Used for years throughout Europe, Alpha Lipoic Acid--an antioxidant
coenzyme--is one of nature's most potent weapons against disease.
Manufactured in the body and found in many foods, it has produced great
results in the prevention and treatment of diabetes, cataracts, heart
disease, liver ailments, cancer, kidney stones, and other illnesses. Now,
readers can discover its life-enhancing benefits.
Alpha Lipoic is an essential enzyme in energy
production because as an antioxidant helps convert the food into energy.
It is both a fatty acid found in every cell of our bodies, and an
antioxidant, a substance that neutralizes harmful chemicals also called
free radicals. Because it is soluble in both water and fat, this enzyme is
different than the other antioxidants and also it has the power to recycle
some of the other antioxidants, after they have been used up by the
body.
Alpha-lipoic acid is used as an antioxidant in a general
strategy for reducing the risk of environmental and metabolic oxidative
damage to cells, and as a powerful reducing agent for supporting the
protective antioxidant network.(1) Alpha-lipoic acid demonstrates an
ability to increase insulin stimulated glucose disposal and can be used to
assist in maintaining proper blood glucose levels in pre-diabetes and Type
2 diabetes.(1,2,20)
Alpha-lipoic acid can be used in prediabetes,
Type 2 diabetes, and Type 1 diabetes to reduce the risk for, or to
ameliorate, diabetic complications relating to the inordinate oxidative
stress associated with life-time accumulative periods of hyperglycemic
states.(3,4,5)
Alpha-lipoic acid was identified in 1951, just around
the beginning of scientific research into the nature of biological
free-radicals. At that time, it was not possible to fully appreciate the
pivotal role alpha-lipoic acid had in antioxidation and it was not until
1989 that it was finally recognized as a bona fide antioxidant.6 Much of
the current understanding of the antioxidant role of alpha-lipoic acid
emerged through the work done by the Packer Laboratory at the University
of California in Berkley, one of the world's leading antioxidant research
centers. Dr. Lester Packer and his colleagues have established that
alpha-lipoic acid is the most versatile and powerful antioxidant in the
body's entire defensive antioxidant network.(6)
The Antioxidant
Network
The concept of an antioxidant defense network developed
from experimental observations of a dynamic interplay between vitamins C
and E, coenzyme Q10, glutathione, and alpha-lipoic acid. These five
antioxidants are now understood to coalesce into a functional network
because each remains redox-sensitive, meaning that they can be regenerated
into their active antioxidant form through redox reduction by a network
member with sufficient reduction potential. This network of antioxidants
comprises a pool of shared redox reducing power. Not all antioxidants
undergo endogenous reduction to be regenerated in the body. Such a dynamic
defensive network serves as a renewable electron-donating system for
neutralizing the destructive metabolic ebb and flow of free-radicals,
reactive oxygen species (ROS), and reactive nitrogen species (RNS).(1,6)
The reduced form of alpha-lipoic acid, dihydrolipoic acid is the
enforcer of network performance. Alpha-lipoic acid is produced
endogenously and reduced to dihydrolipoic acid in the mitochondria, as is
also dietary and supplemental alpha-lipoic aid. Dihydrolipoic acid is
exported into the cytosol to help facilitate cellular and extracellular
redox balance, either directly interacting with reactive oxygen or
nitrogen species or, by recycling antioxidants in the antioxidant
network.(1,26) It is unique in that it can function as an antioxidant in
both the aqueous and lipid phases of cells.
According to Packer,
dihydrolipoic acid is the most powerful antioxidant in the antioxidant
network, with a redox potential of -320 mV, compared to -280 mV for
glutathione.(1) Dihydrolipoic acid is able to dissolve in the lipid phase
of membranes and reduce spent vitamin E and coenzyme Q10, or it can reduce
spent vitamin C and glutathione in the aqueous phase.(1,27-29)
The
practical versatility of the antioxidant network is in the enabled
shuttling of electrons throughout the aqueous and lipid phases of cell
membranes, intracellular regions, and interstitial spaces.1 Since cellular
membrane functional integrity is pivotal to life and health, and
accumulative oxidative damage to membranes diminishes or ultimately
destroys functionality, ongoing redox reduction of membrane-bound vitamin
E and coenzyme Q10 is required for health and life quality. Alpha-lipoic
acid has been called correctly the antioxidant of antioxidants, making it
an important part of any general antioxidant supplemental program. This
becomes even a greater consideration as we grow older since endogenous
alpha-lipoic acid titers fall off due to general metabolic decline.
