Medical Physiology, 3rd Edition

Carbohydrate Digestion

Carbohydrates, providing ~45% of total energy needs of Western diets, require hydrolysis to monosaccharides before absorption

We can classify dietary carbohydrates into two major groups: (1) the monosaccharides (monomers), and (2) the oligosaccharides (short polymers) and polysaccharides (long polymers). The small intestine can directly absorb the monomers but not the polymers. Some polymers are digestible, that is, the body can digest them to form the monomers that the small intestine can absorb. Other polymers are nondigestible, or “fiber.” The composition of dietary carbohydrate is quite varied and is a function of culture. The diet of individuals in so-called developed countries contains considerable amounts of “refined” sugar and, compared with individuals in most developing countries, less fiber. Such differences in the fiber content of the Western diet may account for several diseases that are more prevalent in these societies (e.g., colon carcinoma and atherosclerosis). As a consequence, the consumption of fiber by the health-conscious public in the United States has increased during the past 3 decades. In general, increased amounts of fiber in the diet are associated with increased stool weight and frequency.

Approximately 45% to 60% of dietary carbohydrate is in the form of starch, which is a polysaccharide. Starch is a storage form for carbohydrates that is primarily found in plants, and it consists of both amylose and amylopectin. In contrast, the storage form of carbohydrates in animal tissues is glycogen, which is consumed in much smaller amounts. Amylose is a straight-chain glucose polymer that typically contains multiple glucose residues, connected by α-1,4 linkages. In contrast, amylopectin is a massive branched glucose polymer that may contain 1 million glucose residues. In addition to the α-1,4 linkages, amylopectin has frequent α-1,6 linkages at the branch points. Amylopectins are usually present in much greater quantities (perhaps 4-fold higher) than amylose. Glycogen—the “animal starch”—has α-1,4 and α-1,6 linkages like amylopectin. However, glycogen is more highly branched (i.e., more α-1,6 linkages).

Most dietary oligosaccharides are the disaccharides sucrose and lactose, which represent 30% to 40% of dietary carbohydrates. Sucrose is table sugar, derived from sugar cane and sugar beets, whereas lactose is the sugar found in milk. The remaining carbohydrates are the monosaccharides fructose and glucose, which make up 5% to 10% of total carbohydrate intake. There is no evidence of any intestinal absorption of either starches or disaccharides. Because the small intestine can absorb only monosaccharides, all dietary carbohydrate must be digested to monosaccharides before absorption. The colon cannot absorb monosaccharides.

Dietary fiber consists of both soluble and insoluble forms and includes lignins, pectins, and cellulose. These fibers are primarily present in fruits, vegetables, and cereals. Cellulose is a glucose polymer connected by β-1,4 linkages, which cannot be digested by mammalian enzymes. However, enzymes from colonic bacteria may degrade fiber. This process is carried out with varying efficiency; pectins, gum, and mucilages are metabolized to a much greater degree than either cellulose or hemicellulose. In contrast, lignins, which are aromatic polymers and not carbohydrates, are not altered by microbial enzymes in the colonic lumen and are excreted unaltered in stool.

As we discuss below, the digestive process for dietary carbohydrates has two steps: (1) intraluminal hydrolysis of starch to oligosaccharides by salivary and pancreatic amylases (Fig. 45-3), and (2) so-called membrane digestion of oligosaccharides to monosaccharides by brush-border disaccharidases. The resulting carbohydrates are absorbed by transport processes that are specific for certain monosaccharides. These transport pathways are located in the apical membrane of the small-intestinal villous epithelial cells.

FIGURE 45-3 Digestion of carbohydrates to monosaccharides. A, Salivary and pancreatic α-amylase are endoenzymes. They can digest the linear “internal” α-1,4 linkages between glucose residues but cannot break “terminal” α-1,4 linkages between the last two sugars in the chain. They also cannot split the α-1,6 linkages at the branch points of amylopectin or the adjacent α-1,4 linkages. As a result, the products of α-amylase action are linear glucose oligomers, maltotriose (a linear glucose trimer), maltose (a linear glucose dimer), and α-limit dextrins (which contain an α-1,6 branching linkage). B, The brush-border oligosaccharidases are intrinsic membrane proteins with their catalytic domains facing the lumen. Sucrase-isomaltase is actually two enzymes, and therefore, there are a total of four oligosaccharidases that split the oligosaccharides produced by α-amylase into monosaccharides. C, SGLT1 is the Na⁺-coupled transporter that mediates the uptake of glucose or galactose from the lumen of the small intestine into the enterocyte. GLUT5 mediates the facilitated diffusion of fructose into the enterocyte. Once the monosaccharides are inside the enterocyte, GLUT2 mediates their efflux across the basolateral membrane into the interstitial space.

