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Diabetes und Stoffwechsel (Germany), 1996, 5/3
SUPPL. (94-97) Oxidative stress is present in the diabetic
state. Our work in streptozotocin-diabetic rats
has focussed on its presence in peripheral nerve.
Antioxidant enzymes are reduced in peripheral
nerve and are further reduced in diabetic nerves.
That lipid peroxidation will cause neuropathy is
supported by evidence of the development of
neuropathy de novo when normal rat nerve is
rendered alpha-tocopherol deficient and
augmentation of the conduction deficit in
diabetic nerves subjected to this insult. The
mechanism of oxidative stress appears to be
primarily due to the processes of nerve ischemia
and hyperglycemia auto-oxidation. The indices of
oxidative stress include an increase in nerve,
dorsal root and sympathetic ganglia lipid
hydroperoxides and conjugated dienes. However the
most reliable and sensitive index is a reduction
in reduced glutathione. Experimental diabetic
neuropathy results in myelinopathy of dorsal
roots and a vacuolar neuropathy of dorsal root
ganglion. The vacuoles are mitochondrial; we
posit that lipid peroxidation causes
mitochondrial DNA mutations that increase reduced
oxygen species, causing further damage to
mitochondrial chain and function, resulting in a
sensory neuropathy. alpha-lipoic acid is a potent
antioxidant that prevents lipid peroxidation in
vitro and in vivo. We evaluated the efficacy of
the drug in doses of 20, 50 and 100 mg/kg,
administered intraperitoneally to streptozotocin
diabetic rats in preventing the biochemical,
electrophysiologic and nerve blood flow deficits
in peripheral nerve of experimental diabetic
neuropathy. alpha-lipoic acid dose- and
time-dependently prevented the deficits in nerve
conduction, nerve blood flow and biochemical
abnormalities of a reduction in reduced
glutathione and lipid peroxidation. The nerve
blood flow deficit was 50% (p < 0.001).
Supplementation dose-dependently prevented the
deficit; at the highest concentration, nerve
blood flow was not different to control nerves.
Digital nerve conduction underwent a
dose-dependent improvement at 1 month (p < 0.05).
By 3 months, all treated groups had lost their
deficit. The antioxidant drug is potentially
efficacious for human diabetic sensory
neuropathy.
Diabetes und Stoffwechsel (Germany), 1996, 5/3
SUPPL. (102-110) Treatment with anti-oxidants reduces oxidative
stress and prevents neuropathy in experimental
diabetes. Such a therapeutic approach based on
pathogenetic mechanisms may have potential in
diabetic patients with neuropathy. The efficacy
and safety of the anti-oxidant alpha-lipoic acid
(thioctic acid) were studied in a 3-week
multicentre, randomized, double-blind
placebo-controlled trial (Alpha-Lipoic Acid in
Diabetic Neuropathy: ALADIN) in 328 Type 2
diabetic patients with symptomatic peripheral
neuropathy who were randomly assigned to
treatment with intravenous infusion of alpha-lipoic
acid using three doses (ALA 1200 mg/600 mg/100
mg) or placebo (PLAC). Neuropathic symptoms
(pain, burning, paraesthesiae, and numbness) were
scored at baseline and each visit (days 2-5,
8-12, and 15-19) prior to infusion. In addition,
the Hamburg Pain Adjective List (HPAL), a
multidimensional specific pain questionnaire, as
well as the Neuropathy Symptom Score (NSS) and
Neuropathy Disability Score (NDS) were assessed
at baseline and day 19. According to the protocol
260 (65/63/66/66) patients completed the study.
The total symptom score (TSS) in the feet
decreased from baseline to day 19 (mean plus or
minus SD;%) by -4.5 plus or minus 3.7 (-58.6%)
points in ALA 1200, -5.0 plus or minus 4.1
(-63.5%) points in ALA 600, -3.3 plus or minus
2.8 (-43.2%) points in ALA 100, and -2.6 plus or
minus 3.2 (-38.4%) points in PLAC (ALA 1200 vs
PLAC: p = 0.003; ALA 600 vs PLAC: p < 0.001). The
response rates, defined as an improvement in the
TSS of at least 30% after 19 days, were 70.8% in
ALA 1200, 82.5% in ALA 600, 65.2% in ALA 100, and
57.6% in PLAC (ALA 600 vs PLAC: p = 0.002). The
total scale of the HPAL was significantly reduced
in ALA 1200 and ALA 600 as compared with PLAC
after 19 days (both p < 0.01). The rates of
adverse events were 32.6% in ALA 1200, 18.2% in
ALA 600, 13.6% in ALA 100, and 20.7% in PLAC.
These findings substantiate the efficacy of
intravenous treatment with alpha-lipoic acid
using a dose of 600 mg/day over 3 weeks that is
superior to placebo in reducing symptoms of
diabetic peripheral neuropathy, without causing
significant adverse reactions.
Diabetes und Stoffwechsel (Germany), 1996, 5/3
SUPPL. (50-54) Background: alpha-Lipoic acid (LA), a cofactor
of alpha-ketodehydrogenase, is a natural
antioxidant. Though clinically used in treating
peripheral diabetic polyneuropathy, its mode of
action is not clear. In this study we tested
whether LA affects glucose homeostasis and muscle
glucose transporters. Methods: LA was
administrated to fasting control and
streptozotocin diabetic rats either acutely (100
mg/kg, i.v.) or chronically (30 mg/kg, i.p. for
10 days). Results: Acute administration reduced
blood glucose, 76 plus or minus 16 vs. 38 plus or
minus 9 mg% (p < 0.01) by 1 hour in control, and
255 plus or minus 22 vs. 185 plus or minus 41 mg%
(p < 0.05) by 2 hours in diabetic rats. Chronic
treatment reduced blood glucose concentration in
diabetic, 341 plus or minus 36 vs. 189 plus or
minus 48 mg% (p = 0.001), but not in control
rats. Gastrocnemius GLUT4-protein content was
increased by LA approximately 2-fold in both
control and diabetic rats, resulting in
normalization ot muscle GLUT4 content in diabetic
rats. Muscle lactate was increased in diabetic
rats (19.9 plus or minus 5.5 vs. 10.4 plus or
minus 2.8 in control p < 0.05, respectively), and
normalized by chronic LA treatment. Conclusions:
Chronic LA treatment improves glycemia of
streptozotocin diabetic rats by increasing muscle
GLUT4-protein content. This may improve diabetes
related muscle glucose metabolism abnormalities.
