Improvement of insulin-stimulated glucose-disposal
in type 2 diabetes after repeated parenteral administration of
Jacob S, Henriksen EJ, Tritschler HJ, Augustin HJ, Dietze GJ.
Hypertension and Diabetes Research Unit, Max Grundig Clinic,
Exp Clin Endocrinol Diabetes. 1996;104(3):284-8.
Insulin resistance of skeletal muscle glucose
uptake is a prominent feature of Type II diabetes (NIDDM); therefore,
pharmacological intervention should aim to improve insulin sensitivity.
Thioctic acid (TA), a naturally occurring compound, was shown
to enhance glucose utilization in various experimental models
after acute and chronic administration. It also increased insulin-stimulated
glucose disposal in patients with NIDDM after acute administration.
This pilot study was initiated to see whether this compound also
augments glucose disposal in humans after repeated treatment.
Twenty patients with NIDDM received TA (500 mg/ 500 ml NaCl, 0.9%)
as daily infusions over a period of ten days. A hyperinsulinaemic,
isoglycaemic glucose-clamp was done on day 0 and day 11. Parenteral
administration of TA resulted in a significant increase of insulin-stimulated
glucose-disposal by about 30% (metabolic clearance rate for glucose,
2.5 +/- 0.3 vs. 3.2 +/- 0.4 ml/kg/min and insulin-sensitivity-index:
3.5 +/- 0.5 vs. 4.7 +/- 0.4 mg/kg/microU/ml; p < 0.05, Wilcoxon-Rank-Sum-Test).
There were no changes in fasting plasma levels for glucose or
insulin; this can be explained, however, by the short period of
treatment and observation. This is the first clinical study to
show that a ten day administration of TA is able to improve resistance
of insulin-stimulated glucose disposal in NIDDM. Experimental
data suggest several mechanisms in the mode of action. As the
present investigation was an uncontrolled pilot trial, the encouraging
results call for controlled studies to further elucidate the clinical
relevance of the findings and the mode of action of this compound
Efficacy of thioctic acid in the therapy of
peripheral diabetic neuropathy.
Sachse G, Willms B.
The therapeutic efficacy of thioctic acid was
studied in patients with peripheral diabetic neuropathy. In a
double-blind study ten diabetics were treated with thioctic acid
or a placebo for 21 days. In a second study ten diabetics were
also treated with thioctic acid intravenously (i.v.) for 21 days.
Before and on the 11th and 21st day of treatment, we examined
the clinical neurological state, the vibration sense according
to biothesiometry, the nerve conduction velocity, and the degree
of diabetic control. In addition the patients were asked about
neuropathic complaints. The therapeutic efficacy of oral or i.v.
thioctic acid could not be verified by measurements of the nerve
conduction velocity or the vibration sensibility. No effect of
oral thioctic acid on subjective complaints was observed. However,
i.v. treatment with thioctic acid resulted in a distinct improvement
of subjective complaints.
Treatment of diabetic polyneuropathy with
the antioxidant thioctic acid (alpha-lipoic acid): a two year
multicenter randomized double-blind placebo-controlled trial (ALADIN
II). Alpha Lipoic Acid in Diabetic Neuropathy.
Reljanovic M, Reichel G, Rett K, Lobisch M, Schuette K, Moller
W, Tritschler HJ, Mehnert H.
University of Clinic for Diabetes, Endocrinology and Metabolic
Diseases Vuk Vrhovac, Medical faculty, University of Zagreb, Coratia.
Free Radic Res. 1999 Sep;31(3):171-9.