Luminal digestion begins with the action of salivary amylase and finishes with pancreatic amylase

Acinar cells from both the salivary glands (see pp. 893–894) and pancreas (see p. 882) synthesize and secrete α-amylases. Salivary and pancreatic amylases, unlike most of the pancreatic proteases that we discuss below, are secreted not in an inactive proenzyme form, but rather in an active form. Salivary and pancreatic α-amylases have similar enzymatic function, and their amino-acid sequences are 94% identical.

Salivary α-amylase in the mouth initiates starch digestion; in healthy adults, this step is of relatively limited importance. Salivary amylase is inactivated by gastric acid but can be partially protected by complexing with oligosaccharides.

Pancreatic α-amylase completes starch digestion in the lumen of the small intestine. Although amylase binds to the apical membrane of enterocytes, this localization does not provide any kinetic advantage for starch hydrolysis. Cholecystokinin (CCK; see pp. 882–883) stimulates the secretion of pancreatic α-amylase by pancreatic acinar cells.

α-amylase is an endoenzyme that hydrolyzes internal α-1,4 linkages (see Fig. 45-3A). α-amylase does not cleave terminal α-1,4 linkages, α-1,6 linkages (i.e., branch points), or α-1,4 linkages that are immediately adjacent to α-1,6 linkages. As a result, starch hydrolysis products are maltose, maltotriose, and α-limit dextrins. Because α-amylase has no activity against terminal α-1,4 linkages, glucose is not a product of starch digestion. The intestine cannot absorb these products of amylase digestion of starch, and thus further digestion is required to produce substrates (i.e., monosaccharides) that the small intestine can absorb by specific transport mechanisms.

“Membrane digestion” involves hydrolysis of oligosaccharides to monosaccharides by brush-border disaccharidases

The human small intestine has three brush-border proteins with oligosaccharidase activity: lactase, glucoamylase (most often called maltase), and sucrase-isomaltase. These are all integral membrane proteins whose catalytic domains face the intestinal lumen (see Fig. 45-3B). Sucrase-isomaltase is actually two enzymes—sucrase and isomaltase (also known as α-dextrinase or debranching enzyme)—bound together. Thus, four oligosaccharidase entities are present at the brush border. Lactase has only one substrate; it breaks lactose into glucose and galactose. The other three enzymes have more complicated substrate spectra. All will cleave the terminal α-1,4 linkages of maltose, maltotriose, and α-limit dextrins. In addition, each of these three enzymes has at least one other activity. Maltase can also degrade the α-1,4 linkages in straight-chain oligosaccharides up to nine monomers in length. However, maltase cannot split either sucrose or lactose. The sucrase moiety of sucrase-isomaltase is required to split sucrose into glucose and fructose. The isomaltase moiety of sucrase-isomaltase is critical; it is the only enzyme that can split the branching α-1,6 linkages of α-limit dextrins. N45-2

Contributed by Emile Boulpaep, Walter Boron

The oligosaccharidases are large integral membrane proteins that are anchored to the apical membrane by a transmembrane stalk; >90% of the protein is extracellular. Villous epithelial cells synthesize the disaccharidases via the secretory pathway (see pp. 34–35). The proteins undergo extensive N-linked and O-linked glycosylation in the Golgi and then traffic to the apical membrane.

Sucrase-isomaltase is a special case. After the insertion of the single sucrase-isomaltase peptide (including its transmembrane stalk) into the brush-border membrane, pancreatic proteases cleave the peptide between the sucrase and isomaltase moieties. After this cleavage, the isomaltase moiety remains continuous with the transmembrane stalk, and the sucrase moiety remains attached to the isomaltase moiety by van der Waals forces. Thus, sucrase-isomaltase differs from the other two oligosaccharidases in that the mature protein consists of two peptide chains (encoded by the same mRNA nonetheless), each with a distinct catalytic site and distinct substrate specificities.

See eFigure 45-1 for a summary of the composition of sugars and oligosaccharides. As we saw in the text, sucrase is unique in splitting sucrose, and the isomaltase is unique in splitting the α-1,6 linkage of α-limit dextrins. The table lists the enzymatic specificities for each of the brush-border oligosaccharidases.

EFIGURE 45-1 Composition of common oligosaccharide.

^*Sucrase and isomaltase are separate peptides, held together by van der Waals forces and anchored to the membrane via the transmembrane stalk of the isomaltase.