Diabetes und Stoffwechsel (Germany), 1996, 5/3
SUPPL. (31-35) The incorporation of 14C-2-deoxyglucose (2DG)
into areas of basal ganglia was investigated in
rats treated acutely or for 5 days with R- or S-thioctic
acid (alpha-lipoic acid). In addition, the effect
of animal source and age (up to 30 months) on the
ability of R- and S-thioctic acid to alter
14C-2DG incorporation was studied. Following
acute administration, R-thioctic acid was more
effective than S-thioctic acid in altering
14C-2DG incorporation. For example, in substantia
nigra of acute administration R-thioctic acid
caused an approximately 40% increase in 14C-2DG
incorporation while S-thioctic acid was without
effect. However, the effects observed were
dependent on basal 14C-DG incorporation in
different rat strains. Following subacute
administration, the pattern of change in 14C-2DG
incorporation was altered and now both isomers
were equally effective. The effects of R-thioctic
acid were largely maintained with increasing
animal age but the ability of the S-isomer to
alter 14C-2DG incorporation was lost by 30
months. The data indicate an ability of thioctic
acid to alter glucose utilisation in vivo which
may be relevant to the treatment of diabetic
neuropathy and neurodegenerative disorders, such
as Parkinson's disease.
Diabetes und Stoffwechsel (Germany), 1996, 5/3
SUPPL. (23-26) In a controlled randomized cross-over study
with two parallel groups 24 type I and type II
diabetics with diabetes-induced polyneuropathy
were given alpha lipoic acid in two different
dosages and methods of administration. Group A
(12 patients) was given 600 mg of alpha lipoic
acid administered intravenously as a defined
short infusion and orally in tablet form. Group B
(12 patients) was given 200 mg of alpha lipoic
acid administered intravenously as a defined
short infusion and orally in tablet form. The
extent of the bioavailability (AUC) of free alpha
lipoic acid in plasma after intravenously
administering 600 mg of alpha lipoic acid was
13.1 microg/ml.h and after 200 mg was 2.2 microg/ml.h.
After 600 mg of orally administered alpha lipoic
acid the AUC was 2.1 microg/ml.h and after 200 mg
it was 0.4 microg/ml.h. The AUC of the single
dose of 600 mg administered intravenously and
orally was thus about twice as high as the
adjusted dosage AUC of 200 mg. This difference
was statistically significant. These results
support the recommended therapy plan of 600 mg
intravenously followed by an oral maintenance
therapy of 1 x 600 mg daily.
Diabetes und Stoffwechsel (Germany), 1996, 5/3
SUPPL. (17-22) After the administration von 600 mg alpha
lipoic acid (alpha-L) per oral (Thioctacid(R) 200
film tablets) or as an intravenous infusion over
20 minutes (Thioctacid(R) T ampules) the kinetics
of alpha-L in plasma were investigated in 12
diabetes type II-patients with normal liver and
renal function and symptoms of diabetic
neuropathy. alpha-L was electrochemically
detected as a total fraction of lipoic and
dihydrolipoic acid. alpha-L is quickly absorbed.
Maximum plasma concentrations were found after
42.9 plus or minus 45.6 minutes. In seven of the
12 patients alpha-L showed alpha second peak
behaviour with a mean difference of 89,1 minutes
between the first and the second plasma peak. a-L
was quickly eliminated from plasma with a mean
terminal half-life time of 32.8 plus or minus 9.4
minutes. 7-10 hours after the start of the
application of alpha-L its endogenous basic
levels in plasma are reached, which are measured
in a magnitude of 10 ng/ml. With respect to
Thioctacid(R) 200 film tablets a mean absolute
oral bioavailability of 20.2% (13.1-26.8%) for
alpha-L was estimated. After a dose of 200 mg
alpha-L healthy volunteers showed with 29.1% a
44% significantly higher bioavailability of a-L.
The reduced bioavailability of alpha-L in
patients with diabetic neuropathy is caused by a
dose-inadequate, stronger elevation of the plasma
levels of alpha-L after its intravenous
administration. In patients with diabetic
neuropathy the oral absorption behaviour of
alpha-L is not different from that of normal
persons.
Munchener Medizinische Wochenschrift
(Germany), 1997, 139/12 (34-37) 28 out of 33 patients (84,8%) previously
treated with alpha-lipoic acid for peripheral
polyneuropathy reported further improvement after
combination with pantothenic acid. The
theoretical basis for this is that both
substances intervene at different sites in
pyruvate metabolism and are thus more effective
than one substance alone. Additional clinical
findings indicated that diabetic neuropathy may
occur in association with a latent prediabetic
metabolic disturbance, and that the symptoms of
neuropathy can be favourably influenced by the
described combination therapy, even in poorly
controlled diabetes.
