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Glycation math is simple: more sugar equals more AGEd proteins. As a result, people with diabetes begin to feel the effects of glycation at much younger ages than do people with more normal blood sugar levels. Watching people with diabetes age is like watching "normal" aging played on fast-forward. Slowly, imperceptibly, AGE reactions create chemical handcuffs, which gum up your proteins, deactivate your enzymes, trigger unhealthy biochemical signaling in your cells, and damage your DNA. Aging you.
Make that: AGEing you.
Two Ways to AGE
There are two major ways that AGEs can form inside the body. One way is through a simple series of chemical reactions known as the "Maillard Pathway," known from food chemistry for a century. But more recently, scientists have come to understand another pathway of AGE formation - a distinctly biological pathway, which only occurs within your cells because of the body's metabolism of carbohydrates.
When blood sugar levels rise, some key kinds of cell - including- nerve cells (neurons) and the cells that make up the fine blood cells of the retina of the eye and the filtering units (glomeruli) of the kidney - are also flooded with glucose. The resulting high sugar levels within these cells cause a logjam in the normal cellular metabolism of glucose. This backlog results in a buildup within the cell of super-reactive glucose-metabolic intermediates known as triosephosphates. And once that happens, the excess triosephosphates attack the surrounding proteins, lipids, and DNA, causing AGE damage from within the heart of the cell. These cells are thus the most vulnerable to the complications of diabetes.
Drugs do exist which can inhibit the formation of AGE, but none are available on the market as yet, and one of the most promising candidates (aminoguanidine) has shown signs of toxicity in human trials and appears to have been abandoned by its developers. On the other hand, some companies are selling supplements are marketed as "AGE-inhibitors." But while many of the herbs and other nutrients may be valuable, and many even inhibit AGEing in a test tube, there's no evidence that most of these "AGE-blocking" ingredients have any effect on AGEing in your body at the dosages used. Examples include thyme extract, inositol, acetyl-L-carnitine, taurine, and a whole host of antioxidants (including n-acetyl-cysteine (NAC) and flavonoids, such as quercetin and resveratrol).
TPP: Our Hero ... in Chains!
There is a nutrient that could, in theory, pack a potent wallop against the AGE onslaught: Thiamin Pyrophosphate (TPP), the active coenzyme form of the B-complex vitamin thiamin. In 1996, researchers showed that TPP could step in to stop AGE formation at the most important point in the process: the late, irreversible conversion of Amadori products into full-blown AGEs. What's more, TPP can exert a two-pronged AGE-inhibiting effect in the body, because boosting TPP in cells stressed by high glucose concentrations opens up an important biochemical "safety valve" in the normal metabolism of blood sugar through an enzyme known as transketolase. Activating transketolase allows the body to shunt excess triosephosphates into a safe alternative metabolic pathway, preventing the logjam that leads to the buildup of triosephosphates and the formation of AGE.
Unfortunately, this does not mean that loading up on regular thiamin (vitamin B1) will free you from glycation's sticky shackles. The problem is that your body's ability to absorb and metabolize conventional thiamin supplements is very limited. In fact, no matter how much thiamin you take, you don't materially increase plasma levels beyond what you get from the first 12 milligrams of the dose. And then getting thiamin into the cells to do its job is just as tricky.
You might think that you can get around this problem by taking supplements containing TPP itself, instead of plain old thiamin. Unfortunately, as part of the normal cellular absorption process, specific enzymes actually strip TPP of its phosphate groups. As a result, you get no additional AGE-battling benefit from taking preformed thiamin pyrophosphate instead of standard thiamin. In fact, when you take supplements based on TPP itself, studies show that thiamin levels and biological activity are actually lower than if you take the same amount of regular thiamin!
