphate to fructose-l,6-phosphate (Step 3). Process: phosphory- lation. ATP supplies the extra high-energy phosphate molecule, thus raising the energy of the compound and rendering the reaction irreversible. Enzyme: phosphofructokinase. 3. Fructose-l,6-phosphate to two molecules ot triose phosphate (Step 4). Fructose-l,6-phosphate is split into two triose phosphate molecules (2 dehydroxy- acetone) each singly phosphorylated. Enzyme: aldolase (zymohexase). A. BOUTROS: CARBOHYDRATE METABOLISM 355 GLYCOGEN4: Glucose 1 phosphate (1) L (13) AT.~ j...~ADP GLUCOSE ~TGlucos~ 6 phosphate I 12) 114) Fructos 6 phosphate ATP 13) ~ ADP Fructose 1-6phosehhate Dohydroxyacetone Dehydroxyacet~ne G lyceraldehyde3 phosphate Inorganic ll /DPN 1-3d|phosphogl yeeric acid +,+ ATP ]<P. 3 phosphogl Drlcacid L (e) 2 phosphoglycericacid Phosphoeno!p~ruvate (9) /ADP (10) ~ATP .,•/T/UVOte (111~~~11acid 1121 Dicarboxylic Coenzyme A (4 carbon compound) (2 carbon compound1 FIGURE 1. Carbohydrate metabolism. The Embden-Meyerhof Pathway. 356 CANADIAN ANAESTHETISTS' SOCIETY JOURNAL 4. Two dehydroxyacetone to two glyceraldehyde-3-phosphate (another triose phosphate) (Step 5). Enzyme: phosphotriose isomerase. 5. Two glyceraldehyde-3-phosphate to two 1,3-diphosphoglyceric acid (Step 6). Enzyme: glyceraldehyde-3-phosphate dehydrogenase inhibited by iodoacetate. This is an important reaction in the process of glycolysis and involves the following: (a) Oxidation by dehydrogenation. The hydrogen is picked up by oxidized diphosphopyridine nucleotide (DPN), which acts as a hydrogen carrier and becomes reduced to DPNH + H. Regeneration of the DPNH is achieved in one of two ways: (i) DPNH can be reoxidized by giving its hydrogen to the riboflavincytochrome hydrogen transfer system and ultimately to molecular oxygen forming water. Obviously this can only occur under aerobolic conditions. (ii) Under anaerobic or relatively anaerobic conditions DPNH can give its hydrogen to pyruvic acid reducing it to lactic acid. In this case pyruvic acid will act as the hydrogen acceptor, thus leaving DPN oxidized and able to participate again in the oxidation of glyceraldehyde to glyceric acid. As will be explained later, all the energy production from the dissimilation of glucose to pyruvic acid occurs in Steps 6, 7, and 10; hence the importance of regenerating DPN. When aerobic conditions are restored, lactic acid will give the hydrogen to DPN and becomes oxidized to pyruvic acid. (b) Phosphorylysis or the addition of inorganic phosphoric acid. It should be noted that glutathione acts as prosthetic group for the enzyme glyceraldehyde-3- phosphate dehydrogenase and that the SH group on the dehydrogenase actually participates in the process of oxidation of the glyceraldehyde.12 6. Two 1,3-diphosphoglyceric acid to two 3-phosphyglyceric acid (Step 7). This is an exergonic reaction, the energy released helping to build up two mole- cules of ATP from ADP (adenosine diphosphate) leaving behind 3-phospho- glyceric acid. Enzyme: phosphoglyceric kinase. 7. Two 3-phosphoglyceric acid to two 2-phosphoglyceric acid (Step 8). Enzyme: phosphoglyceromutase. 8. Two 2-phosphoglyceric acid to two phosphoenolpyruvic acid (Step 9). Process: dehydration. Enzyme: enolase, inhibited by fuoride ion; hence the addition of flouride salts to the anticoagulant mixture added to blood collected for blood sugar estimation, to inhibit glycolysis. 9. Two phosphoenolpyruvic acid to two pyruvic acid (Step 10). This is a dephosphorylation exergonic reaction supplying two high-energy phosphate bonds to two molecules of ADP to form two molecules of ATP. THE ENERGY VALUE OF THE EMBDEN-MEYERHOF REACTION As was mentioned before, energetic compounds are either in the form of high- energy phosphate bonds added to ADP to produce ATP or in the form of reduced diphosphopyridine nucleotide (DPNH), each molecule of which, when picked up by the riboflavine cytochrome hydrogen transfer system, produces energy, which is used to build up three molecules of adenosine triphosphate from ADP. It is important to realize that if the reduced DPNH were to give its hydrogen to molecular oxygen without the intervention of the electron 1.ransfer