Diabetes Care (USA), 1997, 20/3 (369-373) OBJECTIVE - To evaluate the efficacy and
safety of oral treatment with the antioxidant
alpha-lipoic acid (ALA) in NIDDM patients with
cardiac autonomic neuropathy (CAN), assessed by
heart rate variability (HRV). RESEARCH DESIGN AND
METHODS - In a randomized, double-blind
placebo-controlled multicenter trial (Deutsche
Kardiale Autonome Neurophatic (DEKAN) Study),
NIDDM patients with reduced HRV were randomly
assigned to treatment with a daily oral dose of
800 mg ALA (n = 39) or placebo (n = 34) for 4
months. Parameters of HRV at rest included the
coeficient of variation (CV), root mean square
successive difference (RMSSD), and spectral power
in the low-frequency (LF; 0.5-0.15 Hz) and
high-frequency (HF; 0.15-0.5 Hz) bands. In
addition, cardiovascular autonomic symptoms were
assessed. RESULTS - Seventeen patients dropped
out of the study (ALA n= 10; placebo n = 7). Mean
blood pressure and HbA1 levels did not differ
between the groups at baseline and during the
study, but heart rate at baseline was higher in
the group treated with ALA (P < 0.05). RMSSD
increased from baseline to 4 months by 1.5 ms
(-37.6 to 77.1) (median (minimum-maximum)) in the
group given ALA and decreased by -0.1 ms (-19.2
to 32.8) in the placebo group (P < 0.05 for ALA
vs. placebo). Power spectrum in the LF band
incresed by 0.06 bpm2 (-0.09 to 0.62) in ALA,
whereas it declined by -0.01 bpm2 (-0.48 to 1.86)
in placebo (P < 0.05 for ALA vs. placebo).
Furthermore, there was a trend toward a favorable
effect of ALA versus placebo for the CV and HF
band power spectrum (P = 0.097 and P = 0.094 for
ALA vs. placebo. The charges in cardiovascular
autonomic symptoms did not differ significantly
between the groups during the period studied. No
differences between the groups were noted
regarding the rates of adverse events.
CONCLUSIONS - These findings suggest that
treatment with AlA using a well-tolerated oral
dose of 800 mg/day for months may slightly
improve CAN in NIDDM patients.
Free Radical Biology and Medicine (USA), 1996,
22/1-2 (359-378) Reactive oxygen species are thought to be
involved in a number of types of acute and
chronic pathologic conditions in the brain and
neural tissue. The metabolic antioxidant alpha-lipoate
(thioctic acid, 1, 2-dithiolane-3- pentanoic
acid; 1, 2-dithiolane-3 valeric acid; and
6,8-dithiooctanoic acid) is a low molecular
weight substance that is absorbed from the diet
and crosses the blood-brain barrier. alpha-Lipoate
is taken up and reduced in cells and tissues to
dihydrolipoate, which is also exported to the
extracellular medium; hence, protection is
afforded to both intracellular and extracellular
environments. Both alpha-lipoate and especially
dihydrolipoate have been shown to be potent
antioxidants, to regenerate through redox cycling
other antioxidants like vitamin C and vitamin E,
and to raise intracellular glutathione levels.
Thus, it would seem an ideal substance in the
treatment of oxidative brain and neural disorders
involving free radical processes. Examination of
current research reveals protective effects of
these compounds in cerebral ischemia-reperfusion,
excitotoxic amino acid brain injury,
mitochondrial dysfunction, diabetes and diabetic
neuropathy, inborn errors of metabolism, and
other causes of acute or chronic damage to brain
or neural tissue. Very few neuropharmacological
intervention strategies are currently available
for the treatment of stroke and numerous other
brain disorders involving free radical injury. We
propose that the various metabolic antioxidant
properties of alpha-lipoate relate to its
possible therapeutic roles in a variety of brain
and neuronal tissue pathologies: thiols are
central to antioxidant defense in brain and other
tissues. The most important thiol antioxidant,
glutathione, cannot be directly administered,
whereas alpha-lipoic acid can. In vitro, animal,
and preliminary human studies indicate that
alpha- lipoate may be effective in numerous
neurodegenerative disorders.
Diabetes (USA), 1996, 45/12 (1798-1804) Thioctic acid (alpha-lipoic acid), a natural
cofactor in dehydrogenase complexes, is used in
Germany in the treatment of symptoms of diabetic
neuropathy. Thioctic acid improves
insulin-responsive glucose utilization in rat
muscle preparations and during insulin clamp
studies performed in diabetic individuals. The
aim of this study was to determine the direct
effect of thioctic acid on glucose uptake and
glucose transporters. In L6 muscle cells and
3T3-L1 adipocytes in culture, glucose uptake was
rapidly increased by (R)-thioctic acid. The
increment was higher than that elicited by the
(S)-isomer or the racemic mixture and was
comparable with that caused by insulin. In
parallel to insulin action, the stimulation of
glucose uptake by thioctic acid was abolished by
wortmannin, an inhibitor of phosphatidylinositol
3-kinase, in both cell lines. Thioctic acid
provoked an upward shift of the glucose-uptake
insulin dose-response curve. The molar content of
GLUT1 and GLUT4 transporters was measured in both
cell lines. 3T3- L1 adipocytes were shown to have
>10 times more glucose transporters but similar
ratios of GLUT4:GLUT1 than L6 myotubes. The
effect of (R)-thioctic acid on glucose
transporters was studied in the L6 myotubes. Its
stimulatory effect on glucose uptake was
associated with an intracellular redistribution
of GLUT1 and GLUT4 glucose transporters, similar
to that caused by insulin, with minimal effects
on GLUT3 transporters. In conclusion, thioctic
acid stimulates basal glucose transport and has a
positive effect on insulin- stimulated glucose
uptake. The stimulatory effect is dependent on
phosphatidylinositol 3-kinase activity and may be
explained by a redistribution of glucose
transporters. This is evidence that a
physiologically relevant compound can stimulate
glucose transport via the insulin signaling
pathway.