Benfotiamine: the TPP Solution
Fortunately, an effective way to boost thiamin pyrophosphate in your cells does exist: Benfotiamine (S-benzoylthiamine-O-monophosphate). Benfotiamine is a a derivative of thiamine. Although benfotiamine is not lipid soluble, it has been shown to have very good bioavailability. This is because benfotiamine is converted into another compound, called S-benzoylthiamin, by the enzymes present in the cells of the intestinal mucosa. S-benzoylthiamine has better fat solubility, and therefore passes easily through cell membranes. S-benzoylthiamine is then transported to the liver where it is converted to thiamine and released into the bloodstream.
As a result, your body absorbs Benfotiamine better than thiamin itself, and levels of thiamin and also TPP remain higher for longer. Thiamin absorption from Benfotiamine has been shown to be about five times as great as from conventional thiamin supplements. Furthermore, studies have shown that Benfotiamine is even more bioavailable than the other thiamine-related compounds called allithiamines, including thiamin tetrahydrofurfuryl disulfide/TTFD. Yet Benfotiamine is actually less toxic than conventional thiamin supplements!
By effectively increasing levels of thiamin itself, Benfotiamine dramatically boosts AGE-fighting thiamin pyrophosphate and cell-shielding transketolase activity in your body.
Shielding Nerve Structure
While most "anti-AGE" supplements rely on test-tube "browning" experiments as the "evidence" of efficacy, Benfotiamine has been proven in multiple real-world human and animal studies to reduce AGE formation and support tissue structure and function in diabetics.
Most impressively, many randomized, double-blind, placebo-controlled human trials have proven that Benfotiamine powerfully supports nerve function in diabetic neuropathy. In one trial, 24 people suffering with diabetic neuropathy took either Benfotiamine (plus doses of common B6 and B12 similar to those used in mutivitamins) or a look-alike dummy pill, spread out into three pills over the course of the day, for twelve weeks. The participants started with 320 milligrams of Benfotiamine per day for the first two weeks, followed by 120 milligrams for the rest of the trial. Before and after the trial, the function of patients's nerve cells were tested using nerve conduction velocity (NCV) and vibratory perception threshold (which tests the nerves's sensitivity by determining the lowest level at which vibrations applied at key nerve sites are first felt).
At the end of the trial, the vibration perception threshold had "clearly" improved by 30% in those who had taken the Benfotiamine supplements, while it had worsened in the placebo group by 5% at one site and by 32% at another. At the same time, people taking Benfotiamine experienced statistically significant improvements in nerve conduction velocity from the feet, even as this aspect of nerve function deteriorated in those taking the look-alike pills!
The power of Benfotiamine to improve vibratory perception threshold and nerve conduction velocity have been confirmed in other trials. Clinical trials have also shown that Benfotiamine supports nerve function in diabetics as measured by many other methods. For instance, Benfotiamine users experience a 50% reduction in diabetic nerve pain, along with an increased ability of the nerves to detect an electrical current, respond to electrical stimulation, and regulate the heartbeat. Similarly, Benfotiamine prevents this loss of control from happening in the first place in diabetic dogs. In another human clinical trial, a B-vitamin combination using Benfotiamine as its thiamin source was put head-to-head with a B-complex supplement that included a megadose of conventional thiamin. Benfotiamine proved its effectiveness on several of these key parameters, while the standard thiamin pill failed.
These benefits are not due to changes in blood sugar levels (either fasting, or after a meal, or averaged over several months (as measured by HbA1c), or improvements in metabolic benchmarks. They are the direct results of Benfotiamine's AGE-fighting, metabolic-balancing powers.
Benfotiamine in Other Vulnerable Tissues
More recently, new studies have begun to document Benfotiamine's ability to shield other tissues from AGE damage. One just-published study tested the ability of thiamin and Benfotiamine to protect diabetic rodents' retinas from the ravages of AGE.
The researchers then gave one group of diabetic rodents Benfotiamine supplements, and left another group unsupplemented, keeping a third group of nondiabetic animals as a control group. Nine months later, they examined the animals' eyes, testing the level of AGE in their retinas, examining metabolic abnormalities of the cells, and looking for acellular capillaries (the dead husks left behind when the cells of the tiny blood vessels of the eye die).
