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Peculiarities of the endocrine time structure in
noninsulin-dependent adult-onset (type II) diabetes
mellitus.
Sackett-Lundeen L, Nicolau GY, Lakatua DJ, Bogdan C, Petrescu
E, Jachimowicz A, Haus E
Prog Clin Biol Res 1987;227A:467-82
Twenty noninsulin-dependent elderly diabetic patients, ten
of whom were treated by oral hypoglycemic agents and ten of
whom were regulated by diet alone, and 20 clinically healthy
subjects matched for age, sex, height, and weight were
examined with six blood and six urine samples at 4-hr
intervals over a 24-hr span. Plasma ACTH, cortisol,
aldosterone, and dehydroepiandrosterone-sulfate (DHEA-S) were
determined by radioimmunoassay (RIA); epinephrine,
norepinephrine, and dopamine in urine were determined by
high-pressure liquid chromatography (HPLC); and magnesium in
urine was determined colorimetrically on a DuPont ACA. There
were a number of changes in some of these functions in type II
diabetic patients with and without oral hypoglycemic agents
that appear to be of interest. The circadian mean in plasma
ACTH concentration in diabetic patients with and without oral
hypoglycemic agents is significantly higher than in matched
nondiabetic controls. The plasma aldosterone concentration is
similar in type II diabetics treated by diet only and in
matched controls but is statistically significantly elevated
in patients on oral hypoglycemic agents. Correspondingly, the
urinary excretion of sodium in type II diabetic patients on
oral hypoglycemic agents is lower than in matched controls.
The plasma cortisol concentration is unchanged in type II
diabetic patients treated by diet alone but shows a slight
increase in patients on oral hypoglycemic agents. The
circadian means of plasma DHEA-S concentration is slightly
higher in diabetic patients with and without oral hypoglycemic
agents than in matched controls. This elevation, however, does
not quite reach the 95% level of statistical significance.
Urinary norepinephrine excretion in type II diabetic patients
is similar to that in matched controls. The urinary
epinephrine excretion in diabetics with and without oral
hypoglycemic agents, however, was lower than in controls, and
the urinary excretion of dopamine was higher in the diabetics.
The urinary magnesium excretion in type II diabetic patients
was lower than in matched controls.
Antiobesity effects of etiocholanolones in diabetes
(db), viable yellow (Avy), and normal mice.
Coleman DL
Endocrinology 1985 Dec;117(6):2279-83
Two metabolites of the adrenal steroid
dehydroepiandrosterone (DHEA), 3alpha-hydroxyetiocholanolone
and 3 beta-hydroxyetiocholanolone, were found to have
antiobesity properties with respect to both prevention of the
development of obesity as well as weight reduction after
obesity was established. All of the obesity types studied
responded to metabolite therapy to a greater or lesser extent.
The more natural obesity seen in certain strains of mice with
aging responded most rapidly to the feeding of either
metabolite. The effective dosage (0.1%) fed in the diet was
only one quarter the dosage required for DHEA to produce the
same effect in preventing diabetes symptoms in C57BL/Ks
diabetic (db) mutant mice. Unlike DHEA, neither metabolite
produced any undesirable estrogenic or androgenic
side-effects. 3 alpha-hydroxyethiocholanolone and 3
beta-hydroxyetiocholanolone, formerly considered only as inert
end products of steroid metabolism, have beneficial actions in
mice with various diabetes-obesity conditions and may be
metabolic effectors in their own right.
Circadian time structure of endocrine and
biochemical parameters in adult onset (type II) diabetic
patients.
Nicolau GY, Haus E, Lakatua D, Bogdan C, Petrescu E, Robu E,
Sackett-Lundeen L, Swoyer J, Adderley J
Endocrinologie 1984 Oct-Dec;22(4):227-43
Forty-one endocrine and biochemical serum parameters were
studied over a 24-hour span with 6 samples at 4-hour intervals
in 20 non-insulin dependent (Type II) diabetics and in 20
non-diabetic subjects matched for sex, age, height and weight.
Circadian rhythms were verified by cosinor analysis.
Group-synchronized circadian rhythms were detected in diabetic
and non-diabetic subjects with no statistically significant
difference in any of the rhythm parameters (rhythm adjusted
mean, amplitude and acrophase) in: Aldosterone, cortisol,
insulin, 17-OH progesterone, prolactin, testosterone, TSH, and
in serum albumin, creatine phosphokinase (CPK), serum iron,
inorganic phosphate and total protein. Statistically
significant (p less than .05) circadian rhythms in both groups
with a difference in some parameters between the diabetic and
the non-diabetic subjects, which were verified by the Bingham
Test (p less than .05) were found with a difference in the
mesor in cholesterol, glucose, urea nitrogen (BUN), in the
amplitude in C-peptide and in the acrophase in triglycerides,
globulin and reverse T3 (rT3). Statistically significant
circadian rhythms were detected as a group phenomenon for the
diabetics only in progesterone, free and total T4, chloride,
calcium, bilirubin and LDH and in the non-diabetic subjects
only in ACTH, LH, total T3, alkaline phosphatase, uric acid
and potassium. In the remainder of the functions studied,
acircadian rhythm was detectable with statistical significance
by cosinor analysis as a group phenomenon neither in the
diabetics nor in the matched non-diabetic controls (DHEA-S,
estradiol, FSH, GH, glucagon, free T3, sodium, GOT and gamma
GT). In the absence of a detectable circadian rhythmas group
phenomenon, the circadian mean was different between the
diabetics and the non-diabetic subjects in sodium, chloride
and calcium which were higher in the diabetic patients and
serum LDH which was lower. In a comparison of endocrine
determinations in the two groups, the circadian mean or mesor
in T3 was lower in the diabetics and ACTH higher, without
corresponding changes in TSH or in corticosteroids. The
circadian time structure of Type II diabetic patients thus
seems to be very similar to that seen in non-diabetic subjects
of the same sex, age, weight and height.The minor differences
found in some rhythm parameters will have to be confirmed or
excluded in larger numbers of subjects. The higher circadian
mean ACTH concentrations without change in steroid rhythm
parameters observed in this group is interesting but will also
require confirmation. (ABSTRACT TRUNCATED AT 400 WORDS)
Effect of genetic background on the therapeutic
effects of dehydroepiandrosterone (DHEA) in diabetes-obesity
mutants and in aged normal mice.