Alpha-lipoic acid is also particularly relevant to oxidative stress in
diabetic states.
Prediabetes & Type 2 diabetes promote
oxidative stress and the diabetic complications
Hyperglycemia
is associated with inordinate oxidative stress, compared to
normoglycemia.(1,32,33)The oxidative stress associated with diabetic
states is evidenced by elevated organic chemical markers of oxidative
stress in the plasma, lower than normal levels of intracellular vitamin E
and glutathione, and elevated enzymatic activity of antioxidant
enzymes.(32)
Hyperglycemia and vascular damage have been linked by
at least four separate metabolic conditions associated with diabetes,
increased polyol pathway flux, increased formation of advanced glycation
end-products (AGE's), activation of protein kinase C,and increased
hexosamine pathway flux, all of which have in common the overproduction of
superoxide by the mitochondrial electron transport chain.(1,32,33) The
vascular endothelial cells are a major target of hyperglycemia-induced
superoxide damage, eventually giving rise to the vascular changes that
underlie the complications of diabetes.(4) An endothelial vascular
oxidative burden is already evident in prediabetes.(47) Cardiovascular
complications of diabetes are reported to commence at the prediabetes
stage,(48) and microvascular disease is already in many individuals with
undiagnosed or newly diagnosed Type 2 diabetes.(49)
The
overproduction of superoxide anion associated with hyperglycemia imposes a
drop in the availability of endothelium-derived regulatory nitric oxide.
This occurs as a result of superoxide reacting with nitric oxide to form
peroxynitrite.(4,32) The reaction between superoxides and nitric oxide is
very rapid when the flow of superoxide anions is continuously elevated
under hyperglycemic states.(34) Nitric oxide provides dynamic regulation
of vasodilation and blood flow, thrombosis, endothelial inflammation, and
vascularsmooth muscle growth.(31) A diminished nitric oxide concentration
due to an ongoing dissipation in peroxynitrite formation is the threshold
for endothelial dysfunction, and the vascular pathological dysregulation
and structural changes in small vessels, arteries, and peripheral nerves
that lead to diabetic complications.(32,35-38) Microvascular disease
associated with diabetes is a leading cause of retinopathy, nephropathy,
and neuropathy, and the macrovascular disease of diabetes-accelerated
atherosclerosis leads to increased risk of myocardial infarction, stroke,
and limb amputation.(39) In diabetic arteries, superoxide anion may also
favor contractions through the formation of hydrogen peroxide and hydroxyl
radical, which stimulate the production of contractile prostanoids.(40,41)
Alpha-lipoic acid resists superoxide and diabetic
complications
Alpha-lipoic acid is a powerful antioxidant
reducing agent that interacts with superoxide. It interferes with the
lowering of available nitric oxide by superoxide. Since superoxide is the
major promoter of vascular pathological changes that lead to diabetic
vascular complications, alpha-lipoic acid attenuates the risk for
complications.(1) Furthermore, alphalipoic acid enhances the de novo
synthesis of glutathione levels,(30) as well as recycles existing levels
of glutathione via the antioxidant network. Glutathione is a key
antioxidant player in maintaining intracellular reductive balance.(1,30)
Enhancing cellular glutathione levels via alpha-lipoic acid may provide
protection against tissue damage by enhancing detoxification systems for
reactive carbonyl compounds that are associated with protein oxidation by
reactive oxygen species seen in the oxidative stress of diabetes.(42)
Vulnerability to diabetic peripheral nerve damage due to oxidative injury
results from impaired antioxidative defense mechanisms manifested by
decreased nerve glutathione levels, and SOD, catalase, and total quinine
reductase activities. Down regulation of these enzymes under diabetic
conditions is caused by reactive oxygen species and prevented by
alpha-lipoic treatment.(43)
Alpha-lipoic acid facilitates
glucose disposal
In vitro studies provide evidence that
alpha-lipoic acid rapidly stimulates tyrosine phosphorylation of the
insulin receptor (IR) and insulin receptor substrate-1 (IRS-1), enhances
PI3-K, Akt, and p38 MAPK activities, elevates membrane GLUT4 content, and
increases glucose uptake.(1,44-46) In animal studies, alpha-lipoic acid
demonstrates an ability to enhance glucose uptake.(2)
Intravenous
studies have demonstrated an increase of insulin sensitivity in type-2
diabetes after acute and chronic intravenous administration of
alpha-lipoic acid.(50) To determine the effect of oral administration,
Jacob et al conducted a 4-week randomized, placebo-controlled, multicenter
pilot study to determine whether oral treatment in humans improved insulin
sensitivity.(20) Alpha-lipoic acid was given to 75 patients with Type-2
diabetes. They were randomized to either placebo (n = 19), or active
treatment in various doses of 600 mg once daily (n = 19), 600 mg BID (1200
mg, n = 18), or 600 mg TID (1800 mg, n = 18). An isoglycemic glucose-clamp
was done on day-0 and on day-29. All four groups were comparable and had a
similar degree of hyperglycemia and insulin sensitivity at baseline. When
compared to placebo, significantly more subjects had an increase in
insulin-stimulated glucose disposal after alpha-lipoic acid treatment in
each group.
