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Primary preventive and secondary interventionary
effects of acetyl-L- carnitine on diabetic neuropathy in the
bio-breeding Worcester rat
Sima A.A.F.; Ristic H.; Merry A.; Kamijo M.; Lattimer S.A.;
Stevens M.J.; Greene D.A.
Wayne State University, 540 East Canfield Avenue, Detroit, MI
48201 USA
Journal of Clinical Investigation (USA), 1996, 97/8
(1900-1907)
The abnormalities underlying diabetic neuropathy appear to
be multiple and involve metabolic neuronal and vasomediated
defects. The accumulation of long-chain fatty acids and
impaired beta-oxidation due to deficiencies in carnitine
and/or its esterified derivatives, such as acetyl-L-carnitine,
may have deleterious effects. In the present study, we
examined, in the diabetic bio-breeding Worcester rat, the
short- and long-term effects of acetyl-L- carnitine
administration on peripheral nerve polyols, myoinositol,
Na+/K+- ATPase, vasoactive prostaglandins, nerve conduction
velocity, and pathologic changes. Short-term prevention (4 mo)
with acetyl-L-carnitine had no effects on nerve polyols, but
corrected the Na+/K+-ATPase defect and was associated with 63%
prevention of the nerve conduction defect and complete
prevention of structural changes. Long-term prevention (8 mo)
and intervention (from 4 to 8 mo) with acetyl-L-carnitine
treatment normalized nerve PGE1 whereas 6-keto PGF(1alpha) and
PGE2 were unaffected. In the prevention study, the conduction
defect was 73% prevented and structural abnormalities
attenuated. Intervention with acetyl-L-carnitine resulted in
76% recovery of the conduction defect and corrected
neuropathologic changes characteristic of 4- mo diabetic rats.
Acetyl-L-carnitine treatment promoted nerve fiber
regeneration, which was increased two-fold compared to
nontreated diabetic rats. These results demonstrate that
acetyl-L-carnitine has a preventive effect on the acute
Na+/K+-ATPase defect and a preventive and corrective effect on
PGE1 in chronically diabetic nerve associated with
improvements of nerve conduction velocity and pathologic
changes.
Vitamin and mineral deficiencies which may
predispose to glucose intolerance of pregnancy
Jovanovic-Peterson L.; Peterson C.M.
Sansum Medical Research Foundation, 2219 Bath Street, Santa
Barbara, CA 93105 USA
Journal of the American College of Nutrition (USA), 1996,
15/1 (14-20)
There is an increased requirement for nutrients in normal
pregnancy, not only due to increased demand, but also
increased loss. There is also an increased insulin resistant
state during pregnancy mediated by the placental anti-insulin
hormones estrogen, progesterone, human somatomammotropin; the
pituitary hormone prolactin; and the adrenal hormone,
cortisol. If the maternal pancreas cannot increase production
of insulin to sustain normoglycemia despite these anti-insulin
hormones, gestational diabetes occurs. Gestational diabetes is
associated with excessive nutrient losses due to glycosuria.
Specific nutrient deficiencies of chromium, magnesium,
potassium and pyridoxine may potentiate the tendency towards
hyperglycemia in gestational diabetic women because each of
these four deficiencies causes impairment of pancreatic
insulin production. This review describes the pathophysiology
of the hyperglycemia and the nutrient loss in gestational
diabetes and further postulates the mechanism whereby
vitamin/mineral supplementation may be useful to prevent or
ameliorate pregnancy-related glucose intolerance.
Antioxidant status in patients with uncomplicated
insulin-dependent and non-insulin-dependent diabetes
mellitus
Maxwell S.R.J.; Thomason H.; Sandler D.; Leguen C.; Baxter
M.A.; Thorpe G.H.G.; Jones A.F.; Barnett A.H.