Short-term trials with the antioxidant thioctic acid (TA) appear
to improve neuropathic symptoms in diabetic patients, but the
long-term response remains to be established. Therefore, Type
1 and Type 2 diabetic patients with symptomatic polyneuropathy
were randomly assigned to three treatment regimens: (1) 2 x 600(mg
of TA (TA 1200), (2) 600)mg of TA plus placebo (PLA) (TA 600)
or (3) placebo and placebo (PLA). A trometamol salt solution of
TA of 1200 or 600 mg or PLA was intravenously administered once
daily for five consecutive days before enrolling the patients
in the oral treatment phase. The study was prospective, PLA-controlled,
randomized, double-blind and conducted for two years. Severity
of diabetic neuropathy was assessed by the Neuropathy Disability
Score (NDS) and electrophysiological attributes of the sural (sensory
nerve conduction velocity (SNCV), sensory nerve action potential
(SNAP)) and the tibial (motor nerve conduction velocity (MNCV),
motor nerve distal latency (MNDL)) nerve. Statistical analysis
was performed after independent reviewers excluded all patients
with highly variable data allowing a final analysis of 65 patients
(TA 1200: n = 18, TA 600: n = 27; PLA: n = 20). At baseline no
significant differences were noted between the groups regarding
the demographic variables and peripheral nerve function parameters
for these 65 patients. Statistically significant changes after
24 months between TA and PLA were observed (mean +/- SD) for sural
SNCV: +3.8 +/- 4.2 m/s in TA 1200, +3.0+/-3.0m/s in TA 600, -0.1+/-4.8m/s
in PLA (p < 0.05 for TA 1200 and TA 600 vs. PLA); sural SNAP:
+0.6+/-2.5 microV in TA 1200, +0.3+/-1.4 microV in TA 600, -0.7
+/- 1.5 microV in PLA (p = 0.076 for TA 1200 vs. PLA and p < 0.05
for TA 600 vs. PLA), and in tibial MNCV: +/- 1.2 +/- 3.8 m/s in
TA 1200, -0.3 +/- 5.2 m/s in TA 600, 1.5 +/- 2.9 m/s in PLA (p
< 0.05 for TA 1200 vs. PLA). No significant differences between
the groups after 24 months were noted regarding the tibial MNDL
and the NDS. We conclude that in a subgroup of patients after
exclusion of patients with excessive test variability throughout
the trial, TA appeared to have a beneficial effect on several
attributes of nerve conduction.
Molecular aspects of lipoic acid in the prevention
of diabetes complications.
Packer L, Kraemer K, Rimbach G.
Department of Molecular Pharmacology and Toxicology, School
of Pharmacy, University of Southern California, 1985 Zonal Avenue,
Los Angeles, CA 90098-9121, USA.
Nutrition. 2001 Oct;17(10):888-95.
Alpha-lipoic acid (LA) and its reduced form,
dihydrolipoic acid, are powerful antioxidants. LA scavenges hydroxyl
radicals, hypochlorous acid, peroxynitrite, and singlet oxygen.
Dihydrolipoic acid also scavenges superoxide and peroxyl radicals
and can regenerate thioredoxin, vitamin C, and glutathione, which
in turn can recycle vitamin E. There are several possible sources
of oxidative stress in diabetes including glycation reactions,
decompartmentalization of transition metals, and a shift in the
reduced-oxygen status of the diabetic cells. Diabetics have increased
levels of lipid hydroperoxides, DNA adducts, and protein carbonyls.
Available data strongly suggest that LA, because of its antioxidant
properties, is particularly suited to the prevention and/or treatment
of diabetic complications that arise from an overproduction of
reactive oxygen and nitrogen species. In addition to its antioxidant
properties, LA increases glucose uptake through recruitment of
the glucose transporter-4 to plasma membranes, a mechanism that
is shared with insulin-stimulated glucose uptake. Further, recent
trials have demonstrated that LA improves glucose disposal in
patients with type II diabetes. In experimental and clinical studies,
LA markedly reduced the symptoms of diabetic pathologies, including
cataract formation, vascular damage, and polyneuropathy. To develop
a better understanding of the preventative and therapeutic potentials
of LA, much of the current interest is focused on elucidating
its molecular mechanisms in redox dependent gene expression. Scientific