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Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy

Nature Medicine volume 9, pages 294–299 (2003)Cite this article

Abstract

Three of the major biochemical pathways implicated in the pathogenesis of hyperglycemia induced vascular damage (the hexosamine pathway, the advanced glycation end product (AGE) formation pathway and the diacylglycerol (DAG)–protein kinase C (PKC) pathway) are activated by increased availability of the glycolytic metabolites glyceraldehyde-3-phosphate and fructose-6-phosphate. We have discovered that the lipid-soluble thiamine derivative benfotiamine can inhibit these three pathways, as well as hyperglycemia-associated NF-κB activation, by activating the pentose phosphate pathway enzyme transketolase, which converts glyceraldehyde-3-phosphate and fructose-6-phosphate into pentose-5-phosphates and other sugars. In retinas of diabetic animals, benfotiamine treatment inhibited these three pathways and NF-κB activation by activating transketolase, and also prevented experimental diabetic retinopathy. The ability of benfotiamine to inhibit three major pathways simultaneously might be clinically useful in preventing the development and progression of diabetic complications.

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Figure 1: Potential mechanism by which benfotiamine blocks 4 pathways of hyperglycemic damage.
Figure 2: Effect of glucose and benfotiamine concentration on transketolase activity in cultured bovine aortic endothelial cells.
Figure 3: Effect of benfotiamine on pathways of hyperglycemic damage in cultured bovine aortic endothelial cells, in the absence and presence of transketolase inhibition by antisense oligonucleotides.
Figure 4: Effect of chronic benfotiamine administration on transketolase activity in retinas from long-term diabetic rats.
Figure 5: Effect of chronic benfotiamine administration on pathways of hyperglycemic damage in retinas from long-term diabetic rats.
Figure 6: Effect of benfotiamine on experimental diabetic retinopathy.

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Acknowledgements

We thank S. Hofmann for comments and suggestions and F. Scharpert for technical assistance. This work was supported in part by grants from the US National Institutes of Health, the Juvenile Diabetes Research Foundation, the American Diabetes Association, the Deutsche Forschungsgemeinschaft and Wörwag Pharma, GmbH & Co. KG (Böblingen, Germany).

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Authors and Affiliations

  1. Medical Clinic V, School of Clinical Medicine, Mannheim, Germany

    Hans-Peter Hammes & Jihong Lin

  2. Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York, USA

    Xueliang Du, Diane Edelstein, Tetsuya Taguchi, Takeshi Matsumura, Qida Ju, Ida Giardino & Michael Brownlee

  3. Department of Internal Medicine I, Heidelberg University, Heidelberg, Germany

    Angelika Bierhaus & Peter Nawroth

  4. Institute of Clinical Chemistry, School of Clinical Medicine, Mannheim, Germany

    Dieter Hannak & Michael Neumaier

  5. Third Medical Department, Justus-Liebig University, Giessen, Germany

    Regine Bergfeld

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Correspondence to Michael Brownlee.

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Hammes, HP., Du, X., Edelstein, D. et al. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med 9, 294–299 (2003). https://doi.org/10.1038/nm834

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