CARBOHYDRATES AND ALTERATIONS IN GLUCOSE METABOLISME Organisms rely on the oxidation of complex organic compounds to obtain energy.

There general types of such compounds are carbohydrates, amino acids, and lipids. Although all there are used as a source of energy, carbohydrates are the primary source for brain, erythrocytes, and retinal cell in humans. Consequently, the concentration of glucose in the extracellular water (including plasma) requires stringent regulation. This is accomplished by many complex and interrelated endocrine and metabolic processes facilitated by the normal functioning of several glands and organs. If one or more of these systems is not functioning properly, a loss of glycemic control occurs, which ultimately results in the formation of a pathologic state. However, disorders of glucose metabolism, such as diabetes mellitus, are more than a simple dysfunction of glucose regulation. These diseases often have multifactorial causes, which can include genetic, immune, autoimmune, and other molecular mechanisms. Classification and chemistry Monosaccharides Carbohydrates are either polyhydroxy aldehydes or polyhydroxy ketones, or multimeric units of such compounds. The general formula of a carbohydrate is (CH2O)n . there are some deviations from this basic formula, because carbohydrate derivatives can be formed by the addition of other chemical groups such as phosphates, sulfates, and amines, the smallest molecule that conforms to the general formula is formaldehyde. However, this compound usually is not considered to be a Carbohydrate and is highly reactive and toxic. Glyceraldehydes, a three-carbon compound, is normally considered to be the smallest carbohydrate . this compound is optically active; that is, it rotates the plane of polarized light, the central carbon of glyceraldehydes is chiral; in other words, all of the chemical bonds originating at it are unique. For each chiral atom there are 2n possible isomers; therefore, there are 2, or two, forms of glyceraldehydes. These isomers are mirror images of each other and are called stereoisomers. Carbohydrates are grouped into generic classifications based on the number of carbonds, tetroses contain four, pentoses contain five, hexoses contain six carbon, and so on. If the carbohydrate is an aldehyde, it is called an aldose. If the compound is a ketone, it is a called a ketose. Thus glucose (Fig. 14-1). A six-carbon aldehyde, is classified as an aldohexose. Fructose, a six-carbon ketone, is a ketohexose (fig. 14-1). Several models can be used to represent carbohydrates (fig. 14-1). The Fisher projection of a carbohydrates has the aldehydes or ketone at the top of the drawing. The carbons are numbered starting at the aldehydes or ketone end, and the compound can be represented as either straight chain or a cyclic, hemiacetal form. D- and L- are terms used to describe some of the possible optical isomers of glucose and other compounds that exist as stereoisomers. Because there are four chiral carbonds in an aldohexose, there are 24 or 16 possible isomers, two of which are stereoisomers named D-glucose and L-glucose. In figure

14-1, D-glucose is represented in Fisher projection with the hydroxyl group on carbon number five positioned on the right. L-glucose has the hydroxyl group of carbon number five positioned on the left. Many carbohydrates favor the formation of hemiacetal ring structures. In fact, only a small fraction of glucose (less than 1 %) in solution is in the open chain form. The formation of a hemiacetal ring structure introduces a new chiral carbon position one. This increases the number of different cyclic aldohexoses to 25 , or 32. Thus, the D-or L-forms of glucose each have two possible representations in the ring form (fig.14-1) the form is represented by drawing the hydroxyl group of carbon one on the right. The form of glucose is represented by drawing the hydroxyl goup of carbon one on the left. Figure 14-1. Fisher and Haworth projections of glucose and fructose. D-glucose, L-glucose, and D-fructose are represented as open chain Fisher projections (top of figure). -D-glucopyranose and -Dglucopyranose are represented as cyclis Fisher projection (middle) and Haworth projections (bottom of figure). -D-glucofuranose is also represented at the bottom. The Hawoth projection represents the compound in a cyclic form, which is more representative of the actual structure. When glucose is drawn in a Haworth projection, the form of D-glucopyranose is represented by the hydroxyl group of carbon ine oriented downward or below the plane of the paper (Fig 