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Acetyl-L-carnitine effects on nerve conduction and
glycemic regulation in experimental diabetes
Soneru I.L.; Khan T.; Orfalian Z.; Abraira C.
Dr. I.L. Soneru, Hines VA Hospital, Hines, IL 60141 USA
Endocrine Research (USA), 1997, 23/1-2 (27-36)
Acetyl-L-Carnitine (ALC), an activator of carnitine, can
accelerate nerve regeneration after experimental surgical
injury in rats. In this study, we examined the ability of ALC
to improve nerve conduction velocity and its effect on
intravenous glucose tolerance test in streptozotocin-induced
diabetic rats. Diabetic (blood glucose > 200 mg%) and
normal animals were treated intraperitoneally for four weeks
with ALC, 50 mg/Kg/d and 150 mg/Kg/d. Nerve conduction
velocity was measured by direct exposure of sural nerve.
Two-hour IVGTT was studied by measuring plasma glucose,
insulin and free fatty acids after intravenous injection of
glucose, 1.75 gm/Kg/body weight in animals treated either with
ALC 150 mg/Kg/d or saline alone. Six weeks of STZ-induced
diabetes resulted in impairment of nerve conduction velocity
in animals injected with saline (16.05 plus or minus 1.09
m/s), as compared to saline-treated normals who did not
receive streptozotocin (31.9 plus or minus 0.84 m/s,
p<0.0005). Diabetic animals treated with ALC, 150 mg/Kg/d,
preserved near normal nerve conduction (27.10plus or minus1.42
m/s), compared with the saline-treated diabetic animals
(p<0.0005), but diabetic animals treated with ALC, 50
mg/Kg/d, had a non-significant increase in nerve conduction
(23.68plus or minus1.6). ALC treatment had no effect on
fasting or post-intravenous plasma glucose in normal or
diabetic rats, although it moderately reduced baseline and 40
minute insulin levels (p<0.02) in normal rats as compared
with their saline- treated counterparts. ALC treatment lowered
baseline free fatty acids in normal (p<0.04) and diabetic
(p<0.03) animals, and the 60 minute levels in the normal
group only (p<0.003). Conclusion: ALC at a dose of 150
mg/Kg/d given for one month, produced near normalization of
nerve conduction velocity in streptozotocin-induced diabetes
with no adverse effects on glucose, insulin or free fatty acid
levels.
Age-related decreases in chromium levels in 51,665
hair, sweat, and serum samples from 40,872 patients -
Implications for the prevention of cardiovascular disease and
type II diabetes mellitus
Davies S.; Howard J.M.; Hunnisett A.; Howard M.
United Kingdom
Metabolism: Clinical and Experimental (USA), 1997, 46/5
(469-473)
This report shows, for the first time using modern
analytical techniques, highly significant age-related
decreases in chromium levels in 51,665 hair, sweat, and serum
samples obtained from 40,872 patients referred by their
physicians to an independent medical research clinic and
laboratory (r = -.598 to -.762, P < .0001 for all
correlations). Males were found to have significantly lower
mean chromium levels than females (P < .05 to .0001). There
was good correlation between chromium levels in hair, sweat,
and serum (r = 536 to .729, P < .0001 for all
correlations), indicating that hair and sweat chromium levels
are valid additions to the serum levels in assessing chromium
status. Chromium measurements in sweat, hair, and serum were
performed using graphite furnace atomic absorption
spectrophotometry. The influences that age-related decreases
in chromium levels might have on increasing the risk to
develop age-related impaired glucose metabolism, disordered
lipid metabolism, coronary heart disease, arteriosclerosis,
and type II diabetes mellitus are outlined, and the role that
refined carbohydrates play in the development of compromised
chromium status is presented.
Lipoic acid (thioctic acid): Antioxidant properties
and their clinical implications
Packer L.
Prof. L. Packer, Dept. of Molecular and Cell Biology,
University of California, 251 LSA, Berkeley, CA 94720
USA
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.
Effect of lipoic acid (thioctic acid) on peripheral
nerve of experimental diabetic neuropathy
Low P.A.; Nagamatsu M.; Nickander K.; Schmelzer J.D.; Raya
A.; Tritschler H.J.
