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GRK 1482 Jahrbuch 2011-2014

Abstract The aim of this study is to identify sequence variants in intestinal fruc- tose transporters that could contribute to fructose malabsorption. So far, we found only 1 amino acid changing variant in GLUT5 (p.T14M) in 1/36 patients but not in any of the control subjects. In GLUT7, we de- tected 5 different non-synonymous variants. The variant p.R224C was found in 3/36 patients, 0/34 controls and 3/250 population controls. The fructose transport capacity of variants found will be analysed in cell culture using stable retroviral transduction. Introduction Fructose malabsorption is a common clinical con- dition characterised by colicky abdominal pain, fla- tulence and diarrhoea. These symptoms are due to bacterial fermentation of fructose in the colon re- sulting in production of hydrogen, carbon dioxide, methane and short-chain fatty acids. So far, the mechanism how fructose is absorbed in the small intestine is poorly understood. The clinical symptoms of fructose malabsorption can be antagonised by equimolar administration of glucose – and this cannot be explained yet [1]. Fructose malabsorption clusters in selected fami- lies suggesting a genetic basis. The fructose trans- porters of the GLUT family that are present in the small intestine could be involved in this condition. It was assumed that mutations within the main in- testinal fructose transporter GLUT5 are responsible for fructose malabsorption. The coding sequence of GLUT5 was tested so far in 8 patients with ne- gative results. [2]. In Glut5 knock-out mice, fructo- se absorption in jejunum was 75% decreased and the concentration of serum fructose was ~90% reduced compared to wild-type mice on increased dietary fructose. As consequence of fructose deli- very to the colon mice showed expanded colon and caecum [3]. The expression of GLUT5 variant I296V in Xenopus oocytes resulted in decreased fruc- tose uptake and unaltered glucose uptake com- pared to expression of wild-type GLUT5 [4]. The closest family member of GLUT5 is GLUT7, which is primarily expressed in small intestine and colon and has a high affinity for glucose and fructose. In vitro mutagenesis of Ile-302 to valine in GLUT7 selectively depressed fructose uptake while glu- cose transport remained unaffected. This effect was also shown for the corresponding variant I335V in GLUT9 [4]. Feeding of high-fructose diet to Glut8 knock-out mice resulted in higher fructose uptake and higher GLUT12 abundance in the jejunum compared to wild-type mice. It was ob- served that fructose uptake and the presence of GLUT12 in Caco2 cells were increased after fructose exposure, whereas GLUT8 expression de- creased [5]. PhD FELLOWS Page 50 | GRK Progress Report 2011-2014 Karolin Saum (Dipl. Ernährungwissenschaftlerin) Paediatric Nutritional Medicine PhD 10/2 Fructose malabsorption – Genetic analysis and functional characterisation of intestinal fructose transporters and the cross-talk with glucose transporters

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