The action of the four oligosaccharidases generates several monosaccharides. Whereas the hydrolysis products of maltose are two glucose residues, those of sucrose are glucose and fructose. The hydrolysis of lactose by lactase yields glucose and galactose. The activities of the hydrolysis reactions of sucrase-isomaltase and maltase are considerably greater than the rates at which the various transporters can absorb the resulting monosaccharides. Thus, uptake, not hydrolysis, is the rate-limiting step. In contrast, lactase activity is considerably less than that of the other oligosaccharidases and is rate limiting for overall lactose digestion-absorption.

The oligosaccharidases have a varying spatial distribution throughout the small intestine. In general, the abundance and activity of oligosaccharidases peak in the proximal jejunum (i.e., at the ligament of Treitz) and are considerably less in the duodenum and distal ileum. Oligosaccharidases are absent in the large intestine. The distribution of oligosaccharidase activity parallels that of active glucose transport.

These oligosaccharidases are affected by developmental and dietary factors in different ways. In many nonwhite ethnic groups, as well as in almost all other mammals, lactase activity markedly decreases after weaning in the postnatal period. The regulation of this decreased lactase activity is genetically determined. N45-3 The other oligosaccharidases do not decrease in the postnatal period. In addition, long-term feeding of sucrose upregulates sucrase activity. In contrast, fasting reduces sucrase activity much more than it reduces lactase activity. In general, lactase activity is both more susceptible to enterocyte injury (e.g., following viral enteritis) and slower to recover from damage than is other oligosaccharidase activity. Thus, reduced lactase activity (as a consequence of both genetic regulation and environmental effects) has substantial clinical significance in that lactose ingestion may result in a range of symptoms in affected individuals (Fig. 45-4A, Box 45-1).

FIGURE 45-4 Effects of lactase deficiency on levels of glucose in the plasma and H₂ in the breath. A, In an individual with normal lactase activity, blood glucose levels rise after the ingestion of either glucose or lactose. Thus, the small intestine can split the lactose into glucose and galactose, and absorb the two monosaccharides. At the same time, H₂ in the breath is low. B, In an adult with low lactase activity, the rise in blood levels is less pronounced after ingesting lactose. Because the rise is normal after ingesting glucose, we can conclude that the difference is due to lactase activity. Conversely, the individual with lactase deficiency excretes large amounts of H₂ into the breath. This H₂ is the product of lactose catabolism by colonic bacteria.

Primary lactase deficiency is most prevalent in nonwhites, and it also occurs in some whites. Primary lactase deficiency represents an isolated deficiency of lactase, with all other brush-border enzymes being at normal levels and without any histological abnormalities. Lactase activity decreases after weaning; the time course of its reduction is determined by hereditary factors. Ingestion of lactose in the form of milk and milk products by individuals with decreased amounts of small-intestinal lactase activity may be associated with a range of gastrointestinal symptoms, including diarrhea, cramps, and flatus, or with no discernible symptoms. Several factors determine whether individuals with lactase deficiency experience symptoms after ingestion of lactose, including rate of gastric emptying, transit time through the small intestine, and, most importantly, the ability of colonic bacteria to metabolize lactose to SCFAs, N45-1 CO₂, and H₂. Figure 45-4A shows the rise of plasma [glucose] following the ingestion of either lactose or glucose in adults with normal lactase levels. This figure also shows that the [H₂] in the breath rises only slightly following the ingestion of either lactose or glucose in individuals with normal lactase levels. Figure 45-4B shows that in individuals with primary lactase deficiency, the ingestion of lactose leads to a much smaller rise in plasma [glucose], although the ingestion of glucose itself leads to a normal rise in plasma [glucose]. Thus, no defect in glucose absorption per se is present, but simply a markedly reduced capacity to hydrolyze lactose to glucose and galactose. In lactase-deficient individuals, breath H₂ is markedly increased after lactose ingestion because nonabsorbed lactose is metabolized by colonic bacteria to H₂, which is absorbed into the blood and is subsequently excreted by the lungs. In contrast, the rise in breath H₂ after the ingestion of glucose is normal in these individuals.

Treatment for symptomatic individuals with primary lactase deficiency is reduction or elimination of consumption of milk and milk products or the use of milk products treated with a commercial lactase preparation.

Contributed by Henry Binder

Some authors object to the statement that lactose intolerance in adults is a lactase “deficiency” and instead propose that the normal course of events is for lactase activity to decline after weaning. According to one view, lactase “persistence” evolved in certain human populations after the domestication of herd animals allowed the consumption of nonhuman milk. This hypothesis could account for the geographical distribution of lactose intolerance in humans.