Benfotiamine and Diabetic Eye Disease:
A Biochemical Rationale for Prevention
Paul
Chous, M.A., O.D. Doctor of Optometry
Type 1 diabetic since 1968
Last year, a great deal of excitement was generated by published findings
demonstrating the prevention of diabetic retinopathy (DRT) in rats administered
the lipid-soluble thiamine analog, benfotiamine (Hammes et al., 2003)
). As a doctor of optometry specializing in the eye complications of
diabetes and diabetes education, and a Type 1 patient of 35 years, it
caught my attention, as well. Here, it is my aim to lay out more clearly
how and why benfotiamine might prevent DRT, and draw attention to some
recent research suggesting that these same biochemical pathways may
prevent or mitigate other eye complications of diabetes including: premature
loss of near focusing ability, cataract, glaucoma, corneal disease and
premature degeneration of the vitreous humor.
In the most recent study, benfotiamine was shown to block at least
3 pathways of hyperglycemia mediated vascular damage (hexosamine pathway,
protein kinase C pathway, and the advanced glycation endproduct pathway.)
Diagramatically, the mechanism looks like this:
The enzyme transketalose provides a mechanism for cells
to use up the injurious glucose metabolites, fructose-6-phosphate and
glyceraldehyde-3-phosphate (via the pentose phosphate shunt). Transketalose
activity depends on intracellular thiamine, which is often reduced in
diabetes due to oxidative stress and malabsorption (Brownlee, 2001)
Whereas ordinary thiamine requires active transport across the cell
membrane, benfotiamine is lipophilic allowing easy diffusion and high
intracellular concentrations, ramping up transketalose activity by 300-400%
and reducing the harmful by-products of F-6-P and G-3-P (AGEs, PKC and
inflammatory cytokeines like IPA-1).
In terms of diabetic eye disease, let’s focus on
PKC and AGEs. In particular, PKC-B causes damage to retinal microvasculature,
resulting in capillary leakage (left branch) and capillary closure (right
branch).
In turn, PKC-B triggers release of vascular endothelial
growth factor (VEGF) and other vascular permeability factors (VPF) necessary
for the development of neovascularization and proliferative diabetic
retinopathy. Additional PKC-B release is initiated and a vicious cycle
is created leading to the two most serious forms of DRT.
Advanced glycation end products describe a heterogeneous group of compounds
resulting from the non-enzymatic glycation of proteins (exactly analogous
to the process of carmelization). AGEs have been implicated in a host
of age and diabetes related pathologies, including atherosclerosis,
Alzheimer’s disease, pulmonary fibrosis and erectile dysfunction
(Brownlee, 2001). As for eye disease: (1) AGEs have been found at high
levels in the optic nerves of both diabetics and those with primary
open angle glaucoma (POAG), causing stiffening of the collagenous “cribriform
plates” that provide structural support for optic nerve axons
as they exit the back of the eye. This may partially explain why diabetics
have a 2 to 4 time relative risk for POAG (Amano et al., 2001; Albon
et al., 1995); (2) Increased
AGEs have been demonstrated just below the corneal epithelium (Bowman’s
layer), and have been implicated in weakened attachments between the
epithelium and its underlying basement membrane, resulting in “recurrent
corneal erosion syndrome” (RCE), a not uncommon finding in diabetic
patients (Kaji et al., 2000); markedly increased AGEs in diabetic lenses
leads to loss of elasticity in lens crystallins that allow for near
focusing ability (“accommodation”) and generation of free
radicals that lead to lens opacity (cataract) – this on top of
increased osmotic pressure on the lens induced by sorbitol via the polyol
pathway (the putative cause of “classic” diabetic cataract).
The identical AGE mechanism occurs in smokers, who have a much higher
risk of premature cataract compared to non-smokers (Saxeena et al.,
2000); premature, AGE-mediated liquefaction (loss of gel structure)
occurs in the vitreous humor of diabetic eyes, increasing symptomatic
“floaters” and possibly exacerbating vitreous traction in
patients more prone to retinal detachment (Stitt et al., 1998; Sebag
et al.2001); increased AGEs in retinal vascular endothelial cells contribute
to pericyte destruction (Yamagishi et al., 1999), breakdown of the blood-retina
barrier and release of PKC (Stitt et al.,1997), providing an important
link between the PKC and AGE pathways in the development of retinopathy,
and further demonstrating the complexity of these biochemical interactions.
Benfotiamine has a good track record, it seems, in terms of safety
and efficacy in European studies for the treatment of diabetic neuropathy.
In theory, at least, benfotiamine should block not only multiple pathways
of hyperglycemia-induced damage, but multiple complications of diabetes,
including several of the diabetic eye diseases. Will it do so? Will
unknown side effects or specific contraindications to its use emerge?
Only time and trials will tell.
Lessons
from a Diabetic Eye Doctor: How to Avoid Blindness and Get Great Eye
More Info:
Dr. Paul Chous received his undergraduate education at Brown University
and the University of California at Irvine, where he was elected to
Phi Beta Kappa in 1985. He received his Masters Degree in 1986 and his
Doctorate of Optometry in 1991, both with highest honors from the University
of California at Berkeley. Dr. Chous was selected as the Outstanding
Graduating Optometrist in 1991. He has practiced in Renton, Kent, Auburn
and Tacoma, Washington for the last 12 years, emphasizing diabetic eye
disease and diabetes education. Dr. Chous has been a Type 1 diabetic
since 1968. He lives in Maple Valley, Washington with his wife and son.
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References:
1. Ascher, E. et al. Thiamine reduces hyperglycemia-induced dysfunction
in cultured endothelial cells. Surgery. 130: 851-8 (2001)
2. Bitsch, R. et al. Bioavailability assessment of the lipophilic benfotiamine
as compared to a water soluble thiamin derivative. Ann. Nutr. Metab.
35: 292-6 (1991)
3. Brownlee, M. Biochemistry and molecular cell biology of diabetic
complications. Nature. 414: 813-20 (2001)
4. Hammes, H. et al. Benfotiamine blocks three major pathways of hyperglycemic
damage and prevents diabetic retinopathy. Nature: Medicine. 9: 294-9
(2003)
5. Pomero, F.et al. Benfotiamine is similar to thiamine in correcting
endothelial cell defects induced by high glucose. Acta Diabetol. 38:
135-8 (2001)
6. Albon, J. et al. Changes in the collagenous matrix in the aging human
lamina cribrosa. BJO. 79: 368-75 (1995)
7. Amano, S. et al. Advanced glycation end products in human optic nerve
head. BJO. 85: 52-5 (2001)
8. Kaji, Y. et al. Advanced glycation endproducts in diabetic corneas.
Invest Ophthalmol Vis Sci. 41: 362-8 (2000)
9. Saxeena, P. et al. Transition metal-catalyzed oxidation of ascorbate
in human cataract extracts: possible role of advanced glycation end
products. Invest Ophthalmol Vis Sci. 41: 1473-81 (2000)
10. Stitt, AW et al. Advanced glycation endproducts (AGEs) colocalise
with AGE receptors in the retinal vasculature of diabetic and AGE infused
rats. Am J Pathol. 150: 523-32 (1997)
11. Stitt, AW et al. Advanced glycation endproducts in vitreous: structural
and functional implications for diabetic vitreopathy. Invest Ophthalmol
Vis Sci. 39: 2517-23 (1998)
12. Yamagishi, S. et al. Advanced glycation endproducts accelerate calcification
in microvascular pericytes. Biochem Biophys Res Comm. 258: 353-7 (1999)
