Last week we reported in a news flash that
exciting new data in an animal model of diabetes suggests lipid soluble
thiamine may help prevent the development of some of the most common side
effects of diabetes. We had many of our readers ask for more information. They
wanted to know, What causes the side effects we commonly see in diabetes and
why is thiamine beneficial? What is lipid soluble thiamine and how much is
known about it?
At its simplest, the story is pretty
straightforward: when glucose levels are too high, numerous biochemical
pathways are thrown out-of-whack, leading to damage to the eyes, kidneys and
nerves. Thiamine seems to be able to prevent some of this damage, at least in
vitro and in animal models, by activating an enzyme that lowers levels of some
of the dangerous metabolites of glucose. Standard versions of thiamine can’t
be absorbed at high enough levels to have the intended effect, but a
lipid-soluble form of thiamine was able to decrease development of
retinopathy, at least in rats. That’s the simple story - here’s the more
complex version.
Patients with diabetes mellitus frequently
suffer from serious eye, kidney and nerve damage. This damage is due to
long-term hyperglycemia, repeated episodes of high blood sugar. Hyperglycemia
can be measured directly over short periods of time through the direct
measurement of glucose levels. Over longer periods of time, hyperglycemia is
monitored by measuring levels of HbA1c, glycosylated hemoglobin. HbA1c
reflects average blood glucose levels over a 2-3 month period of time. In the
Diabetes Control and Complications Trial, HbA1c levels were lowered 2% by
intensive control of blood glucose levels. Although this seems like a small
decrease, it was associated with dramatic effects: 75% reduction in risk of
developing eye disease, 50% reduction in risk of kidney disease, and 60%
reduction in risk of nerve disease (DCCT Research Group, 1993).
Why is hyperglycemia so dangerous and so
damaging? The answer is surprisingly complex, reflecting the complex metabolic
systems within cells. To understand it, it helps to remember college
biochemistry and all of the intersecting metabolic pathways and cycles. Four
different biochemical pathways have been implicated in hyperglycemia-mediated
damage. First, as glucose levels increase, the percentage of glucose that is
processed through the polyol pathway increases. This leads to decreased levels
of NADPH and increased oxidative stress within the cells. Second, breakdown
products of glucose are very reactive with the amino groups of proteins, and
generate increased levels of advanced glycation endproducts (AGEs). These
modified proteins have altered functions, their interactions with matrix
proteins changes, and they bind to AGE receptors, activating reactive oxygen
species. This again increases oxidative stress within the cell. Third, a
breakdown product of glucose is a precursor of diacyl glycerol (DAG), a potent
activator of protein kinase C (PKC). PKC activation has a myriad of effects on
the function of cells. Although the exact mechanism is not established, it is
known that PKC activation leads to abnormal blood flow in the eyes and
kidneys. Finally, high levels of glucose increases the amount of glucose being
processed through the hexosamine pathway, and increases the levels of
fructose-6-phosphate in the cell. This leads to complex changes in gene
expression that are believed to be responsible for some of the side effects of
diabetes (the exact mechanism is unknown).
These destructive pathways may all derive from
the effect of hyperglycemia on superoxide production. Superoxide inhibits the
enzyme glyceraldehydes phosphate dehydrogenase (GAPDH), an enzyme involved in
glucose metabolism. When GAPDH is inhibited, it backs up the pathway,
increasing levels of fructose-6-phosphate and of glucose itself. Thus the
superoxide production could either cause or exacerbate all four of the
pathways described here.
Understanding the biochemistry is the first
step, but the real question is how can these destructive processes be blocked?
The most straightforward answer is to tightly control glucose levels. However,
technology and behavior both limit success in this area, and some level of
hyperglycemia is almost always present in diabetic patients. As a result,
there has also been a long search for novel medications and many clinical
trials aimed at inhibiting one or more of these pathways (Bril, 2001). To
date, nothing has come to market.
Recently, Dr. Michael Brownlee of Albert
Einstein Medical School in New York and his colleagues have found a promising
new approach using lipid soluble thiamine (Hammes et al, 2003). To understand
how thiamine can affect the systems, we need to return to the biochemical
pathways. The investigators focused on an enzyme of the pentose phosphate
shunt, transketolase. Transketolase provides a way for the cell to use up the
glucose metabolites, particularly fructose-6-phosphate and
glyceraldehydes-3-phosphate, that are responsible for most of the damage seen
in diabetes. Transketolase is a thiamine-dependent enzyme - thiamine is the
cofactor that allows it to catalyze the reaction. By providing higher levels
of thiamine to cells, transketolase activity can be maximized, thus decreasing
the concentrations of the dangerous glucose metabolites.