Benfotiamine supplements normalized AGE levels in the diabetics' retina, as well as several key metabolic parameters within the diabetic animals' cells - without influencing body weight or blood sugar (as measured by HbA1c). More importantly, Benfotiamine prevented the AGE-associated retinal damage. After nine months of diabetes, diabetic animals had suffered three times as many acellular capillaries as were found in healthy animals. But with the protection afforded by Benfotiamine, the number of acellular capillaries in the supplemented diabetics was indistinguishable from that of their normal, healthy cousins!
And there's another AGE-related disease that researchers believe Benfotiamine may fight: the loss of kidney function which accompanies "normal" aging, and which is accelerated by diabetes. Dr. Paul Thornalley of the University of Essex has just completed a study designed to see if Benfotiamine will protect diabetic rodents against kidney damage. While the results have not yet been published, Dr. Thornalley has indicated that both megadose thiamin and Benfotiamine caused clear-cut reductions in the leakage of protein - with Benfotiamine showing itself to be the superior intervention. A second study is now underway to see if Benfotiamine will actually improve kidney function in diabetic animals with pre-existing kidney damage, as it has already been shown to do in the nerves of diabetic animals and humans.
The End of an AGE
These are not test-tube studies. The results experienced when taking Benfotiamine occur not merely in labs, but in lives: in the bodies - and in the health - of living things, from experimental animals to human beings. In Benfotiamine, we finally have a proven way to protect tissues from the AGE assault.
References
i. Loew D. "Pharmacokinetics of thiamine derivatives especially of Benfotiamine." Int J Clin Pharmacol Ther. 1996 Feb; 34(2): 47-50.
ii. Stracke H, Lindemann A, Federlin K. "A Benfotiamine-vitamin B combination in treatment of diabetic polyneuropathy." Exp Clin Endocrinol Diabetes 1996; 104(4): 311-6.
iii. Lin J, Alt A, Liersch J, Bretzel RG, Brownlee MA, Hammes HP. "Benfotiamine inhibits intracellular formation of advanced glycation endproducts in vivo." Diabetes. 2000 May; 49(Suppl1): A143 (P583).
iv. Hammes HP, Du X, Edelstein D, Taguchi T, Matsumura T, Ju Q, Lin J, Bierhaus A, Nawroth P, Hannak D, Neumaier M, Bergfeld R, Giardino I, Brownlee M. "Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy." Nat Med. 2003 Mar; 9(3): 294-9.
v. Winkler G, Pal B, Nagybeganyi E, Ory I, Porochnavec M, Kempler P. "Effectiveness of different Benfotiamine dosage regimens in the treatment of painful diabetic neuropathy." Arzneimittelforschung. 1999 Mar; 49(3): 220-4.
vi. Koltai MZ. "Prevention of cardiac autonomic neuropathy in dogs with Benfotiamine." In Gries FA, Federlin K. "Benfotiamine in the Therapy of Polyneuropathy." New York: Georg Thieme Verlag, 1998; 45-9.
Diabetic neuropathy: new strategies for treatment.
Diabetes Obes Metab. 2007 Jun 26;
Várkonyi T, Kempler P.
Current therapeutic possibilities can be divided into two groups: the pathogenetically oriented and the symptomatic therapy. One of the most important component of etiology-based treatment is the stabilization of glycemic control. Based on efficacy and safety data benfotiamine and alpha-lipoic acid should be considered as first choices among pathogenetically oriented treatments of diabetic neuropathy. Promising data were published about the aldose reductase inhibitor ranirestat. The symptomatic effect of antiepileptic drugs in diabetic painful neuropathy (DPN) is originated from several possible pharmacological properties. Pregabalin and gabapentin have the highest efficacy and the lowest frequency of adverse events among these drugs. Antidepressants also extensively used for symptomatic treatment in DPN. In the last years several studies were published about the benefial effect of duloxetine. Most likely combination therapy will be frequently applied in the future for the treatment of DPN, the optimal choice could be to combine pathogenetically oriented and symptomatic treatment.