14-1). -D-glucopyranose has the hydroxyl group of carbon one oriented upward to figuratively represent it to be above the plane of the paper ( Fig 14-1). Most sugars in humans are of the D form. The proportion of -D-glucopyranose and -Dglucopyranos in solution is determined by the nature of the solvent and its temperature. Thus, if a pure solution of -D-glucose is allowed to sit at 40 C, it forms an equilibrium mixture of 36 % -D-glucose and 4 % -D-glucose. This reaction is called mutarotation. Theoretically, it is also ossible for the six-carbon hemiacetal to form two different rings. One ring is similar to a furan, which contains four carbons and one oxygen; the other ring contains five carbons and one oxygen and is similar to a pyran ring (Fig. 14-1). Glucose thermodynamically favors the formation of ix-member rings (five carbons with one oxygen); therefore it is a pyranose. Fructose, on the other hand, favors the formation of furanose rings. Disaccharides and polysaccharides Separate carbohydrates, or monosaccharides, can be joined to-gether to form disaccharides or multimeric structures called aligosaccharides and polysaccharides. When two carbohydrate molecules join together, a water molecule is generated. When they split, one molecule of watewr is lost. This reaction is called hydrolysis. Polysaccharides are the most abundant organic molecules in nature. Cellulose, for example, is a highly insoluble polysaccharide occurring widely in plants; starches are the principal carbohydrate (polysaccharide) storage products of higher plants; and glycogen is the principal carbohydrate strorage product in animals. The glycoside linkages of carbohydrates can involve any of the carbons; however, certain carbons are favored depending on the carbohydrate. A common disaccharide used by human is sucrose,

often known as table sugar. Sucrose is D-glucopyranosyl (1 2) -D-Fructofuranoside (fig.14-2). The oxygen from carbon on -D-fructose. Two other common disaccharides are maltose and lactose (fig-142). Maltose is composed two -D-glucose units in a (1 4) linkage. . Maltose is a disaccharide, which is formed by the digestion of starch by enzyme amylase. Lactose is the disaccharide found in milk. Lactose is composed of -D-galactose and D-glucose in a (1 4) linkage. Figure 14-2. Haworth projections of sucrose, maltose, and lactose three common disaccharides. The carbons involved in each glycoside linkage are designated in parentheses. Sucrose is not a reducing sugars because glucopyranoside has an available carbonyl group. All monosaccharides and many disaccharides are reducing agents. Thi is because a free aldehyde or ketone (the open chain form) can be oxidized the proper conditions. As a disaccharide, one of the aldehyde or ketons is usually to the glycosidic linkage, the other aldehyde or keton still free to function as a reducing agent. However, when both aldehydes or ketones are to the glycosidic linkage, such as in sucrose, then the disaccharide is incapable of undergoing mutarotation and is therefore incapable of functioning as a reducing agent. Both maltose and lactose are reducing agents, whereas sucrose is not. Single units of carbohydrates cannot be stored easily in cells. All carbohydrates are powerful osmotic agents due to the number of hydroxyl groups that can contribute to hydrogen bonding and organization of water. Additionally, intracellular enzymes readily recognize glucose and its congeners and quickly shunt them into metabolic pathways. Therefore, to store glucose molecules efficiently until they are needed for energy, cells convert the carbohydrate into the polymers starch in plants and glycogen in animals 9fig.14-3). Starch in plants and glycogen in animals (fig. 14-3). Starch and glycogen polymers can range in size from less than 100 to more than 2000 linked glucose units. Starch and glycogen are similar because their main chains are composed of 1,4-glycosidic linkage (fig.14-3). Branches occur off the main chain at 1,6-glycosidic linkages (fig.14-3). Glycogen is more branched than starch, and its branches are somewhat shorter. Presumably, branching permits the organism to store a large amount of carbohydrate in a smaller, more compact volume than world otherwise be possible for linear polymers. The two tissues that synthesize and store glycogen are liver and muscle. Figure 14-3. Representation of a growing glycogen molecule. Numbers indicate the main chain (14) and branched (16)glycosidic linkages. Open arrows (=>) designate potential extension points for the chains. Reactivity of Carbohydrates The ability of glucose to function as a reducing agent has been useful in the detection and quantitation of carbohydrates in body fluids. Glucose and other carbohydrates are capable of converting cupric ions in alkaline solution to cuprous ions. The solution loses its deep blue color and a red precipitate of cuprous oxide forms. Benedicts and fehlings reagents, which contain an alkaline solution of cupric ions stabilizied by citrate or titrate, respectively, have been used to detect reducing agents in urine and other body fluids. Another chemical characteristic that used to be exploited to quantitate carbohydrates in the past is the ability of these molecules to form Schiff bases with aromatic