Coleman DL, Schwizer RW, Leiter EH
Diabetes 1984 Jan;33(1):26-32
Dehydroepiandrosterone (DHEA) was fed at 0.1-0.4% in the
diet to genetically diabetic (db/db) or obese (ob/ob)
C57BL/KsJ (BL/Ks) or C57BL/6J (BL/6) mice. Treatment of
BL/Ks-db/db or ob/ob mice with 0.4% DHEA prevented
hyperglycemia, islet atrophy, and severe diabetes associated
with this inbred background, but did not affect weight gain
and food consumption. Homozygous obese (ob) or diabetes (db)
mice on the BL/6 background were more sensitive to DHEA, and
the mild, transient hyperglycemia associated with ob or db
gene expression on the BL/6 inbred background could be
prevented by 0.1% DHEA. Both body weight and food consumption
were decreased in BL/6 mutants maintained on 0.1% DHEA whereas
this effect was not seen in BL/Ks mutants fed up to 0.4% DHEA.
Early therapy with 0.4% DHEA, initiated at 2 wk of age,
prevented the developmentof most diabetes symptoms and
decreased the rate of weight gain in pups of all genotypes. In
addition to therapeutic effects on both obese mutants, DHEA
effected significant changes in an aging study using normal
BL/6 female mice. Four weeks of DHEA treatment initiated at 2
yr of age improved glucose tolerance and at the same time
reduced plasma insulin to a "younger" level. This suggests
that DHEA may act in insulin-resistant mutant mice and in
aging normal mice to increase the sensitivity to insulin.
Amniotic fluid beta-endorphin and beta-lipotropin
concentrations during the second and third trimesters.
Petrucha RA, Goebelsmann U, Hung TT, Haase HR, Lobo RA
Am J Obstet Gynecol 1983 Jul 15;146(6):644-51
Amniotic fluid beta-endorphin (beta-EP) and beta-lipotropin
(beta-LPH) were measured by radioimmunoassay after silicic
acid extraction and gelchromatographic separation of the two
peptides in uncomplicatedsecond-trimester and term
pregnancies, in diabetic patients at term, and inpregnancies
complicated by Rh-isoimmunization, premature labor, and
intrauterine growth retardation. Furthermore, the
lecithin/sphingomyelin (L/S) ratios as well as the
dehydroepiandrosterone sulfate (DHEA-S) and cortisol levels
were determined in most of the amniotic fluid specimens. Both
the mean (+/- SE) beta-EP (65.3 +/- 9.1 fmol/ml) and beta-LPH
(150 +/-15.8 fmol/ml) concentrations were significantly higher
in the 20 patients with normal pregnancies of 16 to 21 weeks'
duration than those found in 21 patients with uncomplicated
term pregnancies of 38 weeks' gestation, averaging 42.6 +/-
6.0 and 80.1 +/- 10.7 fmol/ml, respectively. The mean amniotic
fluid beta-EP and beta-LPH concentrations measured in the
latter subjects were similar to those observed in 23 diabetic
patients with otherwise uncomplicated term pregnancies. The
mean amniotic fluid beta-EP and beta-LPH levels found in the
limited number of patients with Rh-isoimmunization (N = 9),
premature labor (n = 8), and intrauterine growth retardation
(n = 5) with pregnancies of 24 to 36, 24 to 36, and 34 to 38
weeks' gestation, respectively, were not significantly
different from the mean amniotic fluid beta-EP and beta-LPH
concentrations of uncomplicated term pregnancies. In all
patients but those with Rh-isoimmunization, beta-EP
concentrations exhibited a positive correlation with beta-LPH
levels. However, the molar beta-LPH:beta-EP ratio was
significantly lower at term than during the early second
trimester. Neither beta-EP nor beta-LPH correlated with the
amniotic fluid L/S ratio and only beta-LPH exhibited a
significant inverse correlation with amniotic fluid DHEA-S.
The latter was significantly higher in uncomplicated term than
second-trimester pregnancies. These results confirm that
immunoassayable beta-EP is present in amniotic fluid and
declines toward term. These data demonstrate that
immunoassayable beta-LPH is present in amniotic fluid and show
a more pronounced decrease toward the end of pregnancy than
beta-EP. Neither peptide, at least on account of the amniotic
fluid levels, appears to be associated with fetal maturation.