Benfotiamine prevents macro- and microvascular endothelial dysfunction and oxidative stress following a meal rich in advanced glycation end products in individuals with type 2 diabetes.
Heart and Diabetes Center NRW, Georgstrasse 11, 32545 Bad Oeynhausen, Germany.
Stirban A, Negrean M, Stratmann B, Gawlowski T, Horstmann T, Gotting C, Kleesiek K, Mueller-Roesel M, Koschinsky T, Uribarri J, Vlassara H, Tschoepe D.
OBJECTIVE: Diabetes is characterized by marked postprandial endothelial dysfunction induced by hyperglycemia, hypertriglyceridemia, advanced glycation end products (AGEs), and dicarbonyls (e.g., methylglyoxal [MG]). In vitro hyperglycemia-induced MG formation and endothelial dysfunction could be blocked by benfotiamine, but in vivo effects of benfotiamine on postprandial endothelial dysfunction and MG synthesis have not been investigated in humans until now.
RESEARCH DESIGN AND METHODS: Thirteen people with type 2 diabetes were given a heat-processed test meal with a high AGE content (HAGE; 15.100 AGE kU, 580 kcal, 54 g protein, 17 g lipids, and 48 g carbohydrates) before and after a 3-day therapy with benfotiamine (1,050 mg/day). Macrovascular flow-mediated dilatation (FMD) and microvascular reactive hyperemia, along with serum markers of endothelial disfunction (E-selectin, vascular cell adhesion molecule-1, and intracellular adhesion molecule-1), oxidative stress, AGE, and MG were measured during both test meal days after an overnight fast and then at 2, 4, and 6 h postprandially.
RESULTS: The HAGE induced a maximum reactive hyperemia decrease of -60.0% after 2 h and a maximum FMD impairment of -35.1% after 4 h, without affecting endothelium-independent vasodilatation. The effects of HAGE on both FMD and reactive hyperemia were completely prevented by benfotiamine. Serum markers of endothelial dysfunction and oxidative stress, as well as AGE, increased after HAGE. These effects were significantly reduced by benfotiamine.
CONCLUSIONS: Our study confirms micro- and macrovascular endothelial dysfunction accompanied by increased oxidative stress following a real-life, heat-processed, AGE-rich meal in individuals with type 2 diabetes and suggests benfotiamine as a potential treatment.
Pharmacokinetics of thiamine derivatives especially of benfotiamine.
Int J Clin Pharmacol Ther 1996 Feb; 34(2): 47-50.
Loew D.
Pharmacokinetic data of orally administered lipid-soluble thiamine analogues like benfotiamine are reviewed and assessed. It is quite clear that benfotiamine is absorbed much more better than water-soluble thiamine salts: maximum plasma levels of thiamine are about 5 times higher after benfotiamine, the bioavailability is at maximum about 3.6 times as high as that of thiamine hydrochloride and better than other lipophilic thiamine derivates. The physiological activity (alphaETK) increased only after benfotiamine was given. Due to its excellent pharmacokinetic profile benfotiamine should be preferred in treatment of relevant indications.
A benfotiamine-vitamin B combination in treatment of diabetic polyneuropathy.
Exp Clin Endocrinol Diabetes 1996; 104(4): 311-6.
Stracke H, Lindemann A, Federlin K.
In a double-blind, randomized, controlled study, the effectiveness of treatment with a combination of Benfotiamine (an Allithiamine, a lipid-soluble derivative of vitamin B1 with high bioavailability) plus vitamin B6/B12 on objective parameters of neuropathy was studied over a period of 12 weeks on 24 diabetic patients with diabetic polyneuropathy. The results showed a significant improvement (p = 0.006) of nerve conduction velocity in the peroneal nerve and a statistical trend toward improvement of the vibration perception threshold. Long-term observation of 9 patients with verum over a period of 9 months support the results. Therapy-specific adverse effects were not seen. The results of this double-blind investigation, of the long-term observation and of the reports in the literature support the contention that the neurotropic benfotiamine-vitamin B combination represents a starting point in the treatment of diabetic polyneuropathy.
