BIOCHEMISTRY: A TEXTBOOK FOR UNIVERSITIES - E. S. Severin - 2004

CHAPTER 7. CARBOHYDRATE METABOLISM

III. Mechanism of Transmembrane Transport of Glucose and Other Monosaccharides into Cells

Monosaccharides resulting from Digestion are absorbed by the epithelial Cells of the jejunum and ileum via specialized transport mechanisms across the membranes of these cells.

A. Intestinal absorption of monosaccharides

The transport of monosaccharides into the intestinal mucosal cells can occur via different mechanisms: Facilitated Diffusion and Active Transport. In active transport, glucose and Na⁺ cross the luminal membrane by binding to different sites on a carrier protein. Concurrently, Na⁺ enters The Cell down its concentration gradient while glucose is transported against its concentration gradient (secondary active transport, see Chapter 5). Consequently, the steeper the Na⁺ gradient, the greater the influx of glucose into enterocytes. If the extracellular concentration decreases, glucose transport drops. The Na⁺ concentration gradient, which serves as the driving force for active symport, is maintained by the action of Na⁺, K⁺-ATPase. Secondary active transport is also the mechanism responsible for the uptake of galactose into the intestinal mucosal cells.

Different transport mechanisms operate depending on the glucose concentration in the intestinal lumen. Thanks to active transport, intestinal epithelial cells can absorb glucose even when its luminal concentration is very low. Conversely, when the luminal glucose concentration is high, it can be transported into the cell via facilitated diffusion. Fructose can be absorbed in the same manner. It should be noted that the absorption rate of glucose and galactose is significantly higher than that of other monosaccharides. The modes of monosaccharide Transport Across the intestinal epithelial cell membrane are illustrated in Fig. 7-18.

Class="center">Fig. 7-18. Intestinal Carbohydrate Absorption. Monosaccharides are absorbed from the gut via facilitated diffusion mediated by specialized carrier Proteins (transporters). In addition, glucose and galactose are transported into enterocytes by secondary active transport driven by the sodium ion concentration gradient. Na⁺-dependent transporter proteins facilitate the uptake of glucose from the intestinal lumen into enterocytes against its concentration gradient. The Na⁺ concentration required for this transport is sustained by Na⁺, K⁺-ATPase, which Functions as a pump, extruding Na⁺ from the cell in exchange for K⁺. Unlike glucose, fructose is transported via a system independent of the sodium gradient.

Following absorption, monosaccharides (primarily glucose) exit the intestinal mucosal cells across the basolateral membrane facing the Blood capillaries via facilitated diffusion. A portion of the glucose (more than half) enters the bloodstream through the capillaries of the intestinal villi and is delivered to the Liver via the portal vein. The remaining glucose is distributed to the cells of other Tissues.

B. Transport of glucose from blood into cells

Cellular uptake of glucose from the bloodstream also occurs via facilitated diffusion. Consequently, The rate of transmembrane glucose flux depends solely on its concentration gradient. An exception is found in Muscle and adipose tissue cells, where facilitated diffusion is regulated by Insulin (a pancreatic hormone). In the absence of insulin, The Plasma Membrane of these cells is impermeable to glucose because it lacks glucose carrier proteins (transporters). Glucose transporters are also referred to as glucose receptors. For instance, a glucose transporter isolated from erythrocytes has been well characterized. It is a transmembrane protein whose polypeptide chain consists of 492 amino acid residues and exhibits a domain Structure. The polar domains of the protein are located on opposite sides of the membrane, whereas the hydrophobic domains span the membrane multiple times. The transporter features a glucose-binding site on the outer surface of the membrane. Upon glucose binding, the protein undergoes a conformational change, which positions the bound glucose at an intracellularly facing site. The glucose is then released into the cell interior (see Chapter 5).

It is believed that facilitated diffusion, as opposed to active transport, prevents the cotransport of ions along with glucose when the latter is transported down its concentration gradient.

Glucose transporters (GLUTs) have been identified in all tissues. There are several isoforms of GLUTs (Table 7-1), numbered in the order of their discovery.

Table 7-1. Distribution of glucose transporter proteins (GLUTs)

The structure of GLUT family proteins differs from that of the proteins responsible for transporting glucose across the intestinal and renal membranes against a concentration gradient.

The 5 described GLUT types share similar primary structures and domain organizations.

✵ GLUT-1 maintains a steady basal influx of glucose into the brain;

✵ GLUT-2 is found in cells of Organs that release glucose into the blood. Specifically, GLUT-2 mediates the efflux of glucose from enterocytes and the liver into the bloodstream. GLUT-2 also participates in Glucose Transport into pancreatic β-cells;

✵ GLUT-3 has a higher affinity for glucose than GLUT-1. It also ensures a continuous supply of glucose to neural and other tissues;

✵ GLUT-4 is the major glucose transporter in muscle and adipose tissue cells;

✵ GLUT-5 is located primarily in the cells of the small intestine. Its exact physiological functions require further elucidation.

All GLUT isoforms can reside in both the plasma membrane and cytosolic vesicles. GLUT-4 (and to a lesser extent, GLUT-1) is sequestered almost entirely within the Cell Cytoplasm. The Action of Insulin on these cells triggers the translocation of GLUT-containing vesicles to the plasma membrane, where they fuse and incorporate the transporters into the membrane. This process enables the facilitated uptake of glucose into the cells. Following a decrease in blood insulin levels, the glucose transporters return to the cytoplasm, and glucose entry into the cell ceases (Fig. 7-19).

Fig. 7-19. Effect of insulin on the translocation of glucose transporters from the cytoplasm to the plasma membrane. 1 — binding of insulin to its receptor; 2 — the intracellular domain of the Insulin Receptor stimulates the mobilization of glucose transporters; 3, 4 — transporter-containing vesicles migrate to the cell plasma membrane, integrate into it, and mediate glucose uptake into the cell.

The movement of glucose from the primary urine into the cells of the renal tubules occurs via secondary active transport, similarly to how glucose is absorbed from the intestinal lumen into enterocytes. Due to this mechanism, glucose can enter the cells even if its concentration in the primary urine is lower than that inside the cells. As a result, almost all glucose (99%) is reabsorbed from the primary urine.

Various disorders affecting glucose transporters are known. A hereditary defect in these proteins may underlie non-insulin-dependent Diabetes Mellitus (see Section 11). However, impaired glucose transporter function can be caused not only by a defect in the protein itself. Dysfunction of GLUT-4 may occur at the following stages:

✵ insulin signal Transduction regarding the translocation of this transporter to the membrane;

✵ intracellular trafficking of the transporter;

✵ insertion into the plasma membrane;

✵ endocytosis (vesicle budding) from the membrane, etc.