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Hindemith
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Untersuchte Arbeit:
Seite: 8, Zeilen: 1ff (entire page)
Quelle: Uldry and Thorens 2004
Seite(n): 487, Zeilen: l.col: 14ff
1.3.1 The facilitative glucose transporters in the CNS and blood brain barrier

Glucose is the preferred energy substrate of the brain. Due to its expression in the endothelial cells forming the blood brain barrier, the glucose transporter GLUT1 is essential for glucose delivery to the brain (22).Given the fact that the abluminal surface of brain capillaries is covered by specialized astrocytic end-feet that also express GLUT1, the astrocytes probably constitute a major site of glucose uptake (23) In astrocytes, glucose is catabolized by glycolysis to lactate, which may be delivered to neurons through a glialspecific monocarboxylate transporter (MCT1) and a neuron-specific one (MCT2). In neurons, lactate is converted to pyruvate, which enters the tricarboxylic acid cycle to generate ATP. Glucose can also be taken up directly by neurons, which express the GLUT3 isoform (24). GLUT2 is also expressed in the brain in specific regions such as the hypothalamus and the brain stem where it may participate in the mechanisms of glucose sensing involved in the control of glucose homeostasis.

The role of GLUT8 in some specific neurons remains unclear. It is localized to intracellular vesicles and may possibly move to the cell surface upon as yet unidentified stimuli (25) . Finally, HMIT is expressed in astrocytes and in neurons. In astrocytes, HMIT is both intracellular and at the plasma membrane, whereas its subcellular localization in neurons is under investigation (26).

1.3.2 The facilitative glucose transporters as pharmaceutical targets

Elevation of blood glucose is the main symptom of types 1 and 2 diabetes. The GLUT isoforms that transport glucose represent therefore a potential therapeutic target for normalizing glycaemia. A compound that increases the Vmax maximal velocity of GLUT1 would increase whole-body glucose utilization. Given the fact that this isoform is almost ubiquitous, such activation could, however, also lead to severe hypoglycaemia. Another possible site of action for limiting the blood glucose level would be inhibition of glucose absorption in the intestine or reabsorption in the kidney. In the intestine, this could be possible by blocking both GLUT2 and the alternative membrane-traffic-based pathway of basolateral glucose release. In the kidney, GLUT2 deficiency results in glucose excretion in the urine, which decreases glycaemia (27). Inhibition of GLUT2 specifically in the kidney could thus treat hyperglycaemia.


22. Klepper,J, Scheffer,H, Leiendecker,B, Gertsen,E, Binder,S, Leferink,M, Hertzberg,C, Nake,A, Voit,T, Willemsen,MA: Seizure control and acceptance of the ketogenic diet in GLUT1 deficiency syndrome: a 2- to 5-year follow-up of 15 children enrolled prospectively. Neuropediatrics 36:302-308, 2005

23. Belanger,M, Desjardins,P, Chatauret,N, Butterworth,RF: Selectively increased expression of the astrocytic/endothelial glucose transporter protein GLUT1 in acute liver failure. Glia 53:557-562, 2006

24. Pellerin,L, Bonvento,G, Chatton,JY, Pierre,K, Magistretti,PJ: Role of neuron-glia interaction in the regulation of brain glucose utilization. Diabetes Nutr.Metab 15:268-273, 2002

25. Ibberson,M, Riederer,BM, Uldry,M, Guhl,B, Roth,J, Thorens,B: Immunolocalization of GLUTX1 in the testis and to specific brain areas and vasopressin-containing neurons. Endocrinology 143:276-284, 2002

26. Uldry,M, Ibberson,M, Horisberger,JD, Chatton,JY, Riederer,BM, Thorens,B: Identification of a mammalian H(+)-myo-inositol symporter expressed predominantly in the brain. EMBO J. 20:4467-4477, 2001

27. Guillam,MT, Hummler,E, Schaerer,E, Yeh,JI, Birnbaum,MJ, Beermann,F, Schmidt,A, Deriaz,N, Thorens,B: Early diabetes and abnormal postnatal pancreatic islet development in mice lacking Glut-2. Nat.Genet. 17:327-330, 1997

GLUTs in the CNS and blood brain barrier

Glucose is the preferred energy substrate of the brain. Due to its expression in the endothelial cells forming the blood brain barrier, GLUT1 is essential for glucose delivery to the brain. Given the fact that the abluminal surface of brain capillaries is covered by specialized astrocytic end-feet that also express GLUT1, the astrocytes probably constitute a major site of glucose uptake. In astrocytes, glucose is catabolized by glycolysis to lactate, which may be delivered to neurons through a glial-specific monocarboxylate transporter (MCT1) and a neuron-specific one (MCT2). In neurons, lactate is converted to pyruvate, which enters the tricarboxylic acid cycle to generate ATP. Glucose can also be taken up directly by neurons, which express the GLUT3 isoform [57]. GLUT2 is also expressed in the brain in specific regions such as the hypothalamus and the brain stem where it may participate in the mechanisms of glucose sensing involved in the control of glucose homeostasis.

The role of GLUT8 in some specific neurons remains unclear. It is localized to intracellular vesicles and may possibly move to the cell surface upon as yet unidentified stimuli [33]. Finally, HMIT is expressed in astrocytes and in neurons. In astrocytes, HMIT is both intracellular and at the plasma membrane, whereas its subcellular localization in neurons is under investigation [74].

Pharmaceutical relevance

Elevation of blood glucose is the main symptom of types-1 or -2 diabetes. The GLUT isoforms that transport glucose represent therefore a potential therapeutic target for normalizing glycaemia. A compound that increases the Vmax of GLUT1 would increase whole-body glucose utilization. Given the fact that this isoform is almost ubiquitous, such activation could, however, also lead to severe hypoglycaemia. Another possible site of action for limiting the blood glucose level would be inhibition of glucose absorption in the intestine or reabsorption in the kidney. In the intestine, this could be possible by blocking both GLUT2 and the alternative membrane-traffic-based pathway of basolateral glucose release. In the kidney, GLUT2 deficiency results in glucose excretion in the urine, which decreases glycaemia [23]. Inhibition of GLUT2 specifically in the kidney could thus treat hyperglycaemia.


23. Guillam MT, Hummler E, Schaerer E, Yeh JI, Birnbaum MJ, Beermann F, Schmidt A, Deriaz N, Thorens B, Wu JY (1997) Early diabetes and abnormal postnatal pancreatic islet development in mice lacking Glut-2. Nat Genet 17:327–330

33. Ibberson M, Riederer BM, Uldry M, Guhl B, Roth J, Thorens B (2002) Immunolocalization of GLUTX1 in the testis and to specific brain areas and vasopressin-containing neurons. Endocrinology 143:276–284

57. Pellerin L, Bonvento G, Chatton JY, Pierre K, Magistretti PJ (2002) Role of neuron-glia interaction in the regulation of brain glucose utilization. Diabetes Nutr Metab 15:268–273; discussion 273

74. Uldry M, Ibberson M, Horisberger JD, Chatton JY, Riederer BM, Thorens B (2001) Identification of a mammalian H+-myoinositol symporter expressed predominantly in the brain. EMBO J 20:4467–4477

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