Free Radical Biology and Medicine (USA), 1996,
21/5 (631-639) Nerve lipid peroxidation is increased in
experimental diabetic neuropathy, and alpha-lipoic
acid will prevent the deficits in nerve blood
flow, oxidative stress, and distal sensory
conduction. Because these alterations can occur
by mechanisms other than augmenting lipid
peroxidation in vivo, and because both
pro-oxidant and antioxidant effects of the agent
have been reported, we undertook studies of in
vitro lipid peroxidation of brain and sciatic
nerve using an in vitro lipid peroxidation model
with an ascorbate- iron-EDTA system. We evaluated
the effectiveness of the R(+)-, S(-)- enantiomers,
and racemate of alpha-lipoic acid in reducing
thiobarbituric acid reactive substances (TEARS)
generation in rat brain and sciatic nerve.
Studies were also done in an incubation medium
containing 20 mM glucose, which increased lipid
peroxidation up to fourfold. A dose-dependent and
statistically significant reduction in lipid
peroxidation was seen with both tissues with
similar potencies for both enantiomers. This
effect was unassociated with any reduction in the
loss of alpha-tocopherol.
Frankfurt am Main Germany Therapiewoche
(Germany), 1995, 45/23 (1367-1370) Causal therapy with alpha lipoic acid is
capable of getting polyneuropathy, the most
frequent concomitant disease of diabetes
mellitus, under control or to influence its
progression favourably: about half of all German
diabetics, hence no less than 2 million people,
suffer from that life-threatening disease. Yet a
basic condition for the effectiveness of an oral
dose of alpha lipoic acid, the per diem doses of
which have been raised to 300 to 600 mg in recent
years, is its absolute bioavailability. This has
been shown to be 71% (arith. Mean) resp. 58%
(geom. Mean) in case of Thiogamma 399 oral
capsules by an open monocentric study covering 12
probands. Thus, a rational treatment with this
preparation is guaranteed
Diabetes Res Clin Pract (IRELAND) Aug 1995, 28
Suppl pS201-7 Since the prevention of chronic diabetic
complications by near normal metabolic control is
not always achievable, alternative therapeutic
principles have been developed. The specific
intervention at metabolic abnormalities which
seem to play a key role in the pathogenesis of
complications has been shown to prevent the
development of microangiopathy and neuropathy in
experimental diabetes, e.g. inhibition of
non-enzymatic glycation by aminoguanidine,
inhibition of polyol pathway activity by aldose
reductase inhibitors, prevention of hypoxia and
oxidative stress by vasodilators and radical
scavengers such as alpha-lipoic acid. Some of
these drugs should soon be available for common
clinical use.
Z Gesamte Inn Med (GERMANY) May 1993, 48 (5)
pg 223-32 Our investigations carried out in patients
with diabetes mellitus revealed oxidative stress
loads. The study presented here was to clarify
whether a therapy with antioxidants can
contribute to an improvement of prognosis. 80
patients affected with a long term diabetic late
syndrome were randomised and arranged to 4 groups
of n = 20 each. In contrast to a control group
these patients received 600 mg of alpha lipoic
acid or 100 micrograms of selenium (sodium
selenite) daily or 1200 IE of D-alpha-tocopherol
respectively for a time of 3 months. In
comparison with the control group all groups
treated in an antioxidative way showed
significantly diminished serum concentrations of
thiobarbituric acid reactive substances and of
urinary albumin excretion rates. The symptoms of
distal symmetric neuropathy measured according to
the thermo- and vibration sensitivity also
improved in a highly significant manner. The
results prove that oxidative stress plays a
promoting role in developing of long term
diabetic late complications and that a therapy
with adjuvant antioxidants may lead to a
regression of diabetic late complications.
MMW Munch Med Wochenschr (GERMANY, WEST) May
30 1975 100 patients were treated with Thioctacid
orally for diabetic neuropathy. A successful
assessment was possible with sufficient certainty
in 89 patients. Of these, 29 received 2 X 50 mg
and 60 patients 2 X 100 mg Thioctacid daily. In
the first group the treatment was successful in
23 patients, and in 51 of the second group.
According to these findings, administration of
thiotic acid is effective in diabetic neuropathy
just as frequently orally as intravenously.
Diabetologia (Germany), 1995, 38/12
(1425-1433) Anti-oxidant treatment has been shown to
prevent nerve dysfunction in experimental
diabetes mellitus, thus providing a rationale of
potential therapeutic value for diabetic
patients. The effects of the anti-oxidant alpha-lipoic
acid (thioctic acid) were studied in a 3-week
multicentre, randomized, double-blind
placebo-controlled trial (Alpha-Lipoic Acid in
Diabetic Neuropathy; ALADIN) in 328
non-insulin-dependent diabetic patients with
symptomatic peripheral neuropathy who were
randomly assigned to treatment with intravenous
infusion of alpha-lipoic acid using three doses
(1200, 600, or 100 mg ALA) or placebo (PLAC).
Neuropathic symptoms (pain, burning,
paraesthesiae, and numbness) were scored at
baseline and at each visit (days 2-5, 8-12, and
15-19) prior to infusion. In addition, the
Hamburg Pain Adjective List, a multidimensional
specific pain questionnaire, and the Neuropathy
Symptom and Disability Scores were assessed at
baseline and day 19. According to the protocol
260 (65/63/66/66) patients completed the study.
The total symptom score in the feet decreased
from baseline to day 19 by -4.5 plus or minus 3.7
(-58.6%) points (mean plus or minus SD) in ALA
1200, -5.0 plus or minus 4.1 (-63.5%) points in
ALA 600, -3.3 plus or minus 2.8 (-43.2%) points
in ALA 100, and -2.6 plus or minus 3.2 (-38.4%)
points in PLAC (ALA 1200 vs PLAC: p = 0.003; ALA
600 vs PLAC: p < 0.001). The response rates after
19 days, defined as an improvement in the total
symptom score of at least 30%, were 70.8% in ALA
1200, 82.5% in ALA 600, 65.2% in ALA 100, and
57.6% in PLAC (ALA 600 vs PLAC; p = 0.002). The
total scale of the Pain Adjective List was
significantly reduced in ALA 1200 and ALA 600 as
compared with PLAC after 19 days (both p < 0.01).