USA 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.
Lipoic acid alpha-potential modulator of insulin
sensitivity in patients with non-insulin-dependent diabetes
mellitus
Jacob S.; Clancy D.E.; Schiemann A.-L.; Simon I.; Jung W.-I.;
Henriksen E.J.; Tritschler H.J.; Augustin H.J.; Dietze
G.J.
Germany
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.
Lipoic acid acutely ameliorates insulin sensitivity
in obese subjects with type 2 diabetes
Rett K.; Wicklmayr M.; Ruus P.; Nehrdich D.; Hermann R.;
Standl E.
Germany
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.
Treatment of symptomatic diabetic peripheral
neuropathy with alpha-lipoic acid. A 3-week multicentre
randomized controlled trial (ALADIN Study)
Ziegler D.; Hanefeld M.; Ruhnau K.J.; Meissner H.P.; Lobisch
M.; Schutte K.; Gries F.A.; Ticinelli E.-C.; Hahnzog B.;
Nehrdich D.; Netten C.; Dannehl K.; Peukert M.; Wessel K.;
Anders M.; Brauning H.; Brun M.; Brunner E.; V. Bultzingslowen
S.; Donaubauer B.; Forchheim W.; Funke K.; Gerlach-Eniyew S.;
Hampel T.; Hoche I.; Hunecke I.; Klinkenstein C.; v. Klitzing
K.L.; Kluttig G.; Konig I.; Krause I.; Kruger R.; Kunz U.;
Mantz S.; Marquardt C.; Meissner H.P.; Mende M.; Myrach-Rahn
A.; Richter E.; Ruhnau K.J.; Ruthe W.D.; Sand K.; Schubert R.;
Schultz U.; Seebacher M.L.; Simonsohn M.; Stoll M.; Stundel
M.; Szilleweit G.; Walch O.; Walz E.; Wittmann N.
Germany
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.
Effect of lipoic acid (thioctic acid) on glucose
homeostasis and muscle glucose transporters in diabetic
rats
Khamaisi M.; Potashnik R.; Tritschler H.; Wessel K.; Bashan
N.
Prof. N. Bashan, Clinical Biochemistry Unit, Faculty of
Health Sciences, Ben-Gurion University of the Negev,
Beer-Sheva Israel
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.
Altered 14C-deoxyglucose incorporation in rat brain
following treatment with alpha-lipoic acid (thioctic acid).
Clinical implications for diabetic neuropathy and
neurodegenerative disorders
Jenner P.; Seaton T.A.; Marsden C.D.
Prof. Dr. P. Jenner, King's College, University of London,
Biomedical Science Division, Manresa Road, London SW3 GLX
United Kingdom
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.
Studies on the bioavailability of alpha lipoic acid
in type I and type II diabetics with diabetic neuropathy
Rosak C, Hoffken P, Baltes W, Drinda H, Ulrich H, Tritschler
HJ, Elze M, Blume H
Germany
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.
On the pharmacokinetics of alpha-lipoic acid in
patients with diabetic polyneuropathy
Preiss R.; Teichert J.; Preiss C.; Kern J.; Tritschler H.J.;
Ulrich H.
Germany
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 hallife 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.
Chromium oligopeptide activates insulin receptor
tyrosine kinase activity
Davis C.M.; Vincent J.B.
USA
Biochemistry (USA), 1997, 36/15 (4382-4385)
A possible new mechanism for the amplification of insulin
receptor tyrosine kinase activity in response to insulin has
been identified. The chromium-containing oligopeptide low
molecular weight chromium-binding substance (LMWCr) does not
effect the tyrosine protein kinase activity of rat adipocytic
membrane fragments in the absence of insulin; however,
insulin- stimulated kinase activity in the membrane fragments
is increased up to 8- fold by the oligopeptide. Using isolated
rat insulin receptor, LMWCr has been shown to bind to
insulin-activated insulin receptor with a dissociation
constant of circa 250 pM, resulting in the increase of its
tyrosine protein kinase activity. The ability of LMWCr to
stimulate insulin receptor tyrosine kinase activity is
dependent on its chromium content. The results appear to
explain the previously poorly understood relationship between
chromium and adult-onset diabetes and cardiovascular
disease.