amines. O-toluidine in a hot acidic solution will yield a colored compound with an absorbance maxima at 630 nm. Galactose, an aldohexose, and mannose, an aldopentose, will also react with 0-toluidine and produce a colored compound that can interfere with the reaction. The Schiff base reaction with 0toluidine is of historical interest only and has been replaced by more specific enzymatic methods, which will be discussed later. Carbohydrate metabolism and fuel homeostasis As mentioned, glucose is a primary source of energy for humans. The nervous system, including the brain, is totally dependent on glucose from the surrounding extracellular fluid (ECF) for energy. Nervous tissue cannot concentrate carbohydrates nor can it store them, therefore it is critical to maintain a steady supply to the tissue. For this reason, the concentration of glucose in the ECF must be maintained in a narrow range. When the concentration falls below a certain level, the nervous tissues lose their primary energy source and are incapable of maintaining normal function. Fate Of Glucose Most of our ingested carbohydrates are polymers such as starch and glycogen. Salivary amylase and pancreatic amylase are responsible for the digestion of these non-absorbable polymers to dextrins and disaccharides, which are further hydrolyzed to monosaccharides by maltose, an enzyme released by the instestinal mucosa. Sucrase and lactase are two other important gut-derived anzymes that hydrolyze sucrose to glucose and fructose and lactose to glucose and galactose. Many individuals are lactose intolerant. This can be either congenital or acquired in adulthood, and is caused by a decrease in the expression of lactase on the intestinal lumen brush border. The consumption of milk product s results in an osmotic imbalance due to the retention of lactose in the gut. Intestinal flora are capable of utilizing lactose. The results is an accumulates in the intestine and distention, pain, flatulence, diarrhea, and dehydration leading to electrolyte imbalances can occur. Adults will normally self-regulate imbalances can occur. Adults will normally self-regulate the ingestion of lactose to avoid the discomfort that they have experienced in the past. Congenital lactase deficiency is more serious because lactose is a major component of milk. Severe dehydration in infants can result in ilfe-threatening electrolyte imbalances. The treatment of lactose intolerance in infants is the substitution of milk for a lactose deficient brand. Glucose Metabolism Once disaccharides are converted into monosaccharides, they are absorbed by the gut and transported to the liver by the hepatic portal venous blood supply. Glucose is the only carbohydrate to be either directly utilized for energy or stored as glycogen. Galactose and fructose must be converted to glucose before they can be utilized. After glucose enters the cell, it is quckly shunted into one of three possible metabolic pathaway (described bellow) depending on the availability of substrates or the nutritional status of the cell. The ultimate goal of the cell is to convert glucose to carbon dioxide and water, during which process the cell obtains the high energy molecule adenosine triphosphate (ATP) from inorganic phosphate and adenosine diphosphate (ADP). The cell requires oxygen for the final steps