The rates of adverse events were 32.6% in ALA
1200, 18.2% in ALA 600, 13.6% in ALA 100, and
20.7% in PLAC. These findings substantiate that
intravenous treatment with alpha-lipoic acid
using a dose of 600 mg/day over 3 weeks is
superior to placebo in reducing symptoms of
diabetic peripheral neuropathy, without causing
significant adverse reactions.
Diabetes und Stoffwechsel (Germany), 1996, 5/3
SUPPL. (98-101) The following article describes the protective
effects of alpha-lipoic acid and the enantiomers
of alpha-lipoic acid and dihydrolipoic acid on
the in vitro cataractogenesis in rat lenses
incubated with glucose (55.6 mM). Glucose also
leads to a leakage of lactate dehydrogenase into
the medium (32 plus or minus 3 units/g lens fresh
weight/day). R-lipoic acid inhibited the leakage
of LDH (4.34 plus or minus 3.23 units/g lens
fresh weight/day, p < 0.001) and lens opacity. In
addition, lipoic acid inhibited cataract
formation in newborn rats under buthionine
sulfoxide (BSO). While 100% of the rats given BSO
showed cataract formation, this was observed only
in 40 plus or minus 8% of the animals receiving
BSO and alpha-lipoic acid (p < 0.005). Further
influences of lipoic acid and dihydrolipoic acid
on the cataract model are under discussion. The
established interactions between dihydrolipoic
acid and other antioxidants certainly have
implications for both cataractogenesis and the
clinical use of alpha-lipoic acid.
Diabetes und Stoffwechsel (Germany), 1996, 5/3
SUPPL. (64-70) Thioctic acid, also known as alpha lipoic acid
(ALA), a naturally occuring compound, is
frequently used for the treatment of diabetic
polyneuropathy and was shown to be a safe and
reliable drug. Experimental studies revealed
enhanced glucose transport and utilization in
different animal models. Therefore, it was of
interest to investigate whether ALA is also
capable to stimulate glucose disposal in clinical
conditions of reduced insulin sensitivity, such
as NIDDM. A case report supported the hypothesis,
and pilot studies were initiated, in which well
controlled Type 2 diabetics received ALA (1.000
mg/500 ml NaCl; or vehicle only) during a
hyperinsulinemic glucose-clamp (placebo
controlled study) or 500 ml ALA/d over 10 d in an
open uncontrolled study. While the acute
administration of vehicle had no significant
effect on insulin sensitivity (MCR1 3,6 plus or
minus 0,21 vs. MCR2 4,01 plus or minus 0,19
ml/kg/min), the infusion of ALA resulted in a
marked increase of glucose disposal by about 50%
(MCR1 3,91 plus or minus 0,6 vs. MCR2 5,89 plus
or minus 0,8 ml/kg/min, p less than or equal to
0,05, Wilcoxon-Rank-Sumtest). The ten day
treatment of type II diabetics with ALA enhanced
insulin-stimulated whole body glucose disposal by
about 30% (MCR1 2,47 plus or minus 0,28 vs. MCR2
3,15 plus or minus 0,35 ml/kg/min, p less than or
equal to 0,05, Wilcoxon-Rank-Sumtest). Meanwhile
other groups have confirmed these observations.
In conclusion, the present data indicate that
parenteral administration of thioctic acid
enhances insulin-stimulated glucose disposal in
NIDDM. Animal studies suggest that the compound
increases insulin-stimulated glucose transport
activity, non-oxidative glucose disposal and
glucose oxidation in peripheral tissues, such as
skeletal muscle.
Diabetes und Stoffwechsel (Germany), 1996, 5/3
SUPPL. (59-63) Background: Alpha-lipoic acid, a natural
cofactor of pyruvate-dehydrogenase, has long been
suggested to improve glucose oxidation. Recent
data from insulin resistant muscle models
demonstrate, that glucose transport and hence
non-oxidative glucose metabolism are ameliorated
with this substance. Corresponding data in man
are lacking. Methods: The effect of an acute
infusion of 600 mg alpha-lipoic acid on insulin
sensitivity was investigated in a double blind
randomised placebo controlled cross-over study
using the isoglycemic glucose clamp technique in
12 obese, insulin resistant subjects (4
postmenopausal women, 8 men) aged between 48 and
69 years with poorly controlled type 2 diabetes.
Results: The infusion was well tolerated, only
one subject complained of headache. Of the 12
multimorbid subjects, Z (58,3%) responded to the
acute infusion of 600 mg alpha-lipoic acid with a
clinically relevant increase (> 20%) in insulin
sensitivity (metabolic clearance rate >MCR<). The
mean relative increase of MCR of all participants
(including nonresponders) was 27% (p = 0.002).
Conclusion: For the first time, a single infusion
of 600 mg alpha-lipoic acid is shown to improve
attenuated insulin sensitivity in a controlled
study in a defined insulin resistant group of
subjects with type 2 diabetes. The high number of
nonresponders gives rise to further studies.
Diabetes und Stoffwechsel (Germany), 1996, 5/3
SUPPL. (23-26) In a controlled randomized cross-over study
with two parallel groups 24 type I and type II
diabetics with diabetes-induced polyneuropathy
were given alpha lipoic acid in two different
dosages and methods of administration. Group A
(12 patients) was given 600 mg of alpha lipoic
acid administered intravenously as a defined
short infusion and orally in tablet form. Group B
(12 patients) was given 200 mg of alpha lipoic
acid administered intravenously as a defined
short infusion and orally in tablet form. The
extent of the bioavailability (AUC) of free alpha
lipoic acid in plasma after intravenously
administering 600 mg of alpha lipoic acid was
13.1 microg/ml.h and after 200 mg was 2.2 microg/ml.h.