The physiologic significance of amniotic fluid beta-EP and
beta-LPH and their possible role as markers of fetal response
to stress remain to be elucidated.
Therapeutic effects of dehydroepiandrosterone
(DHEA) in diabetic mice.
Coleman DL, Leiter EH, Schwizer RW
Diabetes 1982 Sep;31(9):830-3
Dehydroepiandrosterone (DHEA), a major adrenal secretory
steroid in humans, was therapeutic when fed in a concentration
of 0.4% to C57BL/KsJ mice with either non-insulin-dependent or
insulin-dependent diabetes. Genetically diabetic (db/db) mice
of both sexes develop obesity and aglucose intolerance and
hyperglycemia associated with insulin resistance by 2 mo of
age, and exhibit beta-cell necrosis and islet atrophy by 4 mo.
In contrast, DHEA feeding initiated between 1 and 4 mo of age,
while only moderately effective in preventing obesity, did
prevent the other pathogenic changes and effected a rapid
remission of hyperglycemia, a preservation of beta-cell
structure and function, and an increased insulin sensitivity
as measured by glucose tolerance tests. DHEA feeding was also
therapeutic to normal C57BL/KsJ male mice made diabetic by
multiple low doses of streptozotocin (SZ). While DHEA
treatments did not block either the direct cytotoxic action of
SZ on beta-cells or the development of insulitis, the steroid
significantly moderated the severity of the ensuing diabetes
(reduced hyperglycemia and water consumption, and increased
plasma insulin and numbers of residual, granulated
beta-cells.
Plasma androgen concentrations in diabetic
women.
Szpunar WE, Blair AJ Jr, McCann DS
Diabetes 1977 Dec;26(12):1125-9
Plasma androgen levels were determined in women assigned to
the following groups: idiopathically hirsute, diabetic, both
idiopathically hirsute and diabetic, and normal. The androgens
examined were androstenedione (AD), dihydrotestosterone (DHT),
testosterone (T), and dehydroepiandrosterone (DHEA). We find
statistical differences between young (less than 38 years) and
older (larger than or equal to 38 years) controls at
confidence levels of p less than or equal to 0.01 for AD, DHT,
and T and of p less than or equal to 0.05 for DHEA. The
results indicate that peak circulating androgen levels occur
prior to age 30-35 years for women. There are no significant
differences between the young controls and young
idiopathically hirsute subjects, but a statistical difference
exists between older hirsute and older controls for all four
androgens (p less than or equal to 0.05). When a comparison is
made among the diabetic, hirsute diabetic, and older control
groups (all groups larger than or equal to 38 years), the
diabetic group is significantly higher than the control in
plasma AD (p less than or equal to 0.01) and DHEA (p less than
or equal to 0.05). These same two steroids are also higher in
the diabetic group than in the hirsute diabetic group (p less
than or equal to 0.05), while the latter differs from controls
only in testosterone levels (p less than or equal to 0.05).
DHT levels are similar for all three groups.
Conversion of DHEA-sulfate to estrogens as a test
of placental function.
Lauritzen C
Horm Metab Res 1969 Mar;1(2):96
No abstract.
[Evaluation of placenta function using DHEA-S
tolerance test; comparison with cardiotocography and placental
histology]
Crabben H van der, Hammacher K, Werner C, Kaiser E
Geburtshilfe Frauenheilkd 1970 Jan;30(1):71-84
No abstract.
Interaction of alpha-lipoic acid enantiomers and
homologues with the enzyme components of the mammalian
pyruvate dehydrogenase complex.
Loffelhardt S, Bonaventura C, Locher M, Borbe HO, Bisswanger
H
Physiologisch-Chemisches Institut, University of Tubingen,
Germany.
Biochem Pharmacol 1995 Aug 25;50(5):637-46
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.
alpha-Lipoic acid as a biological
antioxidant.
Packer L; Witt EH; Tritschler HJ
Department of Molecular & Cell Biology, University of
California, Berkeley, CA 94720 USA
Free Radic Biol Med 1995 Aug;19(2):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. (153 Refs.)
[Diabetes mellitus--a free radical-associated
disease. Results of adjuvant antioxidant
supplementation]
Kahler W, Kuklinski B, Ruhlmann C, Plotz C
Klinik fur Innere Medizin, Klinikums Rostock-Sudstadt.
Z Gesamte Inn Med 1993 May;48(5):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.
Lipoate prevents glucose-induced protein
modifications.
Suzuki YJ, Tsuchiya M, Packer L
Department of Molecular & Cell Biology, University of
California, Berkeley 94720.
Free Radic Res Commun 1992;17(3):211-7
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.
Effect of DL-alpha-lipoic acid on the citrate
concentration and phosphofructokinase activity of perfused
hearts from normal and diabetic rats.
Singh HP, Bowman RH
Biochem Biophys Res Commun 1970 Nov
9;41(3):555-61
No abstract.
Increased anti-Gal activity in diabetic patients
transplanted with fetal porcine islet cell clusters.
Galili U, Tibell A, Samuelsson B, Rydberg L, Groth CG
Department of Microbiology and Immunology, Medical College of
Pennsylvania, Philadelphia, Pennsylvania 19129, USA.
