AGEs and microvascular circulation

Effects of low- and high-advanced glycation endproduct meals on macro- and microvascular endothelial function and oxidative stress in patients with type 2 diabetes mellitus.
Negrean M, Stirban A, Stratmann B, Gawlowski T, Horstmann T, Götting C, Kleesiek K, Mueller-Roesel M, Koschinsky T, Uribarri J, Vlassara H, Tschoepe D.
Source

Diabetes Clinic, Heart and Diabetes Centre NRW Bad Oeynhausen, Ruhr University Bochum, Germany.
Erratum in * Am J Clin Nutr. 2007 Oct;86(4):1256.

Abstract
BACKGROUND:

An advanced glycation endproducts (AGEs)-rich diet induces significant increases in inflammatory and endothelial dysfunction markers in type 2 diabetes mellitus (T2DM).

OBJECTIVE:
The aim was to investigate the acute effects of dietary AGEs on vascular function in T2DM patients.

DESIGN:
Twenty inpatients with T2DM [x (+/-SEM) age: 55.4 +/- 2.2 y; glycated hemoglobin: 8.8 +/- 0.5%] were investigated. In a randomized crossover design, the effects of a low-AGE (LAGE) and high-AGE (HAGE) meal on macrovascular [by flow-mediated dilatation (FMD)] and microvascular (by Laser-Doppler flowmetry) function, serum markers of endothelial dysfunction (E-selectin, intracellular adhesion molecule 1, and vascular cell adhesion molecule 1), oxidative stress, and serum AGE were assessed. The meals had identical ingredients but different AGE amounts (15.100 compared with 2.750 kU AGE for the HAGE and LAGE meals, respectively), which were obtained by varying the cooking temperature and time. The measurements were performed at baseline and 2, 4, and 6 h after each meal.

RESULTS:
After the HAGE meal, FMD decreased by 36.2%, from 5.77 +/- 0.65% (baseline) to 3.93 +/- 0.48 (2 h), 3.70 +/- 0.42 (4 h), and 4.42 +/- 0.54% (6 h) (P<0.01 for all compared with baseline). After the LAGE meal, FMD decreased by 20.9%, from 6.04 +/- 0.68% (baseline) to 4.75 +/- 0.48% (2 h), 4.69 +/- 0.51% (4 h), and 5.62 +/- 0.63% (6 h), respectively (P<0.01 for all compared with baseline; P<0.001 for all compared with the HAGE meal). This impairment of macrovascular function after the HAGE meal was paralleled by an impairment of microvascular function (-67.2%) and increased concentrations of serum AGE and markers of endothelial dysfunction and oxidative stress.

CONCLUSIONS:
In patients with T2DM, a HAGE meal induces a more pronounced acute impairment of vascular function than does an otherwise identical LAGE meal. Therefore, chemical modifications of food by means of cooking play a major role in influencing the extent of postprandial vascular dysfunction.

The high-AGE meal induced a 67.2% decrease in microvascular function. Considering that hair follicles are embedded in capillaries, this study shows how metabolic disease can directly cause hair loss. Cooking high-carbohydrate foods would result in increased dietary AGE. Raw foodism is sounding better and better.

Why are you using this info to make carbohydrates sound like the enemy? A high carb meal would mean less AGE's. High protein meals are what cause AGE's.

It sounds like cooking anything would be the problem, whether protein or carb... In their raw natural form both are just fine, though I'd prefer my meat cooked at least a little... As stated countless times on this forum, just eat things as close to their natural form as you can. It's a huge first step.

Espio wrote:Why are you using this info to make carbohydrates sound like the enemy? A high carb meal would mean less AGE's. High protein meals are what cause AGE's.

AGEs are produced when simple carbohydrates bind to lipid or protein molecules without enzymatic intervention. It happens both endogenously (especially when there's oxidative stress) and exogenously (during food processing, especially cooking with high temperatures).

By the way, whole grains are a source of all three macromolecules...lipids, proteins, and carbohydrates. So you can assume that any thoroughly cooked foods containing whole grains will contain AGEs, especially when the grain is crushed prior to cooking (flour).

I'll also point out that fructose undergoes glycation at a rate ten times that of glucose. So if intake of fructose is high you should take anti-glycation measures like anti-oxidant supplementation. Supposedly green tea inhibits glycation.

Good stuff.

CS has brought this up before, but here is a study that I found:

http://www.benfotiamine.org/Benfotiamine.htm

ABSTRACTS:

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 beneficial 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 other 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.

Prevention of cardiac autonomic neuropathy in dogs with Benfotiamine.
Koltai MZ.
In Gries FA, Federlin K. Benfotiamin in the Therapy of Polyneuropathy.
New York: Georg Thieme Verlag, 1998; 45-9.

Experimentally-induced diabetes of the dog leads to disturbances in the autonomous neurological function of the heart after approximately 3 months of continuously- observed diabetes. As signs of autonomic cardiac neuropathy, the heart rate variability and Valsalva ratio clearly fell in the untreated diabetic animals. Oral benfotiamine, administered from the sixth day after diabetes-induction, prevented or at least delayed these changes. According to the results, treatment with fat-soluble benfotiamine can play an important role in the therapy and prevention of cardiac autonomic neuropathy, apart from any effect on diabetic metabolic disturbances.

PRODUCT SUMMARY: (Compiled by Advanced Orthomolecular Research (AOR) of Canada)

Benfotiamine and the "Caramelization of the Flesh"

Advanced Glycation Endproducts, or “AGEs” as they’re appropriately called, are the end result of the complex chemical process through which the structure of proteins is warped by exposure to sugars or by other, much more reactive molecules. AGE chemistry is the cause of the “browning” you see when you roast a chicken or make toast, but the same “browning” chemistry is at work in your body every day of your life. In your arteries. In your kidneys. In your heart, your eyes, your skin, your nerves. In every cell, the sugar that your body uses for fuel is busily at work at this very moment, caramelizing your body through exactly the same chemical processes that caramelize onions or peanut brittle.
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. It’s these cells that 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 candidate (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 marketed as “AGE-inhibitors.” But while many of these herbs and other nutrients may be valuable, and may 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, and a whole host of antioxidants (including 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 the most potent of the allithiamines, a unique class of thiamin-derived compounds present in trace quantities in roasted crushed garlic and other vegetables from the Allium genus (such as onions, shallots, and leeks). Benfotiamine’s unique open-ringed structure makes it able to pass directly through cell membranes, readily crossing the intestinal wall and being taken straight into the cell.
As a result, your body absorbs Benfotiamine better than thiamin itself, and levels of thiamin and TPP remain higher for longer. Thiamin absorption from Benfotiamine is about five times as great as from conventional thiamin supplements. And the effect is even more impressive at the tissue level: brain and muscle, for instance, take in five- to twentyfive-fold as much thiamin in the form of allithiamines as they do of an equal amount of regular thiamin. And Benfotiamine is even more bioavailable than the other 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 multivitamins) 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 mega dose 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.

KEEP IN MIND THAT THESE STATEMENTS HAVE NOT BEEN EVALUATED BY THE FDA

EDIT: High doses of B vitamins with meals are very beneficial for hair and health from what I am understanding.

Benfotiamine, riboflavin, niacin and pyridoxal phosphate are appealing individually and as a group with meals. I know pancake takes some of these and seems to have benefited from them.

I'm not sure if that study that I posted is completely legit. Maybe someone else can verify it's contents.

I noticed Benfotiamine in CS' regimen a while ago, and now I guess I know its purpose. It also makes sense that he takes it after having "civilized foods."

I'd like to hear what CS has to say about all of this!