After 600 mg of orally administered alpha lipoic
acid the AUC was 2.1 microg/ml.h and after 200 mg
it was 0.4 microg/ml.h. The AUC of the single
dose of 600 mg administered intravenously and
orally was thus about twice as high as the
adjusted dosage AUC of 200 mg. This difference
was statistically significant. These results
support the recommended therapy plan of 600 mg
intravenously followed by an oral maintenance
therapy of 1 x 600 mg daily.
Biochemical Pharmacology (USA), 1997, 53/3
(393-399) The therapeutic potential of alpha-lipoic acid
(thioctic acid) was evaluated with respect to its
influence on cellular reducing equivalent
homeostasis. The requirement of NADH and NADPH as
cofactors in the cellular reduction of alpha-lipoic
acid to dihydrolipoate has been reported in
various cells and tissues. However, there is no
direct evidence describing the influence of such
reduction of alpha-lipoate on the levels of
cellular reducing equivalents and homeostasis of
the NAD(P)H/NAD(P) ratio. Treatment of the human
Wurzburg T-cell line with 0.5 mM alpha-lipoate
for 24 hr resulted in a 30% decrease in cellular
NADH levels. alpha-Lipoate treatment also
decreased cellular NADPH, but this effect was
relatively less and slower compared with that of
NADH. A concentration-dependent increase in
glucose uptake was observed in Wurzburg cells
treated with alpha-lipoate. Parallel decreases
(30%) in cellular NADH/NAD+ and in lactate/pyruvate
-*--ratios were observed in alpha-lipoate-treated
cells. Such a decrease in the NADH/NAD+ ratio
following treatment with alpha-lipoate may have
direct implications in diabetes,
ischemia-reperfusion injury, and other
pathologies where reductive (high NADH/NAD+
ratio) and oxidant (excess reactive oxygen
species) imbalances are considered as major
factors contributing to metabolic disorders.
Under conditions of reductive stress, alpha-lipoate
decreases high NADH levels in the cell by
utilizing it as a co-factor for its own reduction
process, whereas in oxidative stress both alpha-lipoate
and its reduced form, dihydrolipoate, may protect
by direct scavenging of free radicals and
recycling other antioxidants from their oxidized
forms.
Neuroscience Letters (Ireland), 1997, 222/3
(191-194) This study compared the effects of treatment
of diabetic rats with either alpha-lipoic acid
(100 mg/kg/day i.p. 5 days/week) or with
recombinant human nerve growth factor (rhNGF; 0.2
mg/kg s.c. 3 days/week) on NGF-like
immunoreactivity (NGFLI) and neuropeptide Y-like
immunoreactivity (NPYLI) levels in the sciatic
nerve and on the release of substance P-like
immunoreactivity (SPLI) from the spinal cord in
response to electrical stimulation of the dorsal
roots In vitro. Diabetic rats showed depletion of
NGFLI and NPYLI, together with reduced release of
SPLI. Treatment with NGF increased the sciatic
nerve NGFLI (to four times that seen in untreated
diabetic rats) and normalised stimulus-evoked
release of SPLI, but did not affect the sciatic
nerve NPYLI. Treatment with alpha-lipoic acid
caused a small non-significant increase in
sciatic nerve NGFLI, but normalised both NPYLI
levels and stimulus;evoked release of SPLI. These
findings indicate that alpha-lipoic acid can
boost neurotrophic support in diabetic rats, with
effects beyond those related to NGF.
Arzneimittelforschung (GERMANY) Aug 1995, 45
(8) p872-4 Insulin resistance of skeletal muscle glucose
uptake is a prominent feature of Type II diabetes
(NIDDM); therefore pharmacological interventions
should aim to improve insulin sensitivity. Alpha-lipoic
acid (CAS 62-46-4, thioctic acid, ALA), a natural
occurring compound frequently used for treatment
of diabetic polyneuropathy, enhances glucose
utilization in various experimental models. To
see whether this compound also augments insulin
mediated glucose disposal in NIDDM, 13 patients
received either ALA (1000 mg/Thioctacid/500 ml
NaCl, n = 7) or vehicle only (500 ml NaCl, n = 6)
during a glucose-clamp study. Both groups were
comparable in age, body-mass index and duration
of diabetes and had a similar degree of insulin
resistance at baseline. Acute parenteral
administration of ALA resulted in a significant
increase of insulin-stimulated glucose disposal;
metabolic clearance rate (MCR) for glucose rose
by about 50% (3.76 ml/kg/min = pre vs. 5.82
ml/kg/min = post, p < 0.05), whereas the control
group did not show any significant change (3.57
ml/kg/min = pre vs. 3.91 ml/kg/min = post). This
is the first clinical study to show that alpha-lipoic
acid increases insulin stimulated glucose
disposal in NIDDM. The mode of action of ALA and
its potential use as an antihyperglycemic agent
require further investigation.