Transplantation 1995 Jun 15;59(11):1549-56
The natural anti-Gal antibody seems to create a major
obstacle for discordant xenotransplantation in humans.
Anti-Gal, which is produced in large amounts in humans (1% of
circulating IgG), interacts specifically with the carbohydrate
structure Gal alpha 1-3Gal beta 1-4Glc-NAc-R (termedthe
alpha-galactosyl epitope). This epitope is present in large
amounts on porcine cells, as well as on cells of other
nonprimate mammals (1 x 10(6)to 35 x 10(6) epitopes/cell). The
interaction of anti-Gal with alpha-galactosyl epitopes on the
xenograft was found to mediate the immune destruction of
discordant xenografts. In the present study, the human immune
response to alpha-galactosyl epitopes on xenografts was
assessed by measuring changes in anti-Gal titers and affinity
in sera of diabetic patients transplanted with fetal porcine
islet cell clusters. The activityof this antibody was assessed
by a hemagglutination assay with RBC, byELISA with mouse
laminin as a solid-phase antigen, and by equilibrium dialysis
with the radiolabeled free haptenic form of the
alpha-galactosylepitope, i.e. [3H]Gal alpha 1-3Gal beta
1-4GlcNAc. All assays revealed a marked increase in anti-Gal
activity after transplantation. The increase in anti-Gal
titers ranged between 8- and 64-fold. A similar increase was
observed in the binding of free alpha-galactosyl epitopes to
anti-Gal, as assayed in equilibrium dialysis. Immunoglobulin
concentration did not increase after transplantation,
suggesting that the observed increase in anti-Gal activity is
the result of a specific immune response against
alpha-galactosyl epitopes on the xenograft. The elevation in
anti-Gal activity was observed in all three immunoglobulin
classes and the highest activity was found within the IgG
class. Analysis of IgG binding to fixed porcine endothelial
cells suggested that most of the observed increased activity
against these cells in transplanted patients may be attributed
to the elevation in anti-Gal activity.
Intracellular glutathione influences collagen
generation by mesangial cells.
Shan Z, Tan D, Satriano J, Silbiger S, Schlondorff D
Department of Medicine, Albert Einstein College of Medicine,
Bronx, New York.
Kidney Int 1994 Aug;46(2):388-95
The cellular redox state is altered in a number of
pathological conditions, including various forms of glomerular
injury and diabetes. For example, glucose, via the pentose
phosphate pathway generates NADPH, which maintains glutathione
(GSH) (part of a major intracellular reducing system) in its
reduced state. GSH in turn influences the activity of
transcription factors on gene expression. We therefore
examined whether changes in cellular GSH influence total
collagen synthesis and mRNA levels for collagen I, collagen IV
and TGF-beta in SV-40 transformed mouse mesangial cells (MC)
maintained in either 5 or 25 mM glucose media. Total
intracellular GSH was increased by N-acetylcysteine (NAC; 10
mM) or decreased with the GSH synthesis inhibitor buthionine
sulfoximine (BSO; 0.2mM) in MC. NAC increased 3H-proline
incorporation into collagenase-sensitive protein while BSO
decreased it under both glucose conditions. The presence of
BSO did not reverse the increased collagen synthesis seen in
the NAC stimulated cells. Northern blot analysis showed
increased mRNA levels for collagen I, collagen IV and TGF-beta
in cells grown in high glucose (25 mM). NAC increased the mRNA
for all three compounds while BSO alone had no effect on these
mRNA levels. However, BSO reversed the increased mRNA levels
for collagen I, IV and TGF-beta seen in the presence of NAC.
These findings suggest that the cellular redox state may
influence gene transcription in MC, and may have implications
in explaining injury-associated alterations of mesangial
matrix generation.
[Cholestyramine in the treatment of severe diarrhea
and diarrhea of the diabetic patient].
Laudanna AA, Germ:an JC, Gama Rodriques JJ, Mekler M, Gama
AH, Bertarello A
Rev Fac Cien Med Univ Nac Cordoba 1985;43(2):3-6
Published erratum appears in Rev Fac Cien Med Univ Nac
Cordoba 1986;44(2):preceding 3
No abstract.
Neural dysfunction and metabolic imbalances in
diabetic rats. Prevention by acetyl-L-carnitine.
Ido Y, McHowat J, Chang KC, Arrigoni-Martelli E, Orfalian Z,
Kilo C, Corr PB, Williamson JR
Department of Pathology, Washington University School of
Medicine, St. Louis, Missouri 63110.
Diabetes 1994 Dec;43(12):1469-77
The rationale for these experiments is that administration
of L-carnitine and/or short-chain acylcarnitines attenuates
myocardial dysfunction
1) in hearts from diabetic animals (in which L-carnitine
levels are decreased);
2) induced by ischemia-reperfusion in hearts from nondiabetic
animals; and
3) in nondiabetic humans with ischemic heart disease.
The objective of these studies was to investigate whether
imbalances in carnitine metabolism play a role in the
pathogenesis of diabetic peripheral neuropathy. The major
findings in rats with streptozotocin-induced diabetes of 4-6
weeks duration were that 24-h urinary carnitine excretion was
increased approximately twofold and L-carnitine levels were
decreased in plasma (46%) and sciatic nerve endoneurium (31%).
