Benfotiamine : A Potent AGE-Inhibitor
By
James South, MA
Advanced glycation end products, also known as AGEs, are toxic byproducts of inappropriate reactions between sugars, oxoaldehydes and proteins (Fig. 1) . AGEs increase with age and many diseases. AGEs have been shown to be intimately involved in the pathology of many diseases, including diabetes,1 inflammatory diseases,2 atherosclerosis and heart failure,3 macular degeneration,4 osteoarthritis,5 rheumatoid arthritis,6 Alzheimer’s disease,7,8 poor bone healing,9 cataracts,10 and kidney disease.11
AGEs especially attack long-lived proteins such as collagen, the most abundant protein in the body, which makes up a significant part of skin, bones, cartilage, tendons, teeth and the cardiovascular system. AGEs cross-link various proteins, making them stiffer and less elastic. They damage normal three-dimensional protein structure, inhibit the physiologic function of proteins, and trigger inflammatory reactions. “These stable compounds [AGEs] accumulate slowly throughout the lifespan and contribute to structural and physiologic changes in the cardiovascular system such as increased vascular and myocardial stiffness, endothelial dysfunction, altered vascular injury responses, and atherosclerotic plaque formation.”3 Quite literally, AGEs are a major causal contributor to aging and the diseases of aging. And unfortunately, there are no enzymes in the body able to break down these AGEs and their pathologic and unwanted cross-links to proteins.
AGEs and Blood Sugar
It is the nonenyzmatic reaction of glucose (blood sugar), glucose metabolic products called “triose phosphates,” and protein that generate AGEs. Not surprisingly, therefore, diabetics are known to accumulate AGEs much faster than nondiabetics, due to their chronic high blood sugar (hyperglycemia). Diabetes is often considered an
accelerated form of aging, with diabetics frequently suffering heart/artery disease, kidney disease, retinopathy and peripheral nerve damage 20 to 40 years earlier than these conditions show up in nondiabetics. AGEs are now known to contribute to these diabetic complications,12 and therapies that reverse or prevent excessive AGE accumulation in diabetic animals also reverse or prevent many of these diabetic complications.13,14
Syndrome X
Syndrome X, or the metabolic syndrome, is an increasingly common condition in America, affecting tens of millions of people. It typically involves the combination of obesity, high blood pressure, high cholesterol/triglycerides and higher-than-normal (but not diabetic-level) blood sugar.
Using an animal model of syndrome X, obese Zucker rats, Alderson and colleagues showed that AGE levels in skin collagen were two-to-three times higher in the obese Zucker rats than in lean controls.11 The obese Zucker rats also had much higher blood triglycerides and cholesterol then the lean control rats, and had hypertension and thickening of blood vessel walls.
Thus, anyone wanting to minimize the toxic AGE effects of diabetes, obesity/syndrome X, or “normal” aging, must get on an anti-AGE anti-aging program as early in life as possible. It is doubtless no coincidence that the one proven life-extension method in animals, caloric restriction, also promotes lower than “normal” blood sugar levels, and thus lowers AGE production as well.
