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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 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 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 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
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
1.
Loew D. “Pharmacokinetics of thiamine derivatives
especially of Benfotiamine.” Int J Clin Pharmacol Ther.
1996 Feb; 34(2): 47-50.
2.
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.
3.
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).
4.
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.
5.
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.
6.
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.
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