Dr. S.R.J. Maxwell, Division of Clinical Pharmacology,
Clinical Sciences Building, Leicester Royal Infirmary,
Leicester LE2 7LX United Kingdom
European Journal of Clinical Investigation (United Kingdom),
1997, 27/6 (484-490)
Oxidative damage by free radicals has been implicated in
the pathogenesis of vascular disease in diabetes. We compared
the radical- scavenging antioxidant activity of serum from 28
patients with insulin- dependent diabetes mellitus and 24
patients with non-insulin-dependent diabetes mellitus
uncomplicated by vascular disease with age-matched non-
diabetic control subjects. Patients with insulin-dependent
diabetes had significantly reduced total antioxidant activity
(320.2plus or minus11.3 vs. 427.5plus or minus19.2similarmolL
1 P<0.001). This was attributable to lower urate (209.4plus
or minus 10.4 vs. 297.1 plus or minus 16.7similarmolL 1;
P<0.001) and vitamin C levels (63.6 plus or minus 6.0 vs.
87.5 plus or minus 4.9 micromol L ; P < 0.0 1). Patients
with non-insulin-dependent diabetes had lower total
antioxidant activity than age-matched control subjects (433.8
plus or minus 25.4 vs. 473.9 plus or minus 30.2micromol L 1
NS), reflecting lower urate (299.5 plus or minus 19.4 vs.
324.8 plus or minus21.4/micromolL -P; NS) and vitamin C levels
(38.6plus or minus5.7 vs. 58.5 plus or minus 5.3micromol L -1;
P<0.05). Multiple regression analysis showed that urate,
vitamin C and vitamin E were the major contributors to serum
total antioxidant activity. These results show that diabetic
patients have significant defects of antioxidant protection,
which may increase vulnerability to oxidative damage and the
development of diabetic complications.
Nutrient intake and food use in an Ojibwa-Cree
community in Northern Ontario assessed by 24h dietary
recall
Wolever T.M.S.; Hamad S.; Gittelsohn J.; Hanley A.J.G.; Logan
A.; Harris S.B.; Zinman B.
Canada
Nutrition Research (USA), 1997, 17/4 (603-618)
As part of a diabetes prevention program in a remote
Ojibwa-Cree community in Northern Ontario, 72% of residents
>9y of age (729/1019) underwent an oral glucose tolerance
test; >98% (718/729) of participants provided a complete
24h dietary recall. Their diet was typical of that for
aboriginal North American populations undergoing rapid
cultural change, being high in saturated fat (similar13%
energy), cholesterol and simple sugars (similar22% energy),
low in dietary fibre (11g/d) and nigh in glycaemic index
(similar90). There were high prevalences of inadequate intakes
of vitamin A (77%), calcium (58%), vitamin C (40%) and folate
(37%). Adolescents aged 10-19y consumed more simple sugars and
less protein than adults aged >49y and ate more potato
chips, flied potatoes, hamburger, pizza, soft drinks and table
sugar. Adults >49y retained more traditional eating habits,
using more bannock (fried bread) and wild meats than younger
individuals. Interventions to prevent diabetes in the
community should include culturally appropriate and effective
ways to improve the nutritional adequacy of the diet, reduce
fat intake and increase the use of less refined carbohydrate
foods.
Effect of vitamin C supplementation on hepatic
cytochrome P450 mixed-function oxidase activity in
streptozotocin-diabetic rats
Clarke J.; Snelling J.; Ioannides C.; Flatt P.R.; Barnett
C.R.
United Kingdom
Toxicology Letters (Ireland), 1996, 89/3
(249-256)
The effect of vitamin C supplementation on hepatic
cytochrome P450 expression was investigated in streptozotocin
(STZ) diabetic male Wistar Albino rats. STZ-treated rats
displayed the usual characteristics of diabetes including;
hyperphagia, polydipsia, decreased body weight gain and also
the increased expression and activity of hepatic CYP1A, 2B, 2E
and 4A proteins. Vitamin C administration in drinking water
(2% w/v) was associated with significant decreases in the
levels of hyperglycaemia (P < 0.05), glycosylated
haemoglobin (P < 0.05), hyperlipidaemia (P < 0.001), and
hyperketonaemia (P < 0.001) associated with STZ-diabetes.
Vitamin C-treatment selectively reduced the activity and
expression of CYP2E proteins (P < 0.001). These effects on
CYP2E expression may be mediated by the reduced levels of
circulating ketone bodies, however, a direct effect on CYP2E
expression in diabetes cannot be discounted.