Effect of chromium nicotinic acid supplementation
on selected cardiovascular disease risk factors
Thomas V.L.K.; Gropper S.S.
S.S. Gropper, Department of Nutrition/Food Science, 328
Spidle Hall, Auburn University, Auburn, AL 36849 USA
Biological Trace Element Research (USA), 1996, 55/3
(297-305)
The effects of daily supplemental chromium (200 microg)
complexed with 1.8 mg nicotinic acid on plasma glucose and
lipids, including total cholesterol, HDL cholesterol, LDL
cholesterol, and triglycerides, were assessed in 14 healthy
adults and 5 adults with noninsulin-dependent diabetes
mellitus (NIDDM) using a double-blind crossover study with
8-wk experimental periods. Eight of the 14 healthy subjects
and all 5 subjects with NIDDM also underwent an oral glucose
tolerance test with assessment of 90 min postprandial plasma
glucose and insulin concentrations. No statistically
significant effects of chromium nicotinic acid supplementation
were found on plasma insulin, glucose, or lipid
concentrations, although chromium nicotinic acid
supplementation slightly lowered fasting plasma total and LDL
cholesterol, triglycerides, and glucose concentrations, and
90-min postprandial glucose concentrations in individuals with
NIDDM.
Modulation of cellular reducing equivalent
homeostasis by alpha-lipoic acid. Mechanisms and implications
for diabetes and ischemic injury
Roy S.; Sen C.K.; Tritschler H.J.; Packer L.
Dr. S. Roy, 251 Life Sciences Addition, Dept. of
Molecular/Cell Biology, University of California, Berkeley, CA
94720-3200 USA
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.
Endothelial dysfunction: Clinical
implications
Drexler H.
Germany
Progress in Cardiovascular Diseases (USA), 1997, 39/4
(287-324)
The endothelium is involved in the control of vascular tone
and homeostasis. Risk factors for arteriosclerosis, as well as
other conditions have been shown to be associated with a
dysfunctional endothelium. Clinically, endothelial function
and dysfunction have been mostly evaluated by the assessment
of endothelial dependent relaxation, for example in response
to acetylcholine or increase inflow. The functional
implications of endothelial dysfunction in cardiovascular
disease are not well defined, but recent clinical trials have
suggested that endothelial dysfunction may affect vascular
tone and organ perfusion particularly during stress situations
such as exercise. Moreover, endothelial dysfunction may
represent an early event in the development of
arteriosclerosis. Therefore, recent clinical studies have been
performed to restore normal endothelial function in patients,
using interventions such as L-arginine, lipid lowering drugs,
vitamin C, other antioxidants, or exercise.
Effects of treatment with the antioxidant
alpha-lipoic acid on cardiac autonomic neuropathy in NIDDM
patients: A 4-month randomized controlled multicenter trial
(DEKAN study)
Ziegler D.; Schatz H.; Conrad F.; Gries F.A.; Ulrich H.;
Reichel G.; Schifferdecker E.; Heieck F.; Koeppen S.; Diener
H.C.; Richter W.O.; Rolfs H.C.; Scharafinski H.-W.;
Schulze-Schleppinghoff B.; Schultz-Venrath U.; Winkelmann
W.
Germany
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.
alpha-Lipoic acid corrects neuropeptide deficits in
diabetic rats via induction of trophic support
Garrett N.E.; Malcangio M.; Dewhurst M.; Tomlinson D.R.
D.R. Tomlinson, Department of Pharmacology,
St.Bartholomew's/Royal Sch. Medicine, Queen Mary/Westfield
College, Mile End Road, London E1 4NS United Kingdom
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.
Chromium picolinate supplementation improves
cardiac metabolism, but not myosin isoenzyme distribution in
the diabetic heart
Morris G.S.; Hasten D.L.; Hegsted M.; Guidry K.L.
