**1. Introduction**

Glucose represents the major energy source of mammalian cells. Due to its hydrophilic nature, glucose requires specific transporters in order to cross cellular membranes. Such transport is, in the case of glucose and also other monosaccharides, mediated by energy-coupled as well as facilitative mechanisms represented by protein families of sodium-driven sugar cotransporters (SGLTs) and glucose transporters (GLUTs), respectively.

SGLT cotransporter family present highly diverse functions. They cotransport Na+ with glucose (SGLT1, SGLT2, SGLT4, SGLT5), or galactose (SGLT1, SGLT5) or mannose (SGLT5) or fructose (SGLT5) but also with myoinositol (SGLT6, SMIT), with iodine (NIS) or with choline (CHT). One family member is not a transporter but a glucose sensor (SGLT3). Na+ gradient for this cotransporter family is maintained by Na+/K(+)-ATPase [1].

The various members of the GLUT protein family is comprised of 14 isoforms [2]

The GLUT protein family consists of three different families that can be distinguished based on their protein sequence homologies: Class I comprises the classical transporters GLUT1-4 as well as the gene duplication of GLUT3 which is GLUT14, Class II contains the isoforms GLUT5, 7, 9, and 11, while GLUT6, 8, 10, 12 and the proton-driven myo-inositol transporter HMIT (GLUT13) belong to the Class III [3].

Current understanding of whole body glucose homeostasis under normal-and, more impor‐ tantly, under disease conditions-is directly linked to the understanding of SGLT and GLUT physiology (Figure 1). The active mechanism of glucose (as well as galactose) absorption in the intestine is primarily catalysed by SGLT1 (Figure 3B), while SGLT2 represents the pre‐ dominant mechanism for glucose reuptake by the kidney (Figure 3A).

© 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**Figure 1.** Overview on the principle physiological role for specific glucose transporters and their involvement in regu‐ lating glucose homeostasis in specific tissues.

**Figure 2. Putative secondary structural models for GLUT and SGLT proteins**. **A-**SGLT family members contain 14 transmembrane domains [21]. Highlighted is the presence of the SSF motif present in all members of the solute sym‐ porter family (SSF) gene family. The motif that is shared between the SGLTs and sodium-myoinositol cotransporters (SMITs) is also indicated. The glucose-binding and-translocation domain is located at the COOH-terminus of the pro‐ tein. The residues that are proposed to be involved in glucose binding at the extra-and intracellular sides of the mem‐ brane are highlighted. **B-**GLUT proteins contain 12 transmembrane regions. Specific structural features for class I and II (upper panel) and class III (lower panel) family members are indicated such as the proposed substrate binding site, the N-linked glycosylation sites, conserved signature sequences. The tryptophan residues implicated in cyto-chalasin B (CB) binding (positions 338 and 412 in GLUT1) and the N-terminal dileucine signal present in class III members (except

Mammalian Sugar Transporters http://dx.doi.org/10.5772/58325 5

for GLUT10) are also shown.

**Figure 2. Putative secondary structural models for GLUT and SGLT proteins**. **A-**SGLT family members contain 14 transmembrane domains [21]. Highlighted is the presence of the SSF motif present in all members of the solute sym‐ porter family (SSF) gene family. The motif that is shared between the SGLTs and sodium-myoinositol cotransporters (SMITs) is also indicated. The glucose-binding and-translocation domain is located at the COOH-terminus of the pro‐ tein. The residues that are proposed to be involved in glucose binding at the extra-and intracellular sides of the mem‐ brane are highlighted. **B-**GLUT proteins contain 12 transmembrane regions. Specific structural features for class I and II (upper panel) and class III (lower panel) family members are indicated such as the proposed substrate binding site, the N-linked glycosylation sites, conserved signature sequences. The tryptophan residues implicated in cyto-chalasin B (CB) binding (positions 338 and 412 in GLUT1) and the N-terminal dileucine signal present in class III members (except for GLUT10) are also shown.

**Figure 1.** Overview on the principle physiological role for specific glucose transporters and their involvement in regu‐

lating glucose homeostasis in specific tissues.

4 Glucose Homeostasis

**Figure 3. SGLT and GLUT family members regulate intestinal absorption and renal reabsorption of hexoses.A-Renal glucose reabsorption.** In the kidney, proximal tubule transepithelial reabsorption of glucose occurs at the api‐ cal membrane by SGLT2 and GLUT2 at the basolateral membrane. In the proximal straight tubule, the remaining glucose is reabsorbed by SGLT1 at the apical site of the epithelium and GLUT1 at the basolateral membrane. **B-Intesti‐ nal glucose absorption.** In the intestine, transepithelial glucose uptake at the apical site is mediated by the Na+-de‐ pendent glucose transporter SGLT1, while fructose is absorbed by facilitated diffusion via GLUT5. These hexoses can all exit the basolateral membrane through GLUT2.