The effect of dietary treatment on lipid
peroxidation and antioxidant status in newly diagnosed
noninsulin dependent diabetes
Armstrong A.M.; Chestnutt J.E.; Gormley M.J.; Young
I.S.
Department of Clinical Biochemistry, Institute of Clinical
Science, Royal Victoria Hospital, Belfast BT12 6BJ
Ireland
Free Radical Biology and Medicine (USA), 1996, 21/5
(719-726)
Increased lipid peroxidation and reduced antioxidant status
may contribute to the development of complications in
diabetes. The aim of this study was to assess the effects of
dietary treatment of noninsulin-dependent diabetes on these
parameters. Twenty patients with newly diagnosed
noninsulin-dependent diabetes were recruited along with 20
age, sex, and smoking-status-matched control subjects. Dietary
intake was assessed by food frequency questionnaire and 24-h
dietary recall and blood collected for biochemical analyses
before and 2 months after dietary treatment was initiated.
Carbohydrate, fat, and protein intake fell in patients
following dietary advice. Among micronutrients, intakes of
vitamins C, E, and A, carotene, selenium, copper, zinc, and
iron were similar in patients and controls. Vitamin C intake
in patients rose following dietary advice (44.6 plus or minus
11.7 vs. 49.5 plus or minus 5.5 mg/d, p < .05), while there
was no change in intake of other micronutrients. Fasting
plasma glucose in diabetic subjects fell from 13.6 plus or
minus 1.1 mmol/l at recruitment to 9.7 plus or minus 1.1
mmol/l after diet (p < .01), and this was accompanied by a
fall in hemoglobin Alc from 7.44 plus or minus 0.67% to 5.91
plus or minus 0.57% (p < .01). Serum malondialdehyde was
higher in patients than controls at T0 (2.39 plus or minus
0.55 micromol/l vs. 1.48 plus or minus 0.33; p < .01), and
fell following diet to 1.42 micromol/l (p < 0.01).
Ascorbate was lower in patients than controls (12.7 plus or
minus 2.9 micromol/l vs. 41.4 plus or minus 9.3; p < .01)
at baseline and rose after diet to 27.8 plus or minus 6.4 (p
< .01). beta-Carotene also rose after diet in patients
(0.13 plus or minus 0.04 micromol/l vs. 0.17 plus or minus
0.04; p < 0.05), as did lipid corrected alpha-tocopherol
(4.39 plus or minus 1.09 micromol/mmol cholesterol vs. 5.16
plus or minus 1.18; p < .05). Reduced lipid peroxidation
and improved antioxidant status may be one mechanism by which
dietary treatment contributes to the prevention of diabetic
complications.
Vitamin B6 alleviates the vascular complications of
insulin-treated STZ-induced diabetic rats
Chang S.-J.; Chiang C.-L.
Graduate Institute of Biology, National Cheng Kung
University, Tainan Taiwan
Nutritional Sciences Journal (Taiwan), 1996, 21/3
(235-248)
The purpose of this study is to investigate whether vitamin
B6 alleviates the vascular complications of insulin-treated
streptozotocin (STZ)-induced diabetes in rats. Diabetic
animals were treated with or without vitamin B6 and/or
insulin. Platelet aggregation induced by ADP (10 microM) or
thrombin (0.05 D/mL) was measured in platelet rich plasma of
normal and diabetic animals. 14C-Thromboxane B2 (14C-TxB2)
production of platelets, using 14C-Arachidonic Acid (14C-AA)
as a precursor, was assayed by means of scanning
radiochromatography and autoradiography. 14C-TxB2 was
quantitied by scintillation counter. The results showed that
vitamin B6 in conjuction with insulin treatment resulted in
lower blood glucose than either vitamin B6 or insulin
treatment alone. Similarly, platelet aggregation and TxB2
production in diabetics with vitamin B6 and insulin treatment
were significantly decreased. These data indicated that
vitamin B6 in conjunction with insulin treatment seemed to be
better than vitamin B6 or insulin treatment alone in
controlling blood glucose, inhibiting platelet aggregation and
decreasing TxA2 production.
Total vitamin C, ascorbic acid, and dehydroascorbic
acid concentrations in plasma of critically ill patients
Schorah C.J.; Downing C.; Piripitsi A.; Gallivan L.; Al-Hazaa
A.H.; Sanderson M.J.; Bodenham A.