in the electron transport chain. Nicotinamide adenine dinucleotide in its reduced form (NADH) will act as an intermediate to couple glucose oxidation to the electron transport chain (ETC) in the mitochondria where much of the ATP is gained. The first step for all three pathways requires glucose to be converted to glucose-6-phosphate using the high-energy molecule ATP. This reaction is catalyzed by the enzyme hexokinase (Fig.14-4). Glucose-6-phosphate can enter the Embden-Meyerhof pathway or the hexose monophosphate pathway, or can be important for the generation of energy from glucose; the latter pathway is important for the storage of glucose. The embden-Meyerhof (EM) pathway occurs in the cytosolic comportment of the cell, In this pathway, glucose is broken down into two three-carbon molecules of pyruvic acid, which can enter the tricarboxylic acid sycle (TCA cycle) or be further oxidized to two molecules of lactic acid (fig.14-4). The EM pathway requires no oxygen. Anaerobic glycolysis is important energy requirements without an adequate oxygen supply. These tissues can drive ATP from glucose in oxygen deficit and will accumulate lactic acid. The lactic acid diffuses from the muscle cell, enters the systematic circulation, and is the taken up and utilized by the liver. This process is called Cori, or glucose-lactase, cycle. In order for anaerobic glycolysis to take place, two moles of ATP must be consumed for each mole of glucose; however, four moles of ATP are directly produced resulting in a net gain of two moles of ATP. Further gains of ATP cycle and NADH into the ETC. Other substrates have the opportunity to enter the pathway at several points. Glycerol released from the hydrolysis of triglycerides can enter at 3phospho-glycerate, and fatty acids and ketonase and some amino acids are converted or catabolized to acetyl coenzyme A (Acetyl CoA), Which is part of the TCA cycle . Other amino acids enter the pathway as piruvate or as deaminated keto- and oxoacids. The conversion of fatty acids to acetyl CoA is called Knoops oxidation. The conversion of amino acids by the liver, and other specialized tissues such as the kidney, to substrates that can be converted to glucose is called gluconeo-genesis. Gluconeogenesis also encompasses the conversation of glycerol, lactase, and pyruvate to glucose. The second energy pathway is the hexose monophosphate shunt (HMP shunt), which is actually a detour of glucose-6-phosphate from the glycolytic pathway to become 6-phosphogluconic acid. This oxidized product permits the formation of ribose-5-phosphate and nicotinamide dinucleotide phosphate I its reduced from (NADPH). NADPH is important for erythrocytes, which lack mitochondria and are therefore incapable of use TCA cycle. The reducing power of NADPH is required for the protection of the cell from oxidative and free radical damage. Without NADPH, the lipid bilayer membrane of the cell and critical enzymes would eventually be destroyed , resulting in the death of the cell. The HMP shunt also permits pentoses, such as ribose, to enter the glycolytic patway. When the cells energy requirements are being met , glucose can be stored as glycogen. This third pathway, which is called glycogenesis, is relatively strainghtforward. Glucose-6-phosphate is converted to glucose-1-phosphate, which is then converted to uridine dispoglucose and then to glycogen by glycogen synthase. Several tissues are capable of the synthesis of glycogen, specially the liver and muscles. Hepatocytes are capable of releasing glucose from glycogen or other sources to

maintain the blood glucose concentration. This is because the liver synthesizes the enzyme glucose-6phosphatase. Without this enzyme, glucose is trapped in the glycolytic pathway. Muscle cell do not synthesize glucose-6-phosphatase, and therefore they are incapable of dephosphorylating glucose. Once glucose enters a muscle cell it remains as glycogen unless it is catabbolized. Glycogenolysis is the process by which glycogen is converted back to glucose-6-phosphate for entry into the glycolytic pathway. Table 14-1 outlines the major energy pathways involved either directly or indirectly with glucose metabolism. In summary, rietary glucose and other carbohydrates can either be utilized by the liver and other cells for energy or can be stored as glycogen for later use. When the supply of glucose is low, the liver will use glycogen and other substrates to elevate the blood glucose concentration. These substrates include glycerol from triglycerides, lactic acid from skin and muscles and amino acids. If the lipolysis of triglycerides is upregulated, it results in the formation of ketone bodies, which the brain can use as a source of energy through the TCA cycle. The synthesis of glucose from amino acids is gluconeogenesis. This process is used in conjuction with the formation of ketone bodies when glycogen stores are deplated-conditions normally associated with starvation. The principle pathway for glucose oxidation is through the Embden-Meyerhof pathway. NADPH can be synthesized through the HMP shunt, which is aside pathway from the anaerobic glycolytic pathway. Regulation of Glucose Metabolism The liver, pancreas, and other