**Figure 4. GLUT family members facilitate glucose transport into tissues that control glucose homeostasis such as hepatocytes, skeletal muscle, adipose tissue, and the pancreatic β-cells of the islets of Langerhans. A-Hexose transport in hepatocytes**. GLUT2 mediates glucose uptake under feeding conditions into hepatocytes where glucose is metabolized by glycolysis or incorporated into glycogen. In patients with FBS fructose handling is normal, therefore

Mammalian Sugar Transporters http://dx.doi.org/10.5772/58325 7

**Figure 4. GLUT family members facilitate glucose transport into tissues that control glucose homeostasis such as hepatocytes, skeletal muscle, adipose tissue, and the pancreatic β-cells of the islets of Langerhans. A-Hexose transport in hepatocytes**. GLUT2 mediates glucose uptake under feeding conditions into hepatocytes where glucose is metabolized by glycolysis or incorporated into glycogen. In patients with FBS fructose handling is normal, therefore

**Figure 3. SGLT and GLUT family members regulate intestinal absorption and renal reabsorption of hexoses.A-Renal glucose reabsorption.** In the kidney, proximal tubule transepithelial reabsorption of glucose occurs at the api‐ cal membrane by SGLT2 and GLUT2 at the basolateral membrane. In the proximal straight tubule, the remaining glucose is reabsorbed by SGLT1 at the apical site of the epithelium and GLUT1 at the basolateral membrane. **B-Intesti‐ nal glucose absorption.** In the intestine, transepithelial glucose uptake at the apical site is mediated by the Na+-de‐ pendent glucose transporter SGLT1, while fructose is absorbed by facilitated diffusion via GLUT5. These hexoses can

all exit the basolateral membrane through GLUT2.

6 Glucose Homeostasis

GLUT2 might not be exclusively involved in uptake of this ketohexose by the hepatocyte [38]. GLUT9 is highly ex‐ pressed in liver and due to its capability to transport uric acid its proposed function in humans might be the release of uric acid from the liver. In mice GLUT9 is required for uric acid uptake into liver for further breakdown by uricase to allantoin [39]. Whether GLUT9 also contributes to hexose transport, namely fructose, in hepatocytes is currently un‐ known. Fructose that is taken up by the liver mainly feeds into triglyceride synthesis, and via ATP depletion stimulates AMP-deaminase and thereby purine degradation leading to an increased generation of uric acid. **B-Insulin stimulat‐ ed glucose uptake into skeletal muscle and adipose tissue**. In muscle and fat, glucose uptake is stimulated by insu‐ lin. After insulin binds to its receptor, auto-phosphorylation of the receptor occurs that triggers a signalling cascade that finally leads to a translocation of GLUT4 vesicles from an intracellular pool to the plasma membrane. The acute increase of GLUT4 molecules at the cell surface leads to an increase in glucose uptake and represents the rate-limiting step in insulin-stimulated glucose uptake in adipose and muscle tissues. **C**-**Pancreatic β-cells secrete insulin in re‐ sponse to elevations in blood glucose**. GLUT2 mediates glucose uptake into β-cells. Phosphorylation of glucose by glucokinase is the rate limiting step of glycolysis which increases the ATP to ADP ratio of the cell leading to closure of the KATP channel and subsequent opening of the of Ca++channels caused presumably by changes of the plasma mem‐ brane polarization. The opening of Ca++channels raises intracellular Ca++concentrations and induces exocytosis of the insulin granules.

human SGLT protein family (SLC5A) comprises 11 isoforms that structurally are characterized by 14 transmembrane domains, where the N-and C-termini face the extracellular (luminal) side of the cell. The 11 family members share an amino acid identity of 21-70%. A broad range

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**Figure 5. Proposed models for the mechanism of facilitative and active glucose transport across cellular mem‐ branes.A-A 6-state model is proposed for SGLT mediated glucose transport.** The empty transporter is assumed to have a valence of-2 (1). Sugar transport is initiated upon binding of two sodium ions to the open form of the outside gate (2). In the next step, glucose binds to the transporter, which induces a conformational change from an outward to an inward occluded state (3, 4). Upon open of the inward gate, the glucose is released into the cytoplasm before the sodium (5). The transport cycle is completed by a conformational change to return the ligand-free inward facing (6) structure to the ligand-free outward-facing structure (1). **B-Model of GLUT mediated glucose transport.** Glucose binds to an outward-facing site of the transporter (1) which induces a conformational changes that allows movement of the hexose through the protein (2-3). After the release of the hexose from its inward-facing binding site into the

The focus of the current chapter is on the sodium-dependent glucose transporters within the *SLC5* gene family, namely SGLT1-5, and the closely related, based on sequence homology and substrate specificity, sodium driven myoinositol transporter SMIT1 (SLC5A3) and SMIT2

cytosol the transporter undergoes a reverse conformational change (4-1).

(SGLT6/SLC5A11).

of substrates are transported by proteins encoded by the *SLC5* genes.

As the brain's main energy source glucose needs to be transported across the blood-brain barrier. This process is facilitated by GLUT1 (Figure 1). Insulin-stimulated clearance of blood glucose through uptake into skeletal muscle, the heart and adipose tissue, the rate-limiting step is defined by translocation of GLUT4 from an intracellular compartment to the plasma membrane; and it's this signalling cascade that represents insulin sensitivity (Figure 4B). The secretion of insulin by the pancreatic β-cells of the islets of Langerhans is dependent on GLUT2 which functions as a β-cell glucose sensor (Figure 4C). However, the involvement of sugar transporters in the regulation of processes such as brain glucose sensing or glucose transport in the mammary gland are not yet well understood.

This chapter summarizes the principal characteristics of SGLT [1] and GLUT-[4] mediated sugar transport, primarily focusing on the human transporters, with emphasis on the current understanding of their physiology, based on inherited disorders and syndromes in humans and phenotypes of genetically modified mice.