Benfotiamin inhibits intracellular formation of advanced Glycation endproducts in vivo.
Diabetes. 2000 May; 49(Suppl1): A143(P583).
Lin J, Alt A, Liersch J, Bretzel RG, Brownlee MA, Hammes HP.
We have demonstrated previously that intracellular formation of the advanced glycation end product (AGE) N-[Epsilon]-(carboxymethyl)lysine (CML) inversely correlates with diabetic vascular complications independently from glycemia (Diabetologia 42, 603, 1999). Here, we studied the effect of benfotiamine, a lipid-soluble thiamine derivative with known AGE-inhibiting properties in-vitro on the intracellular formation of (CML) and methylglyoxal-derived AGE in red blood cells. Blood was collected from 6 Type 1 diabetic patients (2m, 4f, age 31.8 ± 5.5 years; diabetes duration 15.3 ± 7.0 years) before and after treatment with 600 mg/day benfotiamine for 28 days. In addition to HbA1c (HPLC), CML and methylglyoxal were measured using specific antibodies and a quantitative blot technique. While treatment with benfotiamine did not affect HbA1c levels (at entry: 7.18 ± 0.86%; at conclusion 6.88 ± 0.88%; p not significant), levels of CML decreased by 40% (737 ± 51 arbitrary units/mg protein (AU) vs 470 ± 86 AU; p<0.01). The levels of intracellular methylglyoxal were reduced by almost 70% (1628 ± AU vs 500 ± 343 AU; p<0.01). The data indicate that thiamine derivatives are effective inhibitors of both intracellular glycoxidation and AGE formation.
Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy.
Nat Med 2003 Mar; 9(3): 294-9.
Hammes HP, Du X, Edelstein D, Taguchi T, Matsumura T, Ju Q, Lin J, Bierhaus A, Nawroth P, Hannak D, Neumaier M, Bergfeld R, Giardino I, Brownlee M.
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-kappaB 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-kappaB 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.
Effectiveness of different benfotiamine dosage regimens in the treatment of painful diabetic neuropathy.
Arzneimittelforschung 1999 Mar; 49(3): 220-4.
Winkler G, Pal B, Nagybeganyi E, Ory I, Porochnavec M, Kempler P.
The therapeutic effectiveness of a benfotiamine (CAS 22457-89-2)-vitamin B combination (Milgamma-N), administered in high (4 x 2 capsules/day, = 320 mg benfotiamine/day) and medium doses (3 x 1 capsules/day), was compared to a monotherapy with benfotiamine (Benfogamma) (3 x 1 tablets/day, = 150 mg benfotiamine/day) in diabetic patients suffering from painful peripheral diabetic neuropathy (DNP). In a 6-week open clinical trial, 36 patients (aged 40 to 70 yrs) having acceptable metabolic control (HbA1c < 8.0%) were randomly assigned to three groups, each of them comprising 12 participants. Neuropathy was assessed by five parameters: the pain sensation (evaluated by a modified analogue visual scale), the vibration sensation (measured with a tuning fork using the Riedel-Seyfert method) and the current perception threshold (CPT) onthe peroneal nerve at 3 frequencies: 5, 250 and 2000 Hz). Parameters were registered at the beginning of the study and at the end of the 3rd and 6th week of therapy. An overall bneneficial therapeutic effect on the neuropathy status was observed in all three groups during the study, and a significant improvement in most of the parameters studied appeared already at the 3rd week of therapy (p < 0.01). The greatest change occurred in the group of patients receiving the high dose of benfotiamine (p < 0.01 and 0.05, resp., compared to the othr groups). Metabolic control did not change over the study. It is concluded that benfotiamine is most effective in large doses, although even in smaller daily dosages, either in combination or in monotherapy, it is effective.
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