Benfotiamine to the Rescue
Over the past decade researchers have discovered a nutrient that has been shown to be an AGE-blocker both in vitro (“test tube”) and in vivo (living animals). It is benfotiamine, a synthetic fat-soluble form of thiamine (vitamin B1), more technically known as S-benzoylthiamine-O-monophosphate.12,17
Benfotiamine (BFT) was synthesized in Japan in the 1960s.16 BFT has been shown in many human and animal studies to have superior bioavailability to thiamine (B1) itself.16 The rate of absorption of therapeutic doses (50 to 100 mg) of B1 is relatively small—usually just four to six percent.16 In the body, both B1 and BFT are transformed into thiamine diphosphate (TDP), the coenzyme form of B1. One study found a 120-fold increase in TDP levels in red blood cells from BFT compared to B1.16
A study with end-stage renal disease patients found that BFT had 430 percent better overall absorption than B1.17 When BFT was compared to two other “allithiamines,” fursultiamine and B1 disulfide, “All biokinetic data demonstrated a significantly improved thiamine bioavailability from benfotiamine compared with the other preparations.”18
When radioactively-tagged B1 and BFT were fed to mice, the level of radiation tracer (reflecting the B1/BFT levels) was five to 25 times higher in muscle and brain with BFT compared to B1.20 When B1 was compared to BFT in diabetic rats, the authors noted: “Unlike treatment with water-soluble thiamine nitrate timely administration of…benfotiamine was effective in the prevention of functional damage and of AGE and CML [a specific AGE] formation in nerves of diabetic rats.”19 When it comes to enhancing bodily TDP-coenzyme B1 status, BFT beats regular B1 every time.
Benfotiamine vs. AGEs
Both human and animal studies have shown BFT to successfully combat AGEs. Lin and colleagues gave six type 1 diabetics 600mg BFT for 28 days.21 Blood samples were taken before and after the supplementation. Red blood cell levels of carboxymethyllysine (CML) dropped 40 percent. The intracellular levels of methylglyoxal-derived AGE were reduced 69 percent. CML levels inversely correlate with diabetic blood vessel complications, and methylglyoxal-AGE is the most important intracellular AGE.21
CML-modified proteins have been found in plasma, renal tissues, retinas and collagen of diabetic patients. CML is the predominant AGE in intracellular neurofibrillary deposits in patients with Alzheimers disease and in macrophage-derived foam cells in human atherosclerotic plaques. Its concentration in humans increases significantly with age. 24
Sadekov and coworkers gave a combination of 100 mg BFT plus 100 mg pyridoxine three times daily for six weeks to 14 patients suffering diabetic polyneuropathy (nerve pain and dysfunction).22 After treatment, the pain intensity suffered dropped from a score of 8.2 to 2.3 on a visual analog scale. Vibratory sensitivity improved significantly, and tests showed improved parasympathetic nerve control of heart rhythm. The latent periods of evoked sympathetic nerve potentials on arms and legs which were initially abnormally lengthened became significantly shorter. Conduction rate for excitation through motor nerves also improved. Thirteen of 14 patients improved with BFT plus pyridoxine treatment.
Thirty diabetic patients with painful peripheral neuropathy got BFT for three months, while 15 got a standard B vitamin complex.23 Significant relief of both background and peak neuropathic pain was achieved in all the BFT patients, while no significant improvement occurred in the B complex group. Vibration perception thresholds “dramatically improved” in the BFT patients, while no such improvement occurred in the B complex group. TDP, the B1 coenzyme so successfully elevated by BFT, is essential for the activation of an enzyme called “transketolase.” Transketolase protects cells from AGE formation by diverting the products of excess glucose metabolism-triose phosphates-into the pentose pathway. If not successfully diverted into this pathway, the triose phosphates become AGEs.10
BFT also inhibits two other metabolic pathways that damage blood vessels in the presence of hyperglycemia.14 Three groups of rats were studied for 36 weeks. Two groups were diabetic/hyperglycemic, one was healthy controls. One diabetic group got BFT, one didn’t. After the study, the retinal blood vessels were examined. The control group had normal, healthy retinal blood vessels. The diabetic/no BFT group had severely damaged blood vessels and retinopathy. The diabetic rats getting BFT had retinas as
healthy as the control group.14
The preceding are just some of the many human and animal studies showing that BFT can inhibit AGE formation and ameliorate AGE-related pathology. A safe and effective human dose of BFT would be 150 mg, taken two or three times daily.
References
1.Metz T et al. Pyridoxamine, an inhibitor of advanced glycation and lipoxidation reactions: a novel therapy for treatment of diabetic complication. Arch Biochem Biophys 2003, 419:41-49.
