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The human genome encodes at least 14 highly homologous GLUT proteins, GLUT1–GLUT14, that are all thought to contain 12 membrane-spanning α helices, suggesting that they evolved from a single ancestral transport protein. In the human GLUT1 protein, the transmembrane α helices are predominantly hydrophobic; several helices, however, bear amino acid residues (e.g., serine, threonine, asparagine, and glutamine) whose side chains can form hydrogen bonds with the hydroxyl groups on glucose. These residues are thought to form the inward-facing and outward-facing glucose-binding sites in the interior of the protein (see Figure 11-5).

The structures of all GLUT isoforms are thought to be quite similar, and all of them transport sugars. Nonetheless, their differential expression in various cell types, the regulation of their numbers on cell surfaces, and isoform-specific functional properties enable different body cells to regulate glucose metabolism differently and at the same time allow a constant concentration of glucose in the blood to be maintained. For instance, GLUT3 is found in neuronal cells of the brain. Neurons depend on a constant influx of glucose for metabolism, and the low K_m of GLUT3 for glucose (1.5 mM), like that of GLUT1, ensures that these cells incorporate glucose from brain extracellular fluids at a high and constant rate.

GLUT2, expressed in liver cells and in the insulin-secreting β islet cells of the pancreas, has a K_m of ~20 mM, about 13 times higher than the K_m of GLUT1. As a result, when blood glucose rises after a meal from its basal level of 5 mM to 10 mM or so, the rate of glucose influx will almost double in GLUT2-expressing cells, whereas it will increase only slightly in GLUT1-expressing cells (see Figure 11-4). In the liver, the “excess” glucose brought into the cell is stored as the polymer glycogen. In β islet cells, the rise in glucose triggers secretion of the hormone insulin (see Figure 16-39), which in turn lowers blood glucose by increasing glucose uptake and metabolism in muscle and by inhibiting glucose production in the liver (see Figure 15-37). Indeed, cell-specific inactivation of GLUT2 in pancreatic β islet cells prevents glucose-stimulated insulin secretion and disrupts the regulated expression of glucose-sensitive genes in liver cells (hepatocytes).

Another GLUT isoform, GLUT4, is expressed only in fat and muscle cells, which respond to insulin by increasing their uptake of glucose, thereby removing glucose from the blood. In the absence of insulin, GLUT4 resides in intracellular membranes, not the plasma membrane, and is unable to facilitate glucose uptake from the extracellular fluid. By a process detailed in Figure 16-40, insulin causes these GLUT4-rich internal membranes to fuse with the plasma membrane, increasing the number of GLUT4 molecules present on the cell surface and thus the rate of glucose uptake. This is one principal mechanism by which insulin lowers blood glucose; defects in the movement of GLUT4 to the plasma membrane are one of the causes of adult-onset, or type II, diabetes, a disease marked by continuously high blood glucose.

GLUT5 is the only GLUT protein with a high specificity (preference) for fructose; its principal site of expression is the apical membrane of intestinal epithelial cells, where it transports dietary fructose from the intestinal lumen to the inside of the cells.