These changes in carnitine levels/excretion were associated
with decreased caudal nerve conduction velocity (10-15%) and
sciatic nerve changes in Na(+)-K(+)-ATPase activity (decreased
50%), Mg(2+)-ATPase (decreased 65%), 1,2-diacyl-sn-glycerol
(DAG) (decreased 40%), vascular albumin permeation (increased
60%), and blood flow (increased 65%). Treatment with
acetyl-L-carnitine normalized plasma and endoneurial
L-carnitine levels and prevented all of these metabolic and
functional changes except the increased blood flow, which was
unaffected, and the reduction in DAG, which decreased another
40%. In conclusion, these observations
1) demonstrate a link between imbalances in carnitine
metabolism and several metabolic and functional abnormalities
associated with diabetic polyneuropathy and
2) indicate that decreased sciatic nerve endoneurial ATPase
activity (ouabain-sensitive and insensitive) in this model of
diabetes is associated with decreased DAG.
Serum and urine levels of levocarnitine family
components in genetically diabetic rats.
Morabito E, Corsico N, Marzo A, Arrigoni Martelli E
Department of Pharmacology, Sigma-Tau S.p.A., Pomezia, Roma,
Italy.
Arzneimittelforschung 1994 Aug;44(8):965-8
Serum concentration and urinary excretion of levocarnitine
(L-carnitine, CAS 541-15-1) family components were evaluated
in a Wistar derived strain of genetically diabetic rats BB/BB,
in comparison with normal Wistar rats, and their control rats
BB/WB of both sexes. BB/BB diabetic animals have lower serum
concentration of total-L-carnitine (TC), L-carnitine (LC),
acetyl-L-carnitine (ALC), and short chain L-carnitine esters
(SCLCE) than both the strains of non-diabetic rats, as
previously observed in streptozotocin diabetic rats. No or
marginal variations between control and diabetic rats were
detected in cumulative urinary excretion of L-carnitine family
components. A strain difference was observed between Wistar
and BB/WB non-diabetic rats, BB/WB showing higher serum
concentration and lower cumulative urinary excretion of LC and
TC than Wistar animals. Renal clearance of L-carnitine
components proved to be markedly higher in BB/BB diabetic
rats, as previously shown in streptozotocin rats. The
reduction of serum concentration of the carnitines endogenous
pool may explain this finding. The lack of an increased
urinary excretion of L-carnitine components in diabetic
animals despite the high increase of diuresis suggests that
the saturable tubular reabsorption of L-carnitine family
components also in diabetes is the primary mechanism to
preserve the homeostatic equilibria of the L-carnitine family,
the variation in serum concentration being attributable to the
complex systemic metabolicalterations typical of diabetes. In
agreement with previous investigations,male animals of all the
strains showed higher serum concentration andurinary excretion
of L-carnitine components as compared to females.
Acetyl-L-carnitine corrects electroretinographic
deficits in experimental diabetes.
Lowitt S, Malone JI, Salem A, Kozak WM, Orfalian Z
Department of Pediatrics, University of South Florida,
Tampa.
Diabetes 1993 Aug;42(8):1115-8
Acetyl-L-carnitine reduces the latencies of
electroretinogram oscillatory potentials in healthy humans.
The effect of acetyl-L-carnitine (50mg.kg-1.day-1) on the
increased electroretinogram latencies found in rats with
STZ-induced hyperglycemia of 3-wk duration was evaluated. The
aldosereductase inhibitor sorbinil, which has been shown to
normalize abnormal electroretinogram tracings associated with
STZ-induced diabetes, was used as a positive control. Aldose
reductase inhibitors are thought to lower tissue sorbitol
while increasing myo-inositol. The electroretinograms of the
STZ-induced diabetic rats in this study were abnormal;
treatment withacetyl-L-carnitine as well as sorbinil
significantly improved electroretinogram b-wave amplitude and
decreased the latencies of oscillatory potentials 2 and 3.
Acetyl-L-carnitine treatment of STZ-induced diabetic rats did
not affect hyperglycemia or erythrocyte polyol pathway
activity as reflected by erythrocyte sorbitol levels. In
contrast, sorbinil did reduce elevated erythrocyte sorbitol
levels. This suggests that the impaired electroretinograms
associated with STZ-induced diabetes may not be caused solely
by increased polyol pathway activity.
Acetyl-L-carnitine effect on nerve conduction
velocity in streptozotocin-diabetic rats.
Morabito E, Serafini S, Corsico N, Martelli EA
Department of Pharmacology, Sigma-Tau S.p.A. Pomezia, Rome,
Italy.
Arzneimittelforschung 1993 Mar;43(3):343-6
Measurement of nerve conduction velocity (NCV) is a useful
and sensitive tool for evaluating diabetes related
neurological dysfunctions. The method used allows to monitor
the parameter at different times in the same group of rats, so
that it is possible to observe simultaneously the development
of the damage in time, and to evaluate the improvement related
to the treatment. The repeated oral treatment with
acetyl-L-carnitine (ALC, CAS 5080-50-2) 250 mg/kg caused an
improvement in NCV of the diabetic rats; the effect was higher
when the treatment started early with respect to the diabetes
induction. The improvement in NCV was constant in time and
comparable from 2 to 6 weeks of the treatment. In conclusion,
oral treatment with ALC was able to normalize the impairment
of NCV in streptozotocin rats, the effect being constant in
time from 2 to 6 weeks of treatment and up to 8 weeks after
induction when administration started in early stage of
diabetes (2-3 weeks after induction); however, at this time
the NCV is already significantly decreased.