USA
Journal of Nutritional Biochemistry (USA), 1996, 7/11
(617-622)
Because chromium (Cr) containing compounds are thought to
improve glucose homeostasis, we hypothesized that chromium
picolinate (CrP) could partially reverse diabetes-induced
damage to cardiac tissue. Young, adult female rats were fed
either a basal diet (CONT), a basal diet containing no CrP and
made diabetic (DIAB-CONT), or a basal diet containing 600 ng/g
of CrP (3 times the suggested daily chromium intake) and made
diabetic (DIAB-CrP). Diabetes was induced by a single
streptozotocin injection, 55 mg/kg i.p. After 8 weeks animals
were sacrificed, hearts removed, and spectrophotometrically
analyzed for citrate synthase (CS), hexokinase (HK), and beta
hydroxyacyl CoA dehydrogenase activity (HOAD). Cardiac myosin
isoenzymes were separated from crude myofibril extracts by
PAGE electrophoresis. Diabetes did not alter CS activity
relative to the CONT group, but did significantly (P <
0.05) reduce HK and HOAD activity and expression of the high
ATPase myosin isoenzyme VI. In contrast, DIAB-CrP animals
displayed normal HK activity and greater HOAD activity
relative to CONT animals. Surprisingly, the addition of CrP to
the diet further reduced expression of the VI myosin
isoenzyme. These results demonstrate thet dietary CrP
supplementation has diverse effects on the subcellular
properties of the diabetic heart. The functional impact of
these CrP-induced changes remains to be defined.
Dehydroepiandrosterone and diseases of aging
Watson R.R.; Huls A.; Araghinikuam M.; Chung S.
Arizona Prevention Center, University of Arizona, School of
Medicine, Tucson, AZ 85724 USA
Drugs and Aging (New Zealand), 1996, 9/4
(274-291)
Dehydroepiandrosterone (DHEA; prasterone) is a major
adrenal hormone with no well accepted function. In both
animals and humans, low DHEB levels occur with the development
of a number of the problems of aging: immunosenesence,
increased mortality, increased incidence of several cancers,
loss of sleep, decreased feelings of well-being, osteoporosis
and atherosclerosis. DHEA replacement in aged mice
significantly normalised immunosenescence, suggesting that
this hormone plays a key role in aging and immune regulation
in mice. Similarly, osteoclasts and lymphoid cells were
stimulated by DHEA replacement, an effect that may delay
osteoporosis, Recent studies do not support the original
suggestion that low serum DHEA levels are associated with
Alzheimer's disease and other forms of cognitive dysfunction
in the elderly. As DHEA modulates energy metabolism, low
levels should affect lipogenesis and gluconeogenesis,
increasing the risk of diabetes mellitus and heart disease.
Most of the effects of DHEA replacement have been extrapolated
from epidemiological or animal model studies, and need to be
tested in human trials, Studies that have been conducted in
humans show essentially no toxicity of DHEA treatment at
dosages that restore serum levels, with evidence of
normalisation in some aging physiological systems. Thus, DHEA
deficiency may expedite the development of some diseases that
are common in the elderly.
Sex hormones and DHEA-SO4 in relation to ischemic
heart disease mortality in diabetic subjects: The Wisconsin
Epidemiologic Study of Diabetic Retinopathy
Haffner S.M.; Moss S.E.; Klein B.E.K.; Klein R.
Univ. of Texas Hlth. Science Center, 7703 Floyd Curl Dr., San
Antonio, TX 78284-7873 USA
Diabetes Care (USA), 1996, 19/10 (1045-1050)
OBJECTIVE - Sex hormones are associated with atherogenic
changes in lipoproteins and changes in glucose and insulin
metabolism, yet few data are available on the relationship of
sex hormones and dehydroepiandrosterone sulfate (DHEA-SO4) to
ischemic heart disease (IHD) in diabetic subjects, a group
with very high levels of IHD.
RESEARCH DESIGN AND METHODS - We examined the relation of
total and free testosterone, sex hormone binding globulin,
estrone, estradiol, and DHEA-SO4 to the 5-year IHD mortality
in the older- onset diabetic subjects in the Wisconsin
Epidemiologic Study of Diabetic Retinopathy (WESDR) in a
matched diabetic subject-control design (two control subjects
for every diabetic subject).
