**4.10. GLUT9** *(SLC2A9)*

**4.7. Class II family members**

26 Glucose Homeostasis

**4.8. GLUT5** *(SLC2A5)*

into the portal vein (Figure 3B).

*Mouse Models of GLUT5 deficiency*

*4.8.1. GLUT5 physiology*

tension.

**4.9. GLUT7** *(SLC2A7)*

to two proteins that only differ in their N-terminal region.

With GLUT5 being identified in 1990 and established as a fructose transporter initial transport studies for GLUT7 and 9 indicated that those transporters might also transport fructose. A specific feature for class II transporters is that cytochalasin B as a classical GLUT inhibitor does not block glucose transport. Furthermore, all isoforms do not show an affinity for 2-DG and galactose. Unique for GLUT9 and GLUT11 is the alternative splicing /promoter usage, where either two or three different mRNA's are transcribed, respectively. In case of GLUT9 this leads

Human GLUT5 was initially cloned from an intestinal epithelial cell line. GLUT5 is considered as the prototypic fructose transporter – when expressed in *Xenopus laevis* oocytes the human protein transports fructose with a Km of 6 mM without any noticeable glucose transport activity. However, fructose transport is not inhibited by cytochalasin B, phlore‐ tin or phlorizin. Besides fructose, the rat GLUT5 transports glucose, an activity that can be blocked by cytochalasin B. In humans, rats and mice, GLUT5 is primarily expressed in the jejunal region of the small intestine. Lower levels of the protein are expressed in the kidney, the brain, skeletal muscle, and adipose tissue. GLUT5 mediates fructose absorption in the jejunum at the apical, and potentially, at the basolateral membrane, of the epithelial cells

GLUT5 deficiency is associated with reduced fructose absorption when animals are challenged by a high fructose diet. While wildtype mice upon high fructose feeding display an enhanced salt absorption in their jejuna and develop systemic hypertension, GLUT5 knockout mice do not show fructose stimulated salt absorption. Instead, the animals display impaired nutrient absorption that is accompanied by hypotension. Absence of GLUT5 leads to a massive dilatation of the cecum and colon, consistent with severe malabsorption. On a normal chow diet, GLUT5 deficient mice have normal blood pressure and display normal weight gain. The phenotype of GLUT5 deficient mice demonstrates that this isoform is essential for fructose absorption by the intestine and thereby fundamentally involved in fructose induced hyper‐

The human GLUT7 was cloned from an intestinal cDNA library using a PCR-based strategy. GLUT7 is primarily expressed in the small intestine and colon, although mRNA has been detected in the testes and prostate as well. The protein has been localized to the apical membrane of the small intestine and colon. GLUT7 shows a rather high affinity for glucose and fructose (*K*m for glucose=0.3mM) while galactose, 2-DG, and xylose are not transported. Sugar transport by GLUT7 is not inhibited by cytochalasin B or phloretin. Sequence alignments Human GLUT9 cDNA was isolated by PCR amplification from a human kidney cDNA library on the basis of sequence information from ESTs and from its genomic sequence. GLUT9 mRNA is detected almost exclusively in the kidney and liver and at low levels in the small intestine, placenta, lung and leucocytes. GLUT9 is localized to the insulin-secreting β-cells of human and mouse islets, where downregulation of the protein by siRNA in rat and mouse insulinoma cells leads to a reduced glucose-stimulated insulin secretion. In humans as well as in mice alternative splicing/or promoter usage results in two proteins, GLUT9a and GLUT9b, which only differ in their N-terminal region. While human and mouse GLUT9b are mainly expressed in the kidney, placenta and liver, GLUT9a shows a broader tissue distribution. The different N-termini of human GLUT9a and b determine basolateral versus apical sorting in polarized cells *in vitro*, respectively. In mouse kidney, GLUT9 is localized to apical as well as basolateral membranes of distal convoluted tubules. Initial characterization of GLUT9 determined a rather low affinity for 2-DG. However, a high affinity transport has been reported for glucose and fructose with Km values of 0.6 mM and 0.4 mM, respectively. More recently, GLUT9 has been identified as a high-affinity uric acid transporter with a Km of 0.9 mM and 0.6 mM for the human and mouse protein, respectively. Although transport of glucose and fructose has not been observed by some investigators, GLUT9 is thought to exchange glucose or fructose for urate. The classical inhibitor cytochalasin B does not block GLUT9 function. GLUT9 has been established to represent a major regulator of urate homeostasis in dogs, mice, and men.

#### *4.10.1. GLUT9 physiology*
