Diabetes Uncomplicated
Evan David Rosen, M.D., Ph.D.
Assistant Professor of Medicine,
Harvard Medical School
Elevated
glucose levels in all types of diabetes can cause damage to
blood vessels, which is the root cause of the complications
of diabetes. When the damage occurs in the tiny blood vessels
of the eye, kidney, or nerves, the result is diabetic retinopathy,
nephropathy, or neuropathy, respectively. Damage to the large
blood vessels of the body leads to atherosclerosis, heart attack,
and stroke. Despite decades of research on diabetic complications,
we are only just beginning to understand the mechanisms by which
hyperglycemia affects blood vessels. Even more frustrating is
our inability to treat these complications once they occur.
Specifically, we have very few efficacious therapies for diabetic
retinopathy, neuropathy and nephropathy. The best advice we
can give our patients is to take responsibility for keeping
their sugar levels down, as this can prevent complications in
the first place.
Slowly, however, researchers
have chipped away at the problem of diabetic complications,
and the result has been a better understanding of the basic
processes involved. This improved understanding, in turn, has
suggested some potentially useful therapies as well.
Studies on diabetic complications
have pointed to four separate pathways activated by hyperglycemia
leading to vascular damage. These pathways include increased
polyol flux, increased advanced glycation endproduct (AGE) formation,
protein kinase C (PKC) activation, and increased hexosamine
flux. Without getting too bogged down in the biochemical details,
suffice it to say that each pathway has had its adherents in
the research community, and drug companies have spent a lot
of time and money trying to halt diabetic complications by blocking
one pathway or the other, with only modest success.
A major breakthrough in the field
occurred a few years ago, when a group at the Albert Einstein
College of Medicine unified the field by identifying a single
glucose-induced mediator of all four pathways. This mediator
is superoxide, a souped up form of oxygen with extra electrons
attached that can cause great mischief when overproduced in
cells. When glucose is metabolized, electrons are pushed down
a chain of proteins that produce ATP, the currency for energy
in cells. In the presence of too much glucose, electrons are
pushed down the chain faster than these proteins can transfer
them, allowing some electrons to “pop off” the chain
where they can stick to oxygen and other similar molecules.
Many cells have the ability to regulate how much glucose they
let in, but for some reason vascular cells can’t do this.
Thus, when blood sugar is high, there is high glucose inside
vascular cells as well. The resulting elevated superoxide levels
then block the metabolism of glucose, which increases the levels
of intermediary compounds that are stuck behind the blockade.
These compounds activate all four of the damaging pathways at
once.
The Einstein researchers then
postulated that if superoxide was causing glucose metabolism
to get backed up, there might be benefit in unplugging the pipeline.
They noted that an enzyme called transketolase could get rid
of the troublesome intermediary compounds if it were sufficiently
activated. They also noted that thiamine (also called vitamin
B1) was necessary for the transketolase enzyme to have full
activity. Perhaps elevating cellular thiamine levels could jack
up transketolase and unblock the pipe, the reasoning went, but
when the researchers added thiamine to cells in culture exposed
to high concentrations of glucose, they found a measly 20% increase
in activity, not enough to do any good.
The next revelation came from
colleagues in Germany, who noted that a modified form of thiamine,
called benfotiamine, had been used in that country for over
a decade to treat diabetic nerve pain with some success, although
nobody understood how or why it worked. When the Einstein researchers
put benfotiamine on their cells, they found a whopping 300%
increase in transketolase activity, enough to reduce the activation
of at least three of the four offending pathways associated
with vascular damage. Furthermore, benfotiamine could reduce
hyperglycemia-induced damage to vascular cells in culture as
well as in diabetic rats, which developed less retinopathy than
did rats receiving placebo.
This study is nice because (a)
it provides further “proof-of-principle” that superoxide-induced
blockade of glucose metabolism is the root cause of diabetic
complications, and (b) because it suggests a potential therapy
for the prevention and treatment of those complications. As
I mentioned earlier, benfotiamine has already been in use for
a while in Europe for the control of diabetic nerve pain. As
far as I have been able to discern, no one has systematically
tested its use in humans to see if complications can be prevented
in the first place, nor have they used it to treat other forms
of diabetic complications such as retinopathy or nephropathy.
Also, there is still controversy over the appropriate dose of
benfotiamine to use even in neuropathy, its best studied indication.
It seems likely that such detailed studies will now be performed,
and we’ll have a better sense of the utility of this agent.
Fortunately, significant side effects have not been reported
from the use of this agent, although that issue will also need
to be more carefully studied in large controlled experiments.
Before you run out and buy jars
of vitamin B1, remember that run-of-the-mill thiamine doesn’t
seem to have any beneficial effect on either transketolase activity
or diabetic complications. Hopefully, benfotiamine or a related
compound will prove to be a valuable adjunct to the antidiabetic
armamentarium, but for now, we’ll have to wait for the
appropriate studies to make that determination
References:
1. Hans-Peter Hammes, Xueliang
Du, Diane Edelstein, Tetsuya Taguchi, Takeshi Matsumura, Qida
Ju, Jihong Lin, Angelika Bierhaus, Peter Nawroth, Dieter Hannak,
Michael Neumaier, Regine Bergfeld, Ida Giardino, Michael Brownlee.
Benfotiamine blocks three major pathways of hyperglycemic damage
and prevents experimental diabetic retinopathy. Nature Medicine
9, 294 - 299 (01 Mar 2003).
2. Michael Brownlee. Biochemistry
and molecular cell biology of diabetic complications Nature
414, 813 - 820 (13 Dec 2001).
Written by Evan D. Rosen, M.D.,
Ph.D.
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