RESULTS - In men (n = 123), none of the sex hormones or
DHEA-SO4 significantly predicted IHD mortality. In women (n =
120), lower levels of DHEA-SO4 (P < 0.01) and total
testosterone (P = 0.07) predicted IHD mortality. These results
were essentially unchanged after adjustment for duration of
diabetes, GHb, diuretic use, and serum creatinine, which are
major predictors of IHD mortality in the WESDR. Finding lower
testosterone levels in diabetic subjects of IHD in women is
contrary to data on risk factors, which suggests that
increased androgen activity may he associated with worse IHD
risk factors.
CONCLUSIONS - This study suggests that alterations in sex
hormones and DHEA-SO4 are unlikely to explain a major
proportion of the variation in IHD mortality in diabetic
subjects.
The effects of acetyl-L-carnitine and sorbinil on
peripheral nerve structure, chemistry, and function in
experimental diabetes
Malone J.I.; Lowitt S.; Salem A.F.; Miranda C.; Korthals
J.K.; Carver J.
USF College of Medicine, MDC Box 45, 12901 Bruce B. Downs
Blvd, Tampa, FL 33612-4799 USA
Metabolism: Clinical and Experimental (USA), 1996, 45/7
(902-907)
Nerve conduction velocity (NCV) increased with age in
nondiabetic male Wistar rats for the first 26 weeks of life.
The NCV of animals made hyperglycemic at age 6 weeks by
administration of streptozotocin (STZ) also increases, but at
a slower rate. Animals with 4 weeks of hyperglycemia and
reduced NCV treated with an aldose reductase inhibitor
(sorbinil) or a short- chain acyl-carnitine
(acetyl-L-carnitine (ALC)) daily for 16 weeks showed an
improvement in NCV. Morphometric studies of tibial nerves
collected from animals after 20 weeks of hyperglycemia (age 26
weeks) showed a consistent reduction in the width of the
myelin sheath and little change in axon area. The number of
large myelinated fibers (>6.5 microm) found in nerves
collected from hyperglycemic animals was less than the number
found in nondiabetic animals. Treatment of hyperglycemic rats
with either sorbinil or ALC was associated with increased NCV,
myelin width, and large myelinated fibers. The apparent
metabolic effect of these agents was similar for fatty acid
metabolism, but different for polyol pathway activity. We
conclude that in animals hyperglycemic long enough to slow
NCV, sorbinil and/or ALC treatment reduces the functional,
structural, and biochemical changes associated with
hyperglycemia that occur in the myelin sheath.
Acetyl-L-carnitine deficiency as a cause of altered
nerve myo-inositol content, Na,K-ATPase activity, and motor
conduction velocity in the streptozotocin-diabetic rat
Stevens M.J.; Lattimer S.A.; Feldman E.L.; Helton E.D.;
Millington D.S.; Sima A.A.F.; Greene D.A.
5570 MSRB II, Box 0678, 1150 W Medical Center Dr, Ann Arbor,
MI 48109-0678 USA
Metabolism: Clinical and Experimental (USA), 1996, 45/7
(865-872)
Defective metabolism of long-chain fatty acids and/or their
accumulation in nerve may impair nerve function in diabetes by
altering plasma or mitochondrial membrane integrity and
perturbing intracellular metabolism and energy production.
Carnitine and its acetylated derivatives such as acetyl-
L-carnitine (ALC) promote fatty acid beta-oxidation in liver
and prevent motor nerve conduction velocity (MNCV) slowing in
diabetic rats. Neither the presence nor the possible
implications of putative ALC deficiency have been definitively
established in diabetic nerve. This study explored sciatic
nerve ALC levels and the dose-dependent effects of ALC
replacement on sciatic nerve metabolites, Na,K-ATPase, and
MNCV after 2 and 4 weeks of streptozotocin- induced diabetes
(STZ-D) in the rat. ALC treatment that increased nerve ALC
levels delayed (to 4 weeks) but did not prevent nerve
myo-inositol (Mf) depletion, but prevented MNCV slowing and
decreased ouabain-sensitive (but not-insensitive) ATPase
activity in a dose-dependent fashion. However,
ouabain-sensitive ATPase activity was also corrected by
subtherapeutic doses of ALC that did not increase nerve ALC
affect MNCV. These data implicate nerve ALC depletion in
diabetes as a factor contributing to alterations in nerve
intermediary and energy metabolism and impulse conduction in
diabetes, but suggest that these alterations may be
differentially affected by various degrees of ALC
depletion.