Biochem Pharmacol (ENGLAND) Aug 25 1995, 50
(5) p637-46 Lipoic acid (alpha-lipoic acid, thioctic acid)
is applied as a therapeutic agent in various
diseases accompanied by polyneuropathia such as
diabetes mellitus. The stereoselectivity and
specificity of lipoic acid for the pyruvate
dehydrogenase complex and its component enzymes
from different sources has been studied. The
dihydrolipoamide dehydrogenase component from pig
heart has a clear preference for R-lipoic acid, a
substrate which reacts 24 times faster than the
S-enantiomer. Selectivity is more at the stage of
the catalytic reaction than of binding. The
Michaelis constants of both enantiomers are
comparable (Km = 3.7 and 5.5 mMfor R- and S-lipoic
acid, respectively) and the S-enantiomer inhibits
the R-lipoic acid dependent reaction with an
inhibition constant similar to its Michaelis
constant. When three lipoic acid homologues were
tested, RS-1,2-dithiolane-3-caproic acid was one
carbon atom longer than lipoic acid, while RS-bisnorlipoic
acid and RS-tetranorlipoic acid were two and four
carbon atoms shorter, respectively. All are poor
substrates but bind to and inhibit the enzyme
with an affinity similar to that of S-lipoic
acid. No essential differences with respect to
its reaction with lipoicacid enantiomers and
homologues exist between free and complex-bound
dihydrolipoamide dehydrogenase. Dihydrolipoamide
dehydrogenase from human renal carcinoma has a
higher Michaelis constant for R-lipoic acid (Km =
18mM) and does not accept the S-enantiomer as a
substrate. Both enantiomers of lipoic acid are
inhibitors of the overall reaction of the bovine
pyruvate dehydrogenase complex, but stimulate the
respective enzyme complexes from rat as well as
from Escherichia coli. The S-enantiomer is the
stronger inhibitor, the R-enantiomer the better
activator. The two enantiomers have no influence
on the partial reaction of the bovine pyruvate
dehydrogenase component, but do inhibit this
enzyme component from rat kidney. The
implications of these results are discussed.
Free Radic Biol Med (UNITED STATES) Aug 1995,
19 (2) p227-50 alpha-Lipoic acid, which plays an essential
role in mitochondrial dehydrogenase reactions,
has recently gained considerable attention as an
antioxidant. Lipoate, or its reduced form,
dihydrolipoate, reacts with reactive oxygen
species such as superoxide radicals, hydroxyl
radicals, hypochlorous acid, peroxyl radicals,
and singlet oxygen. It also protects membranes by
interacting with vitamin C and glutathione, which
may in turn recycle vitamin E. In addition to its
antioxidant activities, dihydrolipoate may exert
prooxidant actions through reduction of iron.
alpha-Lipoic acid administration has been shown
to be beneficial in a number of oxidative stress
models such as ischemia-reperfusion injury,
diabetes (both alpha-lipoic acid and
dihydrolipoic acid exhibit hydrophobic binding to
proteins such as albumin, which can prevent
glycation reactions), cataract formation, HIV
activation, neurodegeneration, and radiation
injury. Furthermore, lipoate can function as a
redox regulator of proteins such as myoglobin,
prolactin, thioredoxin and NF-kappa B
transcription factor. We review the properties of
lipoate in terms of (1) reactions with reactive
oxygen species; (2) interactions with other
antioxidants; (3) beneficial effects in oxidative
stress models or clinical conditions. (153 Refs.)
Free Radic Res Commun (SWITZERLAND) 1992, 17
(3) p211-7 Nonenzymatic glycation has been found to
increase in a variety of proteins in diabetic
patients. The present study examined a
possibility of preventing glycation and
subsequent structural modifications of proteins
by alpha-lipoic acid (thioctic acid) as lipoate,
a substance which has gained attention as a
potential therapeutic agent for diabetes-induced
complications. Incubation of bovine serum albumin
(BSA) at 2 mg/ml with glucose (500 mM) in a
sterile condition at 37 degrees C for seven days
caused glycation and structural modifications of
BSA observed by SDS-PAGE, near UV absorption,
tryptophan and nontryptophan fluorescence, and
fluorescence of an extrinsic probe, TNS
(6-(p-toluidinyl) naphthalene-2-sulfonate). When
BSA and glucose were incubated in the presence of
lipoate (20mM), glycation and structural
modifications of BSA were significantly
prevented. Glycation and inactivation of lysozyme
were also prevented by lipoate. These results
suggest a potential for the therapeutic use of
lipoic acid against diabetes-induced
complications.
Biochem Biophys Res Commun (UNITED STATES) Apr
16 1996, 221 (2) p422-9 This study revealed a marked stereospecificity
in the prevention of buthionine sulfoximine-induced
cataract, and in the protection of lens
antioxidants, in newborn rats by alpha-lipoate,
R- and racemic alpha-lipoate decreased cataract
formation from 100% (buthionine sulfoximine only)
to 55% (buthionine sulfoximine + R-alpha-lipoic
acid) and 40% (buthionine sulfoximine +
rac-alpha-lipoic acid) (p<0.05 compared to
buthionine sulfoximine only). S-alpha-lipoic acid
had no effect on cataract formation induced by
buthionine sulfoximine. The lens antioxidants
glutathione, ascorbate, and vitamin E were
depleted to 45, 62, and 23% of control levels,
respectively, by buthionine sulfoximine
treatment, but were maintained at 84-97% of
control levels when R-alpha-lipoic acid or
rac-alpha-lipoic acid were administered with
buthionine sulfoximine; S-alpha-lipoic acid
administration had no protective effect on lens
antioxidants. When enantiomers of alpha-lipoic
acid were administered to animals, R-alpha-lipoic
acid was taken up by lens and reached
concentrations 2- to 7-fold greater than those of
S-alpha-lipoic acid, with rac-alpha-lipoic acid
reaching levels midway between the R-isomer and
racemic form. Reduced lipoic acid, dihydrolipoic
acid, reached the highest levels in lens of the
rac-alpha-lipoic acid-treated animals and the
lowest levels in S-alpha-lipoic acid-treated
animals. These results indicate that the
protective effects of alpha-lipoic acid against
buthionine sulfoximine-induced cataract are
probably due to its protective effects on lens
antioxidants, and that the stereospecificity
exhibited is due to selective uptake and
reduction of R-alpha-lipoic acid by lens cells.
