Medical Physiology, 3rd Edition

Carbohydrate Absorption

The three monosaccharide products of carbohydrate digestion—glucose, galactose, and fructose—are absorbed by the small intestine in a two-step process involving their uptake across the apical membrane into the epithelial cell and their coordinated exit across the basolateral membrane (see Fig. 45-3C). Na/glucose transporter 1 (SGLT1) is the membrane protein responsible for glucose and galactose uptake at the apical membrane. The exit of all three monosaccharides across the basolateral membrane uses a facilitated sugar transporter (GLUT2). Because SGLT1 cannot carry fructose, the apical step of fructose absorption occurs by the facilitated diffusion of fructose via GLUT5. Thus, although two different apical membrane transport mechanisms exist for glucose and fructose uptake, a single transporter (GLUT2) is responsible for the movement of both monosaccharides across the basolateral membrane.

SGLT1 is responsible for the Na⁺-coupled uptake of glucose and galactose across the apical membrane

The uptake of glucose across the apical membrane via SGLT1 (Fig. 45-5A) represents active transport, because the glucose influx occurs against the glucose concentration gradient (see pp. 121–122). Glucose uptake across the apical membrane is energized by the electrochemical Na⁺ gradient, which in turn is maintained by the extrusion of Na⁺ across the basolateral membrane by the Na-K pump. This type of Na⁺-driven glucose transport is an example of secondary active transport (see p. 115). Inhibition of the Na-K pump reduces active glucose absorption by decreasing the apical membrane Na⁺ gradient and thus decreasing the driving force for glucose entry.

FIGURE 45-5 Na⁺-coupled hexose transporter. A, The SGLT family of proteins has 14 membrane-spanning segments. This diagram represents the structure of the vSGLT Na/galactose cotransporter from the bacterium Vibrio parahaemolyticus. B, SGLT1 transports only hexoses in a D configuration and with a pyranose ring. This figure shows D-glucose; D-galactose is identical, except that the H and OH on carbon 4 are inverted. (A, Data from Faham S, Watanabe A, Besserer GM, et al: The crystal structure of a sodium galactose transporter reveals mechanistic insights into Na+/sugar symport. Science 321:810–814, 2008.)

The affinity of SGLT1 for glucose is markedly reduced in the absence of Na⁺. The varied affinity of SGLT1 for different monosaccharides reflects its preference for specific molecular configurations. SGLT1 has two structural requirements for monosaccharides: (1) a hexose in a D configuration, and (2) a hexose that can form a six-membered pyranose ring (see Fig. 45-5B). SGLT1 does not absorb L-glucose, which has the wrong stereochemistry, and it does not absorb D-fructose, which forms a five-membered ring (Box 45-2). N45-4

Molecular studies have been performed on jejunal mucosa from patients with so-called glucose-galactose malabsorption (or monosaccharide malabsorption). These individuals have diarrhea when they ingest dietary sugars that are normally absorbed by SGLT1. This diarrhea results from both reduced small-intestinal Na⁺ and fluid absorption (as a consequence of the defect in Na⁺-coupled monosaccharide absorption) and fluid secretion secondary to the osmotic effects of nonabsorbed monosaccharide. Eliminating the monosaccharides glucose and galactose, as well as the disaccharide lactose (i.e., glucose + galactose), from the diet eliminates the diarrhea. The monosaccharide fructose, which crosses the apical membrane via GLUT5, does not induce diarrhea. Early studies identified the abnormality in this hereditary disorder as a defect at the apical membrane that is presumably related to defective or absent SGLT1. Molecular studies of SGLT1 have revealed multiple mutations that result in single amino-acid substitutions in SGLT1, each of which prevents the transport of glucose by SGLT1 in affected individuals. Patients with glucose-galactose malabsorption do not have glycosuria (i.e., glucose in the urine), because glucose reabsorption by the proximal tubule normally occurs via both SGLT1 and SGLT2 (see p. 772).

Contributed by Emile Boulpaep, Walter Boron

Because the membrane potential across the luminal membrane is 40 to 50 mV (cell interior negative), and intracellular [Na⁺] is far less than luminal [Na⁺], a “downhill” electrochemical Na⁺ gradient exists across the apical membrane that is the primary driving force for the uptake of glucose (and other actively transported monosaccharides) by SGLT1 (see pp. 121–122).

Glucose uptake at the apical membrane has other characteristics of a carrier-mediated active transport process, including saturation kinetics, competitive inhibition, and energy dependence.

SGLT1 belongs to the SLC5 family of transporters that couple Na⁺ to monosaccharides and other small molecules. These membrane proteins have 14 predicted membrane-spanning segments. The gene for SGLT1 has been localized to human chromosome 22. Kinetic studies of the SGLT1 expressed in host cells have confirmed many of the characteristics of the Na/glucose cotransport system that had been identified in native tissue. Expression studies have established that the Na⁺:sugar stoichiometry of SGLT1 is a 2 : 1 ratio. Its cousins SGLT2 and SGLT3 both have an Na⁺:sugar stoichiometry of 1 : 1.

For a discussion of the stereospecificity of sugars, see the biochemistry text by Voet and Voet, page 254 (Fig. 10–4).

References

Voet D, Voet J. Biochemistry. ed 2. Wiley: New York; 1995.

Wright EM, Turk E. The sodium/glucose cotransport family SLC5. Pflugers Arch. 2004;447:510–518.

The GLUT transporters mediate the facilitated diffusion of fructose at the apical membrane and of all three monosaccharides at the basolateral membrane

Early work showed that fructose absorption is independent of Na⁺ but has characteristics of both a carrier-mediated and a passive process. These observations show that the small intestine has separate transport systems for glucose and fructose. Subsequent studies established that facilitated diffusion is responsible for fructose absorption. Fructose uptake across the apical membrane is mediated by GLUT5, a member of the GLUT family of transport proteins (see p. 114). GLUT5 is present mainly in the jejunum. N45-5

Contributed by Emile Boulpaep, Walter Boron

The GLUT transporters are part of the SLC2 family of hexose and polyol transporters. Based on hydropathy analysis and other data, these proteins are believed to have 12 transmembrane segments. Note that the GLUT transporters (see p. 114) have no homology to Na/glucose cotransporters—or SGLTs (see pp. 121–122).

GLUT2 is a basolateral membrane transport protein that carries glucose, galactose, and fructose. It consists of 524 amino acids.

GLUT5 is an apical membrane protein that carries fructose. It consists of 501 amino acids, and its mRNA has been primarily identified in the jejunum. GLUT5 has 41% homology to GLUT2.

Reference

Uldry M, Thorens B. The SLC2 family of facilitated hexose and polyol transporters. Pflugers Arch. 2004;447:480–489.

The efflux of glucose, fructose, and galactose across the basolateral membrane also occurs by facilitated diffusion. The characteristics of the basolateral sugar transporter, identified as GLUT2, are similar to those of other sugar transport systems in erythrocytes, fibroblasts, and adipocytes. GLUT2 has no homology to SGLT1 but is 41% identical to GLUT5, which is responsible for the uptake of fructose from the lumen.