2. Anderson M, Heinecke J. Production of N-epsilon-(carboxymethyl)-lysine is impaired in mice deficient is NADPH oxidase. Diab 2003, 52:2137-43.
3. Zieman S, Kass D. Advanced glycation end product cross-linking: pathophysiologic role and therapeutic target in cardiovascular disease. Congest Heart Fail 2004, 10:144-49.
4. Howes K et al. AGE (advanced glycation end products) receptors in age-related macular degeneration. Invest Ophthalmol Vis Sci 2004, 45:E-abstract 2286.
5. DeGroot J et al. Accumulation of advanced glycation end products as a molecular mechanism for aging as a risk factor in osteoarthritis. Arthritis Rheum 2004, 50:1207-15.
6. Drinda S. et al. Identification of the receptor for advanced glycation end products in synovial tissue of patients with rheumatoid arthritis. Rheumatol Int 3-26-2004.
7. Choei H. Glyceraldehyde-derived advanced glycation end products in Alzheimer’s disease. Acta Neuropathol (Berl) 2004, 108:189-93.
8. Lueth H-J et al. Age-and stage-dependent accumulation of advanced glycation end products in intracellular deposits in normal and Alzheimer’s disease brains. Cerebral Cortex advance access published online July 6, 2004.
9. Santana R. et al. A role for advanced glycation end products in diminished bone healing in type I diabetes. Diab 2003, 52:1502-10.
10. Nagariaji R. et al. Pyradoxamine inhibits alpha-dicarbonyl-www.ed modifications of lens proteins in diabetic rats. Invest Ophthalmol Vis Sci 2002, 43:E-abstract 2382.
11. Alderson N et al. The AGE inhibitor pyridoxamine inhibits lipemia and development of renal and vascular disease in Zucker obese rats. Kidney Int 2003, 63:2123-33.
12. Karachalias N et al. Accumulation of fructosyl-lysine and advanced glycation end products in the kidney, retina and peripheral nerve of streptozotocin-induced diabetic rats. Biochem Soc Trans 2003, 31:1423-25.
13.Babaei-Jadidi R et al. Prevention of incipient diabetic neuropathy by high-dose thiamine and benfotiamine. Diab 2003, 52:2110-20.
14. Hammes H et al. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med 2003, 9:294-99.
16. Woelk H et al. Benfotiamine in treatment of alcoholic polyneuropathy: an 8-week randomized controlled study (BAP I study). Alcohol Alcoholism 1998, 33:631-38.
17. Frank T et al. High thiamine diphosphate concentrations in erythrocytes can be achieved in dialysis patients by oral administration of benfotiamine. Eur J Clin Pharmacol 2000, 56:251-57.
18. Greb A, Bitsch R. Comparative bioavailability of various thiamine derivatives after oral administration. Int J Clin Pharmacol Ther 1998, 36:216-21.
19. Stracke H et al. Efficacy of benfotiamine versus thiamine on function and glycation products of peripheral nerves in diabetic rats. Exp Clin Endocrinol Diab 2001, 109:330-36.
20. Hilbig R, Rahmann H. Comparative autoradiographic investigations on the tissue distribution of benfotiamine versus thiamine in mice. Arzneimittelforschung 1998, 48:461-68.
21. Lin J et al. Benfotiamine inhibits intracellular formation of advanced glycation end products in vivo. Diab 2000, 49 (suppl 1): A143.
22. Sadekov R. et al. Diabetic polyneuropathy treatment by milgamma-100 preparation. Zh Nevrol Psikhiatr Im S S Korsakova 1998, 98:30-32.
23. Simeonov S et al. Therapeutic efficacy of “Milgamma” in patients with painful diabetic neuropathy. Folia Med (Plovdiv) 1997, 39:5-10.
24. Voziyan P et al. Modification of proteins in vitro by physiological levels of glucose. J Biol Chem 2003, 278:46616-24.
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