Effect of acetyl-L-carnitine treatment on the
levels of levocarnitine and its derivatives in
streptozotocin-diabetic rats.
Marzo A, Corsico N, Cardace G, Morabito E
Department of Drug Metabolism and Pharmacokinetics, Sigma-Tau
S.p.A., Pomezia, Rome, Italy.
Arzneimittelforschung 1993 Mar;43(3):339-42
The effect of diabetes induced by streptozotocin and that
of acetyl-L-carnitine (ALC) hydrochloride (CAS 5080-50-2)
treatment on the homeostasis of the levocarnitine
(L-carnitine) moiety was investigated in Sprague-Dawley rats.
The diabetic status was ascertained by measuring blood
glucose. L-carnitine (LC), total acid soluble L-carnitine (TC)
and ALC were measured in serum, tissues and urine by
radioenzymatic methods. Short-chain L-carnitine esters (SCLCE)
were obtained by subtracting LC from TC. Serum concentration
of L-carnitine moiety was decreased in diabetic when compared
to normal rats; whereas ALC oral treatment (50 and 150 mg/kg
p.o. for 4 weeks) in diabetic rats increased,
dose-dependently, all the components of L-carnitine moiety,
SCLCE and ALC being completely restored. In the liverof
diabetic rats all the analytes proved to be higher than in
normal rats, mainly LC and TC. A similar trend was observed in
skeletal muscle, at least with LC and TC, whereas SCLCE and
ALC were not affected. The treatment with ALC increased the
liver concentration of all the analytes in a dose-related way
whereas in skeletal muscle only LC and TC showed an increase
with the highest dose of ALC. Myocardium and kidneys showed a
decrease of all the analytes in diabetes; the treatment with
ALC normalized the situation in kidneys, in a dose-related
way, but not in the myocardium. Urinary excretion and renal
clearance of L-carnitine moiety increased in diabetes; an
additional dose-related increase was observed with the ALC
treatment.
Acetyl-L-carnitine prevents substance P loss in the
sciatic nerve and lumbar spinal cord of diabetic
animals.
Di Giulio AM, Gorio A, Bertelli A, Mantegazza P, Ferraris L,
Ramacci MT
Department of Medical Pharmacology, University of Milan,
Italy.
Int J Clin Pharmacol Res 1992;12(5-6):243-6
Diabetic neuropathy is a disease of peripheral nerves,
characterized by axonal atrophy and degeneration that might be
preceded by a marked impairment of axonal transport and by a
reduced conduction velocity. Sensory nerves are particularly
susceptible to diabetes. In the present report it is shown
that experimental diabetes in rats causes a significant
reduction of the content of the pain-related neuropeptide
substance P insciatic nerve and lumbar spinal cord. Such a
loss of substance P is fully prevented by acetyl-L-carnitine
treatment. The neuroprotective pharmacological effect is
selective and takes place without significant changes of
hyperglycaemia and without modifications of the reduced rate
of body growth typical of diabetic animals.
Altered neuroexcitability in experimental diabetic
neuropathy: effect of acetyl-L-carnitine.
Malone JI, Lowitt S, Corsico N, Orfalian Z
University of South Florida, Tampa.
Int J Clin Pharmacol Res 1992;12(5-6):237-41
Sciatic nerve conduction velocity (NCV) is reduced in rats
made hyperglycaemic with streptozotocin (STZ). This
neurophysiologicaldys function has been associated with
increased nerve sorbitol and reduced nerve inositol. Treatment
of STZ diabetic rats with aldose reductase inhibitors (ARIs)
which reduce sorbitol and increase inositol in the nerve
results in normalization of NCVs. Male Wistar rats were made
diabetic with 50 mg/kg of streptozotocin given
intraperitoneally. Those animals with blood glucose > 300
mg/dl two weeks later were included in this study. The
STZ-diabetic rats were treated with either the ARI sorbinil
(40 mg/kg per day), or acetyl-L-carnitine (ALC) (300 mg/kg per
day) or sterile 0.15% aqueous NaCl for 16 weeks after 4 or 8
weeks of untreated hyperglycaemia. A control group of
non-diabetic rats received no treatment during the interval.
Sciatic-nerve sorbitol was elevated (1.08 +/- 0.13 nanomol/mg
wet weight vs. 0.19 +/- 0.03 nm/mg wet weight) and inositol
was reduced (1.21+/- 0.12 nm/mg ww vs. 2.02 +/- 0.08 nm/mg ww)
in the STZ diabetic rats, which were untreated for 4 weeks.
