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Typus
Verschleierung
Bearbeiter
Hindemith
Gesichtet
Yes.png
Untersuchte Arbeit:
Seite: 9, Zeilen: 1 ff. (entire page)
Quelle: Uldry and Thorens 2004
Seite(n): 481, 487, Zeilen: 481: l.col: 19ff; 487: r.col: 3ff
[However, the sodium dependent glucose transporter] SGLT2 (SLC5A1) seems to be a more interesting target in the kidney for this purpose since its expression is more limited.

Type 2 diabetes is characterized by the loss of insulin sensitivity that leads to a decrease in GLUT1 translocation to the plasma membrane in response to a high blood glucose. To compensate the resulting reduced flux of glucose into muscle and adipocytes, it would be useful to find a pharmacological compound that increases the Vmax of GLUT1 for glucose, or stimulate its translocation to the cell surface.

An impaired brain inositol metabolism has been linked to psychiatric diseases, in particular bipolar disorders (28). Indeed, current treatments of these mood disorders relies on the use of Li+ salts, valproic acid and carbamazepine, drugs whose action may interfere with inositol metabolism.(28) It is well established that one mechanism of action of Li+ is the inhibition of inositol monophosphate phosphatase and polyphosphoinositide 1-phosphate phosphatase (29), which blocks recycling of inositol phosphate and reduces the availability of inositol for subsequent cycles of intracellular signal transduction. Inhibition of HMIT could also lead to such beneficial effects for bipolar disorders by decreasing the intracellular inositol concentration.

Some members of the GLUT family (GLUT1, 2 and 4) can transport glucosamine, which is important in the biosynthesis of glycoproteins and, in particular, glycosaminoglycan synthesis in cartilage (30). In association with collagen fibres, these molecules are responsible for the resilience of the cartilage to deformation. Destruction of joint cartilage occurs in osteoarthritis, and several studies have shown that glucosamine is beneficial for this disease . Given the fact that GLUT1 is expressed in chondrocytes, the cells that synthesize cartilage, glucosamine has favourable effects for osteoarthritis are probably mediated by transport across GLUT1 into these cells. Furthermore, glucosamine absorption seems to be mediated in part by GLUT2. This provides an example of the use of GLUT isoforms to deliver therapeutic molecules to their site of action.

1.3.3 The facilitative glucose transporter GLUT1

GLUT1 cDNA was isolated from an expression library using antibodies against the human´s erythrocyte glucose transporter(4). Although cloned from a hepatoma cDNA library, GLUT1 is not expressed in normal hepatocytes. It is, however, induced during oncogenic transformation of most cell types and its expression correlates with the increase in glucose [metabolism observed in tumour cells (31).]


4. Kloppel,G, Lohr,M, Habich,K, Oberholzer,M, Heitz,PU: Islet pathology and the pathogenesis of type 1 and type 2 diabetes mellitus revisited. Surv.Synth.Pathol.Res. 4:110-125, 1985

28. Shaldubina,A, Buccafusca,R, Johanson,RA, Agam,G, Belmaker,RH, Berry,GT, Bersudsky,Y: Behavioural phenotyping of sodium-myo-inositol cotransporter heterozygous knockout mice with reduced brain inositol. Genes Brain Behav. 6:253-259, 2007

29. Berridge,MJ, Downes,CP, Hanley,MR: Neural and developmental actions of lithium: a unifying hypothesis. Cell 59:411-419, 1989

30. Uldry,M, Ibberson,M, Hosokawa,M, Thorens,B: GLUT2 is a high affinity glucosamine transporter. FEBS Lett. 524:199-203, 2002

31. Haber,PS, Pirola,RC, Wilson,JS: Clinical update: management of acute pancreatitis. J.Gastroenterol.Hepatol. 12:189-197, 1997

[page 481]

GLUT1

Glut 1 was the first transporter to be characterized by molecular cloning, and its cDNA was isolated from an expression library using antibodies against the humans erythrocyte glucose transporter [53]. Although cloned from a hepatoma cDNA library, GLUT1 is not expressed in normal hepatocytes. It is, however, induced during oncogenic transformation of most cell types and its expression correlates with the increase in glucose metabolism observed in tumour cells [20].

[page 487]

However, SGLT2 seems to be a more interesting target in the kidney for this purpose since its expression is more limited.

Type-2 diabetes is characterized by the loss of insulin sensitivity that leads to a decrease in GLUT4 translocation to the plasma membrane in response to a high blood glucose. To compensate the resulting reduced flux of glucose into muscle or adipocytes, it would be useful to find a pharmacological compound that increases the Vmax of GLUT4 for glucose, or stimulate its translocation to the cell surface.

An impaired brain inositol metabolism has been linked to psychiatric diseases, in particular bipolar disorders. Indeed, current treatments of these mood disorders relies on the use of lithium salts, valproic acid and carbamazepine, drugs whose action may interfere with inositol metabolism. It is well established that one mechanism of action of Li+ is the inhibition of inositol monophosphate phosphatase and polyphosphoinositide 1-phosphate phosphatase [6], which blocks recycling of inositol phosphate and reduces the availability of inositol for subsequent cycles of intracellular signal transduction. Inhibition of HMIT could also lead to such beneficial effects for bipolar disorders by decreasing the intracellular inositol concentration.

Some members of the GLUT family (GLUT1, 2 and 4) can transport glucosamine, which is important in the biosynthesis of glycoproteins and, in particular, glycosaminoglycan synthesis in cartilage [75]. In association with collagen fibres, these molecules are responsible for the resilience of the cartilage to deformation. Destruction of joint cartilage occurs in osteoarthritis, and several studies have shown that glucosamine is beneficial for this disease. Given the fact that GLUT1 is expressed in chondrocytes, the cells that synthesize cartilage, glucosamine’s favourable effects for osteoarthritis are probably mediated by transport across GLUT1 into these cells. Furthermore, glucosamine absorption seems to be mediated in part by GLUT2. This provides an example of the use of GLUT isoforms to deliver therapeutic molecules to their site of action.


6. Berridge MJ, Downes CP, Hanley MR (1989) Neural and developmental actions of lithium: a unifying hypothesis. Cell 59:411–419

20. Flier JS, Mueckler MM, Usher P, Lodish HF (1987) Elevated levels of glucose transport and transporter messenger RNA are induced by ras or src oncogenes. Science 235:1492–1495

53. Mueckler M, Caruso C, Baldwin SA, Panico M, Blench I, Morris HR, Allard WJ, Lienhard GE, Lodish HF (1985) Sequence and structure of a human glucose transporter. Science 229:941–945

75. Uldry M, Ibberson M, Hosokawa M, Thorens B (2002) GLUT2 is a high affinity glucosamine transporter. FEBS Lett 524:199–203

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