If all of this biochemistry leaves your head
spinning, there may be a simpler way to understand the importance of thiamine
and transketolase. There have been suggestions for many years that diabetic
patients have impaired absorption of thiamine and may display low levels of
thiamine deficiency (Rindi and Laforenza, 2000). Interestingly, this
deficiency may be particularly notable in vascular endothelial cells. The
superoxide generated by hyperglycemia can also destroy thiamine itself,
leaving these cells with a functional deficiency (Hammes et al., 2003). By
normalizing thiamine levels in the cells, metabolic balance may be restored,
potentially protecting against the kidney, eye and nerve damage due to
diabetes.
Dr. Brownlee and colleagues were successfully
able to demonstrate that thiamine could do everything outlined here. They used
a particular form of thiamine (more about that below), both in tissue culture
and in animal models, to increase the activation of transketolase. They were
able to show a decrease in the activation of the hexosamine pathway, a
decrease in DAG production and PKC activation, and a decrease in AGE
formation. Most importantly, they were able to block the development of
diabetic retinopathy in a well established animal model of the disease. It is
important to note that this is not an isolated finding - many other
investigators have also demonstrated beneficial effects of thiamine in
blocking hyperglycemia-induced damage Ascher et al, 2001; Pomero et al, 2001).
Together, these data point to the potential value of thiamine supplementation
in diabetes.
To achieve the results, Dr. Brownlee and
colleagues didn’t use off-the-shelf thiamine. Only limited amounts of
thiamine can be absorbed through the gastrointestinal tract - thiamine is
actively transported and only 4-5 mg can be absorbed from a single oral dose.
To treat acute deficiencies, such as those seen in alcohol withdrawal,
thiamine is generally given either intramuscularly or intravenously (in the
developed world, thiamine deficiency is most frequently associated with heavy
alcohol use). This is obviously not the preferable route for routine vitamin
supplementation, and variants of thiamine have been developed that have
improved absorption. These variants are known as allithiamins or lipid-soluble
thiamines. They are passively absorbed, easily diffusing into the circulation,
and can generate levels of thiamine in the blood comparable to those seen with
injections.
Lipid-soluble thiamine has been used for many
years in Europe and in Asia. The forms most commonly used are benfotiamine (Bitsch
et al., 1991) and thiamine propyl disulfide (Thomson et al, 1971). They are
most useful in treating thiamine deficiencies, typically associated with
alcoholism, but their strong safety record suggests they may be more broadly
applicable. The work with lipid soluble thiamine opens up an exciting new
avenue in diabetes research and treatment.
For more information:
Ascher, E. et al. Thiamine reverses
hyperglycemia-induced dysfunction in cultured endothelial cells. Surgery. 130:
851-858 (2001).
Bitsch, R. et al. Bioavailability assessment of
the lipophilic benfotiamine as compared to a water-soluble thiamin derivative.
Ann. Nutr. Metab. 35: 292-296 (1991).
Bril, V. Status of current clinical trials in
diabetic polyneuropathy. Can. J. Neurol. 28: 191-198 (2001).
Brownlee, M. Biochemistry and molecular cell
biology of diabetic complications. Nature. 414: 813-820 (2001).
Diabetes Control and Complications Trial (DCCT)
Research Group. The effect of intensive treatment of diabetes on the
development and the progression of long-term complications in
insulin-dependent diabetes mellitus. N. Engl. J. Med. 329:977-986 (1993).
Hammes, H. et al. Benfotiamine blocks three
major pathways of hyperglycemic damage and prevents diabetic retinopathy.
Nature Medicine 9:294-299 (2003).
Pomero, F. et al. Benfotiamine is similar to
thiamine in correcting endothelial cell defects induced by high glucose. Acta
Diabetol. 38: 135-138 (2001).
Rindi, G. and Laforenza, U. Thiamine intestinal
transport and related issues: Recent aspects. Proc. Soc. Exp. Biol. Med. 224:
246-255 (2000).
Thomson et al. Thiamine propyl disulfide:
Absorption and utilization. Ann. Int. Med. 74: 529-534 (1971).