Treatment with sorbinil was associated with normalization of
the tissue sorbitol (0.10 +/- 0.05 nm/mg ww), while ALC
treatment also significantly reduced the nerve sorbitol but
only to a level (0.34 +/- 0.08 nm/mg ww) more elevated than
the normal level. The nerves of STZ animals treated with
sorbinil or ALC had inositol levels no different from
untreated diabetic rats. Thus, hyperglycaemic animals treated
with either ALC or sorbinil had similar improvements in NCVs
as the diabetic, even though the effect on nerve sorbitol was
different and nerve inositol was unchanged.(ABSTRACT TRUNCATED
AT 250 WORDS)
[The action of carnitine-series preparations in
experimental alloxan diabetes mellitus]
Kim EK, Trevisani C, Trevisani M
Eksp Klin Farmakol 1992 Jul-Aug;55(4):35-6
The study was undertaken to examine the effects of
l-carnitine and acetyl-l-carnitine in rats and mice with
experimental alloxan diabetes. The findings suggest that
acetyl-l-carnitine is more effective against diabetes in
increasing glucose tolerance, restoring the impaired response
of glucagon to glucose, showing glycogen-sparing action than
is l-carnitine.
Aminoguanidine and diabetic neuropathy
Monnier VM
Institute of Pathology, Case Western Reserve University,
Cleveland, OH, USA.
Eur J Endocrinol 1996 Apr;134(4):398-400
No abstract.
Evaluation of the mechanism of endothelial
dysfunction in the genetically-diabetic BB rat.
Pieper GM, Moore-Hilton G, Roza AM
Department of Transplant Surgery, Medical College of
Wisconsin, Froedtert Memorial Lutheran Hospital, Milwaukee,
53226 USA.
Life Sci 1996;58(9):PL147-52
Endothelial dysfunction is known to occur in
chemically-induced animal models of diabetes. The BB diabetic
rat is a genetic diabetes-prone model which more closely
resembles Type I diabetes mellitus. In this study, we examined
the role of superoxide anion radical and cyclooxygenase
activity on endothelial dysfunction in aorta of the
spontaneous diabetic BB rat.Vascular endothelial function was
studied in vitro in aortic rings from 8-wk diabetic rats and
age-matched nondiabetic littermates. There was no alteration
in reactivity to norepinephrine as a result of diabetes.
Relaxation to acetylcholine (but not nitroglycerin) was
impaired in diabetic rings. Relaxation to acetylcholine was
abolished by 100 micro ML-nitroarginine but unaltered by an
equimolar concentration of aminoguanidine (an inducible nitric
oxide synthase inhibitor) in both control and diabetic rings.
Incubation with 10 microM indomethacin did not alter
relaxation to acetylcholine in either control or diabetic
rings. In contrast, addition of 20 U/ml superoxide dismutase
enhanced relaxation to acetylcholine in diabetic rings but had
no effect on relaxation to acetylcholine in control rings.
Thus, nitric oxide-mediated, endothelium-dependent relaxation
is diminished in aortic rings of the genetic diabetic BB rat.
Furthermore, superoxide anion radicals but not cyclooxygenase
products play an important role in endothelial dysfunction in
this genetic diabetic model.
Effect of aminoguanidine on the frequency of
neuroaxonal dystrophy in the superior mesenteric sympathetic
autonomic ganglia of rats with streptozocin-induced
diabetes.
Schmidt RE, Dorsey DA, Beaudet LN, Reiser KM, Williamson JR,
Tilton RG
Department of Pathology, Washington University of Medicine,
St. Louis, Missouri 63110, USA.
Diabetes 1996 Mar;45(3):284-90
Aminoguanidine, which prevents formation of advanced
glycation end products and is a relatively selective potent
inhibitor of the inducible (versus constitutive) isoform(s) of
nitric oxide synthase, has been reported to ameliorate
structural and functional abnormalities in peripheral somatic
nerves in rats with streptozocin (STZ)-induced diabetes. In
the present studies, the effects of aminoguanidine treatment
on ultrastructural changes in the autonomic nervous system of
rats with STZ-induced diabetes were examined. The frequency of
neuroaxonal dystrophy, the neuropathological hallmark of
sympathetic autonomic neuropathy in diabetic rats, increased
9- to 11-fold in the superior mesenteric ganglia of 7- and
10-month STZ-diabetic rats compared with that in age-matched
controls. Administration of aminoguanidine continuously from
the time of induction of diabetes at a dose equal to or in
excess of that providing a salutary effect in the diabetic
somatic peripheral nervous system did not alter the severity
of diabetes as assessed by plasma glucose level, 24-hurine
volume, and levels of glycated hemoglobin. Chronic
aminoguanidine therapy did not diminish the frequency or
affect the ultrastructural appearance of neuroaxonal dystrophy
in diabetic or age-matched control rat sympathetic ganglia
after 7 or 10 months of continuous administration. Our
findings (under these experimental conditions) do not support
a role for aminoguanidine-sensitive processes in the
development of sympathetic neuroaxonal dystrophy in diabetic
rats. Glycation-linked aminoguanidine-insensitive processes,
however, such as the formation of early glucose adducts
(Schiff bases and Amadori products) withintra cellular and/or
extracellular proteins and amine-containing lipids, superoxide
anion generation during subsequent autoxidation of these
glucoseadducts, and non-glycative processes, remain potential
pathogenetic mechanisms for diabetic autonomic neuropathy.
[The relation between the changes of width and
anionic sites of glomerular basement membrane and
transferrinuria in rats]
Chen Y, Qian Y
Department of Endocrine, First Hospital, Beijing Medical
University.