Free Radic Biol Med (UNITED STATES) Aug 1995,
19 (2) p 227-50 alpha-Lipoic acid, which plays an essential
role in mitochondrial dehydrogenase reactions,
has recently gained considerable attention as an
antioxidant. Lipoate, or its reduced form,
dihydrolipoate, reacts with reactive oxygen
species such as superoxide radicals, hydroxyl
radicals, hypochlorous acid, peroxyl radicals,
and singlet oxygen. It also protects membranes by
interacting with vitamin C and glutathione, which
may in turn recycle vitamin E. In addition to its
antioxidant activities, dihydrolipoate may exert
prooxidant actions through reduction of iron.
alpha-Lipoic acid administration has been shown
to be beneficial in a number of oxidative stress
models such as ischemia-reperfusion injury,
diabetes (both alpha-lipoic acid and
dihydrolipoic acid exhibit hydrophobic binding to
proteins such as albumin, which can prevent
glycation reactions), cataract formation, HIV
activation, neurodegeneration, and radiation
injury. Furthermore, lipoate can function as a
redox regulator of proteins such as myoglobin,
prolactin, thioredoxin and NF-kappa B
transcription factor. We review the properties of
lipoate in terms of (1) reactions with reactive
oxygen species; (2) interactions with other
antioxidants; (3) beneficial effects in oxidative
stress models or clinical conditions.
Biochem Biophys Res Commun (UNITED STATES) Oct
14 1994 alpha-Lipoic acid, an essential cofactor in
mitochondrial dehydrogenases, has recently been
shown to be a potent antioxidant in vitro, as
well as being capable of regenerating vitamin E
in vitro. In this study, using a new animal model
for rapid vitamin E deficiency in adult animals
and a new technique for tissue extraction of
oxidized and reduced alpha-lipoic acid, we
examined the antioxidant action of alpha-lipoic
acid in vivo. Vitamin E-deficient adult hairless
mice displayed obvious symptoms of deficiency
within five weeks, but if the diet was
supplemented with alpha-lipoic acid the animals
were completely protected. At five weeks on a
vitamin E-deficient diet animals exhibited
similar decreases in tissue vitamin E levels,
whether supplemented or unsupplemented with
alpha-lipoic acid: vitamin E levels in liver,
kidney, heart, and skin decreased 70 to 85%;
levels in brain decreased only 25%. These data
show that there was no effect of alpha-lipoic
acid supplementation on vitamin E tissue
concentrations, arguing against a role for alpha-lipoic
acid in regenerating vitamin E in vivo.
Free Radic Biol Med (UNITED STATES) Apr 1995, 18 (4) p823-9 We investigated the effect of alpha-lipoic
acid, a powerful antioxidant, on cataract
formation in L-buthionine(S,R)-sulfoximine (BSO)-treated
newborn rats and found that a dose of 25 mg/kg
b.w. protected 60% of animals from cataract
formation. L-buthionine(S,R)-sulfoximine is an
inhibitor of glutathione synthesis, whose
administration to newborn animals leads to the
development of cataracts; this is a potential
model for studying the role of therapeutic
antioxidants in protecting animals from cataract
formation. Major biochemical changes in the lens
associated with the protective effect of alpha-lipoic
acid were increases in glutathione, ascorbate,
and vitamin E levels, loss of which are effects
of BSO administration. Treatment with alpha-lipoic
acid also restored the activities of glutathione
peroxidase, catalase, and ascorbate free radical
reductase in lenses of L-buthionine(S,R)-sulfoximine-treated
animals but did not affect glutathione reductase
or superoxide dismutase activity. We conclude
that alpha-lipoic acid may take over some of the
functions of glutathione (e.g., maintaining the
higher level of ascorbate, indirect participation
in vitamin E recycling); the increase of
glutathione level in lens tissue mediated by
lipoate could be also due to a direct protection
of protein thiols. Thus, alpha-lipoic acid could
be of potential therapeutic use in preventing
cataracts and their complications.
Med Hypotheses (ENGLAND) Oct 1981, 7 (10)
p1287-1302 The preventive merits of "nutritional
insurance" supplementation can be considerably
broadened if meaningful doses of nutrients such
as mitochondrial "metavitamins" (coenzyme Q,
lipoic acid, carnitine), lipotropes, and key
essential fatty acids, are included in insurance
supplements. From the standpoint of
cardiovascular protection, these nutrients, as
well as magnesium, selenium, and GTF-chromium,
appear to have particular value. Sophisticated
insurance supplementation would likely have a
favorable impact on many parameters which govern
cardiovascular risk--serum lipid profiles, blood
pressure, platelet stability, glucose tolerance,
bioenergetics, action potential regulation--and
as a life-long preventive health strategy might
confer substantial benefit. (111 Refs.)
DIABETE METABOL. (France), 1994, 20/2 BIS
(219-228) The development of drugs in order to block
metabolic pathways of glucose responsible for
diabetic vascular dysfunction is in progress.
Aldose reductase inhibitors prevent or reduce the
different components of vascular dysfunction,
cataract, neuropathy and nephropathy in animal
models of diabetes. Promising results have been
observed in diabetic patients concerning the
prevention of neuropathy and of retinopathy.
Larger scale studies with the second generation
compounds are in progress. Glycation inhibitors,
mainly aminoguanidine, have been shown to prevent
or reduce vascular dysfunction and microvascular
complications in animal models. Trials in
diabetic patients with aminoguanidine are just
beginning. Anti-oxidant therapy is also at its
early stage of development (vitamine E, vitamine
C, alpha lipoic acid). Antiplatelet agents
(aspirin, ticlopidine) have been demonstrated to
reduce the progression of non proliferative
diabetic retinopathy. Angiotensin converting
enzyme inhibitors are of particular interest in
preventing diabetic glomerulopathy.
All Contents Copyright © 1995-1999 By The Life Extension Foundation
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