Unrecognized pandemic subclinical diabetes of the
affluent nations: Causes, cost and prevention
Ely J.T.A.
Radiation Studies, University of Washington, Box 351560,
Seattle, WA 98195 USA
Journal of Orthomolecular Medicine (Canada), 1996, 11/2
(95-99)
Regarding populations on the industrialized 'western
affluent diet', arguments are made that:
(1) plasma glucose values commonly seen and accepted as
normal are abnormal;
(2) their glucose tolerance is innately unstable;
(3) most of their morbidity and mortality is produced by
hyperglycemia far below glycosuria and/or arteriosclerosis
which can occur independently or together;
(4) simple low cost methods for preventing and treating both
have been in the literature for decades (correction of the
sugar, fat and protein excesses; and controlled
supplementation of pyridoxine (vitamin B6). Mg, Cr and
coenzyme Q10); and
(5) these lessons were missed by main stream medicine because
of the vast size of the literature, enforcement of 'treatment
of choice', and lack of computer aided diagnosis. Cited as
striking evidence of this tragic situation is the failure of
mainstream clinical medicine to understand the cause of the
remarkable decline in CVD in the 1960s and 1970s that followed
U.S. enrichment of cereals with pyridoxine (vitamin B6).
Recommendations are made for correction of unnecessary costly
delays between publication and implementation of such research
findings.
Evidence of a relationship between childhood-onset
type I diabetes and low groundwater concentration of
zinc
Haglund B.; Ryckenberg K.; Selinus O.; Dahlquist G.
Dept. of Epidemiology/Public Health, Umea University, S-901
85 Umea Sweden
Diabetes Care (USA), 1996, 19/8 (873-875)
OBJECTIVE - Zinc deficiency ha shown to increase the risk
for diabetes in diabetes-prone experimental animals. Low
concentrations of zinc have also been shown in serum of recent
onset cases with IDDM. The present study examines the
hypothesis that exposure to a low concentration of zinc in
drinking water could increase the risk for future onset of
IDDM.
RESEARCH DESIGN AND METHODS - Using the Swedish childhood
diabetes registry and data on residence 3 years before the
onset of disease, a case-control study was designed comparing
cases and control subjects with estimates of groundwater
contents of zinc obtained in biogeochemical samples from areas
of residence.
RESULTS - A high groundwater concentration of zinc was
associated with a significant decrease in risk (odds ration
(OR) = 0.8; 95% CI = 0.7-0.9). The same OR was obtained when
the model included information of other metals that might act
as possible confounders (chromium, vanadium, cobalt selenium,
cadmium, lead, and mercury). In small rural areas, in which
drinking water is taken from local wells and thus is closely
associated with the groundwater content within the area, an
even stronger association between zinc and diabetes (OR = 0.6;
95% CI = 0.4-0.9) was found.
CONCLUSIONS - It is concluded that this study for the first
time provides evidence that a low groundwater content of zinc,
which may reflect long-term exposure through drinking water,
is associated with later development of childhood onset
diabetes.
Improved pallesthetic sensitivity of pudendal nerve
in impotent diabetic patients treated with
acetyl-L-carnitine
Giammusso B.; Morgia G.; Spampinato A.; Motta M.
Catania University, Catania Italy
Acta Urologica Italica (Italy), 1996, 10/3
(185-187)
Neurogenic impotence in diabetic patients seems to be
largely associated with abnormal sensory nerve conduction of
pudendal nerve afferent pathways. This condition accounts for
a hypoactivity in the mechanisms of erection reflex and has
been described as sensory-deficit impotence. Our study
investigates the pharmacological action of acetyl-L-carnitine
(ALC) in the treatment of this neurological disorder. Penile
biothesiometry was applied to two groups of diabetic patients,
whose impotence was principally neurogenic, in order to assess
their vibration perception threshold variables. The groups
were treated with ALC (1,500 mg/day) and placebo,
respectively. The results obtained show a significant
improvement in dorsal nerve somatosensory conduction in
patients treated with ALC.
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