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J. Biol. Chem., Vol. 281, Issue 14, 9307-9313, April 7, 2006

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Regulation of Intracellular Glucose and Polyol Pathway by Thiamine and Benfotiamine in Vascular Cells Cultured in High Glucose^*

From the Department of Internal Medicine, University of Turin, I-10126 Turin, Italy

Hyperglycemia is a causal factor in the development of the vascular complications of diabetes. One of the biochemical mechanisms activated by excess glucose is the polyol pathway, the key enzyme of which, aldose reductase, transforms D-glucose into D-sorbitol, leading to imbalances of intracellular homeostasis. We aimed at verifying the effects of thiamine and benfotiamine on the polyol pathway, transketolase activity, and intracellular glucose in endothelial cells and pericytes under high ambient glucose. Human umbilical vein endothelial cells and bovine retinal pericytes were cultured in normal (5.6 mmol/liter) or high (28 mmol/liter) glucose, with or without thiamine or benfotiamine 50 or 100 µmol/liter. Transketolase and aldose reductase mRNA expression was determined by reverse transcription-PCR, and their activity was measured spectrophotometrically; sorbitol concentrations were quantified by gas chromatography-mass spectrometry and intracellular glucose concentrations by fluorescent enzyme-linked immunosorbent assay method. Thiamine and benfotiamine reduce aldose reductase mRNA expression, activity, sorbitol concentrations, and intracellular glucose while increasing the expression and activity of transketolase, for which it is a coenzyme, in human endothelial cells and bovine retinal pericytes cultured in high glucose. Thiamine and benfotiamine correct polyol pathway activation induced by high glucose in vascular cells. Activation of transketolase may shift excess glycolytic metabolites into the pentose phosphate cycle, accelerate the glycolytic flux, and reduce intracellular free glucose, thereby preventing its conversion to sorbitol. This effect on the polyol pathway, together with other beneficial effects reported for thiamine in high glucose, could justify testing thiamine as a potential approach to the prevention and/or treatment of diabetic complications.

Received for publication, January 17, 2006

^* This work was supported by a 2002 European Association for the Study of Diabetes/Eli Lilly Research Fellowship in Diabetes Microvascular Complications (to E. Beltramo) and by a grant from the Italian Ministry of University and Research (COFIN 2002). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Internal Medicine, University of Turin, Corso A. M. Dogliotti 14, I-10126 Torino, Italy. Tel.: 39-011-6336487; Fax: 39-011-6634751; E-mail: elena.berrone{at}unito.it.

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