Division of Clinical Sciences, Old Medical School, University
of Leeds, Leeds LS2 9JT United Kingdom
American Journal of Clinical Nutrition (USA), 1996, 63/5
(760-765)
Plasma concentrations of the antioxidant vitamin ascorbic
acid were measured by high-performance liquid chromatography
in critically ill patients in whom the excessive generation of
reactive oxygen species could compromise antioxidant defense
mechanisms. Median concentrations of both total vitamin C
(ascorbic acid and dehydroascorbic acid) and ascorbic acid in
these patients were < 25% (P < 0.001) of the values
found in healthy control subjects and in subjects in two other
disease groups (diabetes, gastritis) in which reactive oxygen
species are reported to be increased. The low values could not
be explained by age, sex, intake, or treatment differences,
but were associated with the severity of the illness and were
not prevented by the use of parenteral nutrition containing
ascorbic acid. In addition, the vitamin was less stable in
blood samples taken from critically ill patients than in
similar samples from subjects in the other groups. The
findings indicate that antioxidant defenses could be
considerably compromised in these very sick patients. If this
reduces the patient's capacity to scavenge reactive species,
then the potential of these species to damage DNA and lipid
membranes could be increased and compromise recovery.
Clinical study of vitamin influence in diabetes
mellitus
Hashizume N.
Dept. of Laboratory Medicine, Ohashi Hosp., Toho Univ. Sch.
of Med., 2-17-6 Ohashi, Meguro, Tokyo Japan
Journal of the Medical Society of Toho University (Japan),
1996, 42/6 (577-581)
Vitamin deficiency is a result of an inadequale diet.
Education on the importance of trace nutrients in diabetic
patients with poor blood sugar control is examined. Those who
prepare meals must consider the loss of vitamins in the
process of cooking. Our study also suggested that marginal
vitamin deficiency plays an indirect but important role in the
development of diabetic complications. Vitamin C as altering
total cholesterol (T-ch) and vitamin E as altering
triglyceride (TG) could modify diabetic angiopathy.
Pharmacologically, niacin might be responsible for the
decrease in Lipoprotein (a) and vitamin C would inhibit the
influence of rapid blood glucose control on diabetic
retinopathy.
Vitamins and metals: Potential dangers for the
human being
Ballmer P.E.
Departement Innere Medizin, Inselspital, Universitat Bern,
CH-3010 Bern Switzerland
Schweizerische Medizinische Wochenschrift (Switzerland),
1996, 126/15 (607-611)
Administration of vitamins or metals may cause severe side
effects. Retinoids (derivatives of vitamin A) used for the
treatment of various skin disorders are teratogenic,
hepatotoxic and may induce a substantial increase in serum
lipids. A case report demonstrates that vitamin D
supplementation in a patient under total parenteral nutrition
can cause hypercalcemia. The isolated administration of
vitamin B1, without concomitant vitamin B6 and nicotinamide
may precipitate potentially life-threatening pellagra
encephalopathy. Repeat blood transfusions may produce
clinically overt organ hemosiderosis, e.g. cirrhosis of the
liver, diabetes mellitus or myocardiopathy. The literature
contains reports on a few cases of sarcoma associated with
orthopedic metal implants. The controversial issue of the
potential dangers of dental amalgams is briefly mentioned.
Leukocyte lipid peroxidation, superoxide dismutase,
glutathione peroxidase and serum and leukocyte vitamin C
levels of patients with type II diabetes mellitus
Akkus I.; Kalak S.; Vural H.; Caglayan O.; Menekse E.; Can
G.; Durmus B.
Selcuk University, School of Medicine, Department of
Biochemistry, Konya Turkey
Clinica Chimica Acta (Netherlands), 1996, 244/2
(221-227)
In the present study, leukocyte lipid peroxidation,
superoxide dismutase (SOD), glutathione peroxidase (GSH-Px)
and serum and leukocyte vitamin C levels of patients with type
II diabetes mellitus and healthy controls were investigated.