Because there was no dose-effect seen in the three
different alpha-lipoic acid groups, all subjects receiving alpha-lipoic
acid were combined into a single "active" group, and then compared to the
placebo group. Alpha-lipoic acid produced a statistically significant (p =
.01) increase in insulin stimulated glucose disposal of essentially 27%
compared to the placebo outcome. This compares very favorably with
essentially 30% seen in intravenous administration of alpha-lipoic
acid.(50)
The pilot study results suggest that oral administration
of alpha-lipoic acid is a practical intervention that can improve insulin
sensitivity in patients with Type-2 diabetes. More clinical investigation
is needed. However, this single pilot study and previous intravenous
studies give sufficient cause to encourage prediabetic and diabetic
patients to consider oral alpha-lipoic acid at 600 mg once per day or 300
mg BID as a means of improving glycemic control. This intervention may
become unnecessary in time when life-style changes are productive.
Since alpha-lipoic acid improves glucose disposal,
relative hypoglycemia may be possible in some Type 1 and Type 2 diabetic
patients initiating alpha-lipoic acid in combination with hypoglycemic
medications and/or insulin.(20) Patients in these categories should
introduce alpha-lipoic acid cautiously. Dose adjustments of hypoglycemic
medications and/or insulin should be expected.(20)
Insufficient
data exist to know what daily amount of alpha-lipoic acid is appropriate
during pregnancy, or the nursing period. This consideration is
particularly relevant in gestational diabetes and should be guided by a
physician.
Theoretically, the concomitant use of chemotherapy drugs
with alpha-lipoic acid may decrease their effectiveness.(21) In general,
oncologists are concerned that the concomitant use of powerful
antioxidants during chemotherapy could frustrate oxidative destruction.
There is some concern that alpha-lipoic acid could interfere with the
production of triiodothyronine (T3) from thyroxine (T4), if alpha-lipoic
acid and thyroxine medication are taken at the same time.(22) However,
adverse effects relating to thyroid function have not been noted in
published clinical trials, some lasting for 6 to 24 months.
Laboratory studies suggest that very large doses of alpha-lipoic
acid can cause fatal toxicity in thiamine deficient animals.(21,23) There
is some concern that alpha-lipoic acid supplementation even in lower doses
could present competition for thiamine absorption, especially in alcoholic
people who are expected to already be low in thiamine.(24)
Alpha-lipoic acid has a similar enough structure to that of biotin
so that it can theoretically interfere with biotin's metabolic role as an
enzyme cofactor. It is recommended that biotin be supplemented when using
alpha-lipoic acid at 100 mg per day or at higher amounts.(6) Biotin
functions as a coenzyme in four different carboxylase enzymes in the
metabolism of fat, sugar, and amino acids. Biotin supplementation enhances
insulin sensitivity and increases the activity of glucokinase, the enzyme
responsible for the first step in the utilization of glucose by the
liver.(25) Fortunately, biotin is produced in the healthy intestinal tract
by the microbial flora, particularly by Bifidobacterium
bifidum.
Long-term or frequent use of antibiotics can diminish
whole body biotin availability, potentially allowing a high intake of
alpha-lipoic acid to competitively interfere with biotin actions.
Antibiotic prescriptions should be complemented with a probiotic
recommendation, dosed to suitably separate the antibiotic and probiotic
bacterial supplement.
It is recommended that those using
alpha-lipoic acid be encouraged to use a multiple B vitamin product daily,
preferably supplying 25 to 50 mg/mcg of thiamine and biotin. A multiple B
product would also address other metabolic concerns relating to the B
vitamins associated with diabetes care.
Alpha-lipoic acid is endogenous to mammalian tissues.