Chung Hua I Hsueh Tsa Chih 1995 Sep;75(9):537-9,
574
The changes of width and anionic sites of glomerular
basement membrane (GBM) are considered early changes of
diabetic nephropathy. Recent work suggests that the normal
barrier to the penetration of renal glomerular basement
membrane by anionic plasma proteins may depend in part on the
existence of negatively charged sites within the membrane. We
evaluated the relationship between the change of width,
anionic sites of GBM and transferrinuria in diabetic rats and
normal controls in 1, 3, 6 months after administration by STZ.
Diabetic rats revealed a thicken GBM(0.40-0.44 microns) and
reduced anionic sites (16-12/1000nm GBM length) compared with
control rats (0.22 microns, 20-22/1000 nm GBM lenth).
Transferrinuria was also significantly greater in diabetic
rats than normals (P < 0.01). The changes in anionic sites
and transferrinuria represented defect of GBM charge barrier
in early phase of diabetic nephropathy. Aminoguanidine
attenuated the rise in transferrinuria and prevented GBM
thickness and loss of anionie sites.
Increased endocytosis in retinal vascular
endothelial cells grown in high glucose medium is modulated by
inhibitors of nonenzymatic glycosylation.
Stitt AW, Chakravarthy U, Archer DB, Gardiner TA
Department of Ophthalmology, Queen's University of Belfast,
Northern Ireland.
Diabetologia 1995 Nov;38(11):1271-5
We sought to determine if hyperglycaemia is responsible for
increased retinal vascular endothelial-cell (RVEC) endocytosis
in diabetes and to assess the role of nonenzymatic
glycosylation in mediation of this novel endothelial-cell
pathology. RVECs were propagated in media containing either 5
or 25 mmol/l glucose for up to 10 days after which they were
exposed to the protein tracer horseradish peroxidase for 30
min. The level of RVEC endocytosis was quantified in intact
cell monolayers by electron microscopic stereology, and in
cell lysates by a simple spectrophotometric method. The effect
of the nonenzymatic glycosylation inhibitors, aminoguanidine
and D-lysine, on high-glucose medium induced changes in RVEC
endocytosis was tested by inclusion of these agents in the
culture medium. RVECs exposed to 25 mmol/l glucose showed a
stepwise increase in endocytosis of horseradish peroxidase
culminating in a two- to threefold increase after 10 days.
Endocytosis returned to normal levels after afurther 10 days
in 5 mmol/l glucose medium. The increase in RVEC endocytosis
was markedly reduced, but not completely normalised, by
aminoguanidine and D-lysine. Exposure of cultured RVECs to 25
mmol/l glucose causes an increase in endocytosis of similar
magnitude to that experienced by RVEC in early diabetes, and
implicates hyperglycaemia in the latter situation. A
significant component of the increase in RVEC endocytosis
appears to be mediated by nonenzymatic glycosylation.
In vitro advanced glycation end product formation
in rat tail tendon fibers: influence of aminoguanidine.
Troncoso IA, Esteban MM, Ruiz MA, Florez L, Barneo L
Functional Biology Department, University of Oviedo,
Spain.
Transplant Proc 1995 Dec;27(6):3345-6
No abstract.
L-fucose reduces collagen and noncollagen protein
production in cultured cerebral microvessel endothelial
cells.
Yorek MA, Conner CE, Spanheimer RG
Department of Internal Medicine, Veterans Affairs Medical
Center, Iowa City, IA 52246, USA.
J Cell Physiol 1995 Dec;165(3):658-66
L-fucose is a monosaccharide which is present in low
concentrations in normal serum but is increased in diabetes,
cancer, and inflammatory diseases. The contribution that
abnormal L-fucose levels make to the progression of these
disorders is unknown. In a previous study we showed that
increased L-fucose concentration reduced proliferation and
proteoglycan production by cultured cerebral microvessel
endothelial cells. In the present study we show that exposing
cerebral microvessel endothelial cells for 2 weeks to medium
containing an increased concentration of L-fucose causes a
significant decrease in collagen and to a lesser extent
noncollagen protein production. The effect of L-fucose on
collagen and noncollagen protein production is
concentration-dependent: 1 mM L-fucose causes a significant
decrease in collagen production but has no effect on
noncollagen protein production; a 5 mM L-fucose concentration
causes a maximum decrease in both collagen and noncollagen
protein production. This defect is unrelated to the reduction
in myo-inositol uptake caused by L-fucose and is not prevented
by aminoguanidine. Collagen production can be improved by
restoring L-fucose-conditioned cells to normal medium.
Culturing cells for 2 weeks in medium containing 10 mM
L-fucose resulted in a 50% decrease in collagen production,
which was restored to 75% of control after cells were
transferred to normal medium for 7 days. In contrast,
noncollagen protein production was totally restored after 3
days in normal medium. Increasing levels of L-fucose in serum
of rats also resulted in a decrease in collagen production.
Collagenase digestible in corporation of L-[2,3,4,5-3H]proline
into protein of the articular cartilage from rats fed a diet
containing 20% L-fucose for 3 weeks was reduced by about
40%compared to rats fed a normal diet. The decrease in
collagen production in L-fucose fed rats was less than the
reduction that occurred in streptozotocin-induced diabetic
rats. These data suggest that changes in L-fucose
concentration itself may be a factor in the regulation of
collagen production.
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