Patients consisted of 53 cases (23 male, 30 female) aged 35-75
years and controls of 34 subjects (15 male, 19 female) aged
34-66 years. Leukocyte lipid peroxidation of diabetics was
significantly increased (P < 0.05) whereas vitamin C level
was decreased (P < 0.05) compared to those of controls.
There was no significant difference in the other parameters.
Also, there was no correlation between the above parameters
and HbA1c and glucose levels. Our results show that leukocytes
of diabetics are affected by oxidative stress which might be a
reason for decreased microbicidal activity.
Erythrocyte and plasma antioxidant activity in type
I diabetes mellitus
Ndahimana J.; Dorchy H.; Vertongen F.
Laboratoire de Chimie Medicale, Hopital Saint-Pierre, 322,
Rue Haute, 1000 Bruxelles Belgium
Presse Medicale (France), 1996, 25/5 (188-192)
Objectives: Some biologic parameters involved in cell
defence against oxygen radicals (plasmatic vitamins C and E,
erythrocyte glutathione peroxidase, glutathione reductase and
superoxide dismutase) were measured in single blood samples
from 119 diabetic infants, adolescents and young adults.
Methods: Data were studied in relation to residual insulin
secretion determined by C peptide, level of metabolic control
appreciated by glycosylated haemoglobin, lipid abnormalities
and subclinical complications (retinopathy, neuropathy and
nephropathy).
Results: There was no change in antioxidant parameters with
insulin secretion. Patients with poor glycaemic control and
high plasma lipids had higher levels of plasma vitamin E.
Patients with nephropathy had lower plasma vitamin C levels
and those with neuropathy showed lower erythrocyte glutathione
peroxidase activity. Plasma vitamin C concentrations and
erythrocyte glutathione reductase activities were negatively
correlated with the age of the patients and the duration of
the disease.
Conclusion: Higher transport capacity of vitamin E probably
explains the elevated levels of vitamin E observed in patients
with high lipid levels and long lasting illness. The lower
levels of vitamin C in the presence of nephropathy may be due
to an increased renal excretion of this vitamin. The reduction
of glutathione peroxidase, glutathione reductase activities
and vitamin C levels confirms the existence of an oxidative
stress in type 1 diabetes.
Vitamin C improves endothelium-dependent
vasodilation in patients with non-insulin-dependent diabetes
mellitus
Ting H.H.; Timimi F.K.; Boles K.S.; Creager S.J.; Ganz P.;
Creager M.A.
Cardiovascular Division, Brigham and Women's Hospital, 75
Francis Street, Boston, MA 02115 USA
Journal of Clinical Investigation (USA), 1996, 97/1
(22-28)
Endothelium-dependent vasodilation is impaired in humans
with diabetes mellitus. Inactivation of endothelium-derived
nitric oxide by oxygen-derived free radicals contributes to
abnormal vascular reactivity in experimental models of
diabetes. To determine whether this observation is relevant to
humans, we tested the hypothesis that the antioxidant, vitamin
C, could improve endothelium-dependent vasodilation in forearm
resistance vessels of patients with non-insulin-dependent
diabetes mellitus. We studied 10 diabetic subjects and 10
age-matched, nondiabetic control subjects. Forearm blood flow
was determined by venous occlusion plethysmography.
Endothelium-dependent vasodilation was assessed by
intraarterial infusion of methacholine (0.3-10 microg/min).
Endothelium-independent vasodilation was measured by
intraarterial infusion of nitroprusside (0.3-10 microg/min)
and verapamil (10-300 microg/min). Forearm blood flow
dose-response curves were determined for each drug before and
during concomitant intraarterial administration of vitamin C
(24 mg/min). In diabetic subjects, endothelium-dependent
vasodilation to methacholine was augmented by simultaneous
infusion of vitamin C (P = 0.002); in contrast,
endothelium-independent vasodilation to nitroprusside and to
verapamil were not affected by concomitant infusion of vitamin
C (P = 0.9 and P = 0.4, respectively). In nondiabetic
subjects, vitamin C administration did not alter
endothelium-dependent vasodilation (P = 0.8). We conclude that
endothelial dysfunction in forearm resistance vessels of
patients with non- insulin-dependent diabetes mellitus can be
improved by administration of the antioxidant, vitamin C.