According to the information given below, its oral use is expected to be
generally well tolerated and safe. In the higher oral doses associated
with treating diabetic neuropathy, it has been generally well tolerated,
with some reports of allergic reactions of the skin, including rashes,
hives, and itching, and gastrointestinal adverse effects, including
abdominal pain, nausea, vomiting, and diarrhea.(12) Researchers have found
that the rates of reported adverse effects in various clinical
investigations did not differ significantly from those in the placebo
groups.(18)
Regarding animal research
Cremer et al
published in 2006 two separate animal safety studies, a 4-week study and a
2-year long-term study, that corroborate the historical safety of oral
alpha-lipoic acid, even when used in high amounts.
The 4-week study
assessed racemic alpha-lipoic acid for acute and subchronic toxicity
through in vitro and in vivo mutagenicity and genotoxicity investigations
with male and female Wistar rats, finding no acute toxicity (LD50 > 2000
mg/kg), and no mutagenic or genotoxic activity.(13)
In the
long-term study, young Sprague-Dawley rats were given orally either 20,
60, or 180 mg/kg of body weight per day for 24 months. No significant
differences were observed between control and treated rats with respect to
behavioral effects, hematological and clinical chemistry parameters, and
gross and histopathological findings. Interestingly, in all treatment
groups, mortality was slightly lower in comparison to the control groups,
which probably reflects the health enhancement of antioxidation.
In
the rats receiving 180 mg/kg/day, the researchers reported that the only
notable finding was a reduction in food intake relative to the controls,
and a concomitant decrease in body weight. These weight changes were
considered to have no toxicological significance.(14) This observation may
be related to the observation by other researchers that leptin, insulin,
glucose and alpha-lipoic acid mediate hypothalamic appetite modulation via
AMP-activated protein kinase.(15,16,17)
The researchers concluded
that the results supported the claimed safety of alpha-lipoic acid and
that they considered the no-observed-adverse-effect level (NOAEL) to be
essentially 60 mg/kg/day, or essentially 4800 mg per day in an 80-kilogram
person. Laboratory studies suggest that very large doses of alpha-lipoic
acid can cause fatal toxicity in thiamine deficient animals.(21,23) There
is some concern that alpha-lipoic acid supplementation even in lower doses
could present competition for thiamine absorption, especially in alcoholic
people who are expected to already be low in thiamine.(24)
Regarding Human Experience
Information on human
adverse effects associated with alpha-lipoic acid is provided in studies
on its safety and efficacy in treating diabetic neuropathy. These studies
have used much higher doses than used in a basic daily antioxidant
supplement routine, and in some neuropathy clinical trials alpha-lipoic
acid has been administered by intravenous infusion. Its use and clinical
investigation for managing diabetic neuropathy have been ongoing in
Germany for more than 30 years. German clinical and post-marketing
surveillance studies have revealed a highly favorable safety profile with
few serious adverse side effects.(12,18)
The most clinically
significant reported adverse effects associated with alpha-lipoic acid
have been allergic reactions of the skin, including rashes, hives, and
itching, and gastrointestinal adverse effects, including abdominal pain,
nausea, vomiting, and diarrhea.(12) In randomized, double-blind,
placebo-controlled clinical trials, researchers have found that the rates
of adverse effects did not differ significantly between treatment and
placebo groups.(18) These trials have been characterized by alpha-lipoic
acid treatments encompassing: - intravenous infusion protocols with
1200, 600, and 100 mg/day for 3 weeks (the ALADIN Study),(12) -
intravenous infusion protocol with 600 mg/day for 5 days per week for 14
treatments (the SYDNEY Study),(8) an intravenous infusion/oral
protocol, with 600 mg intravenously for 3 weeks, followed by 600 mg TID
for 6 months,(9) - an oral protocol with 800 mg/day for 4 months,(10)
and, - an intravenous infusion/oral protocol, with 1200mg or 600 mg
intravenously once per day for 5 days, followed by 2 years of oral
administration of 600 mg BID, or 600 mg once.
Two minor
anaphylactic reactions and one severe anaphylactic reaction, including
laryngospasm, have been reported after intravenous infusion.(19)
For general use, there are no established optimal
amounts per day. Recommendations for 50 to 600 mg/day are found in the
literature.(6,7) Use 600 mg per day (or 300 mg BID to favour
compliance) for enhancing insulin stimulated glucose disposal.(20)This
recommended daily amount is based on one placebo-controlled, multi-centre,
4-week pilot study that found 600 mg once per day enhanced insulin
stimulated glucose disposal as well as 600 mg BID and 600 mg TID.
Alpha-lipoic acid at 600 mg once per day produced a 27% greater
glucose disposal compared to placebo.
In treating diabetic
neuropathy, German researchers have used various oral doses ranging from
600 mg/day to 800 mg/day, and 600 mg BID and TID.(8-11)
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