endocrine glands do a remarkable job of keeping blood glucose concenteations within a narrow range. During a brief fast, glucose is supplied to the ECF from the liver through glycogenolysis. When the fasting period is longer than one day, glucose is synthesized from other sources through gluconeogenesis. Control of blood glucose is under two major hormones: insulin and glucagon (Figs. 14-5 and 14-6a). Other hormones and neuroendocrine substance also exert some control over blood glucose concentrations. This permits the body to respond to increased demands for glucose or to survive prolonged fasts. It also permits the conservation of energy as lipids when excess substrates are ingested. HORMONAL REGULATION Hormones function at several levels and in many different tissues. Their actions can affect the entry of glucose into the cell and can also influence the fate of glucose once it has entered the cell. To Understand the action of hormones on the cell, first consider what would occur I we did not have regulatory mechanisms for glucose control. After a meal is ingested and as digestion occurs, the simple sugars will be absorbed first. This will be followed by the digestion and absorption of more complex sugars. The absorptive state is referred to as the postprandial state. The concentration of glucose in blood increases soon after a meal, and without endocrine control this concentration would keep increasing for a few hours. Hyperglycemia, an elevation of glucose in the ECF, including blood, would pull water from cells. If the concentration of glucose rose above 180 mg/dL, the tubular cells of the renal epithelium would not be able to completely reabsorb it from the filtrate, and some glucose would pass into the urine. This is called glucosuria an would result in the loss of water and electrolytes from the

body. Remember that the brain requires a steady supply of glucose. Other tissues, such as muscle, very their glucose requirements depending on their energy needs. After the carbohydrates from the meal are completely absorbed, the bodys needs must still be met. This is the postabsorptive state. Unless another meal is eaten, the concentration of ECF glucose will decrease and the bodys nervous tissue will lose function, resulting in hypoglycemic shock and, eventually, coma. Therefore, the endocrine system must assist in the meeting of three requirements: a steady supply of glucose must be available under all normal circumstances, excess glucose must be safely stored to prevent it from causing alterations is fluid and electrolyte balance or being lost, and the stored glucose must be to supply the ECF when glucose is not being absorbed by the gut. Insulin is a peptide hormone that is synthesized in the cell of the islets of Langerhans in the cells of the islets of Langerhans in the pancreas. Insulin is the primary hormone responsible for the entry of glucose into celss; therefore insulin production and release increases after a meal, when ECF glucose concentrations are increasing (see Fig. 14-5). This protein is synthesized and stored in vesicles in the cytosol of the cells unit it is needed. As with most proteins that are synthesized with the specific aim of release into the blood stream, insulin is synthesized with a short leader peptide sequence. Once the pre-proinsulin leader peptide is cleaved, the proinsulin peptide, which is 82 amino acids long, is further cleaved by specific proteases. A 31-amino acid stretch is removed from the middle of the protein leaving a dipeptide with an and chain of 21 and 30 amino acids long, respectively. The dipeptide is held together by disulfide bons between cysteines on the and chains. The internal peptide that was cleaved by the protease is called the C-peptide. It has no known function in glucose regulation and is released from the vesicle along with insulin. Insulin release is response to an increase in ECF glucose concentration is biphasic. There is an initial small rapid increase in circulating insulin that is additional to the prolonged release of insulin from the cell. Insulin release is terminated when ECF glucose concentrations begin to decrease. Insulin binds to a receptor on the surface of most cells except neurons, erythrocytes, and retinal epithelium . These specialized cells obtain glucose without endocrine control. On all other cells the insulin-insulin reseptor complex initiates a chain of events in the cell, which first increases the number of glucose transporters on the cell surface and then increases glycogenesis. This glucose transporters provide for the passage of glucose into the cell.