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.
More
Info
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)
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