These findings support the hypothesis that nitric oxide
inactivation by oxygen-derived free radicals contributes to
abnormal vascular reactivity in diabetes.
Effects of aspirin or basic amino acids on collagen
cross-links and complications in NIDDM.
Contreras I; Reiser KM; Martinez N; Giansante E; Lopez T;
Suarez N; Postalian S; Molina M; Gonzalez F; Sanchez MR;
Camejo M; Blanco MC
Luis Razetti Medical School, Central University of Venezuela,
Caracas, Venezuela.
Diabetes Care (United States) May 1997, 20 (5)
p832-5
OBJECTIVE: To determine if long-term therapy with aspirin
or basic amino acids for subjects with NIDDM reduces the
severity of clinical complications and/or reduces tissue
levels of markers of glycooxidative damage.
RESEARCH DESIGN AND METHODS: Subjects with NIDDM were
administered either aspirin (100 mg/day) or a combination of
basic amino acids consisting of L-arginine (2 g/day) plus
L-lysine (0.5 g/day) for 1 year. The study was double-blind
and placebo-controlled. The presence and severity of
retinopathy, nephropathy, and neuropathy were assessed in all
subjects at 4-month intervals, as were serum blood glucose,
glycohemoglobin levels, and presence of albuminuria. Collagen
cross-linking and collagen glycation were measured in skin
collagen obtained by biopsy at the beginning and the end of
the study. Skin biopsies were also obtained from age-matched
control subjects.
RESULTS: Skin samples obtained from NIDDM subjects at the
beginning of the study had significantly increased levels of
glucitolyllysine, pentosidine, and hydroxypyridinium, as
compared with age-matched control subjects. Pentosidine levels
were significantly correlated with severity of retinopathy and
neuropathy, but not nephropathy. Subjects receiving aspirin,
but not amino acids or placebo, had significantly decreased
levels of skin pentosidine after 1 year of therapy.
CONCLUSIONS: It is concluded that 1) low-dose aspirin may
reduce glycooxidative damage in people with NIDDM, and 2)
treatment may need to continue for more than 1 year before
clinical status improves.
Acute and chronic response to vanadium following
two methods of streptozotocin-diabetes induction.
Yao J; Battell ML; McNeill JH
Division of Pharmacology and Toxicology, Faculty of
Pharmaceutical Sciences, University of British Columbia,
Vancouver, Canada.
Can J Physiol Pharmacol (Canada) Feb 1997, 75 (2)
p83-90
Controversial reports on the efficacy and possible toxicity
of vanadium obtained from various studies may be attributed to
differences in the method of diabetes induction and (or) to
differences in animal strains. The objective of this study was
to evaluate the contribution of these two factors to the
effects of vanadium in the treatment of experimental diabetes.
Two methods of streptozotocin induction of diabetes in rats
have been used for studying the antidiabetic effects of
vanadium. One involves a single intravenous injection of 60
mg/kg streptozotocin, and the other uses two subcutaneous
injections of 40 mg/kg streptozotocin, to either Wistar or
Sprague-Dawley rats. In a 7-week chronic study, Sprague-Dawley
rats appeared to develop a more severe diabetes (indicated by
higher plasma cholesterol and higher fasting plasma glucose
levels) following the single intravenous injection of
streptozotocin than rats made diabetic by two subcutaneous
injections of streptozotocin. Irrespective of the method of
diabetes induction, the responses of all the diabetic animals
to chronic vanadyl sulphate treatment were similar. In an
acute study, Wistar diabetic rats were more responsive than
Sprague-Dawley diabetic rats to vanadyl sulphate and to lower
doses (0.6 and 0.8 mmol/kg) of a new organic vanadium
compound, bis(maltolato)oxovanadium(i.v.).
[Comparison of metabolism of water-soluble vitamins
in healthy children and in children with insulin-dependent
diabetes mellitus depending upon the level of vitamins in the
diet]
Kodentsova VM; Pustograev NN; Vrzhesinskaia OA; Kharitonchik
LA; Pereverzeva OG; Iakushina LM; Trofimenko LS; Spirichev
VB
Vopr Med Khim (Russia) Apr-Jun 1996, 42 (2)
p153-8
Metabolism of vitamins C, B2, B6 and niacin in children
with insulin-dependent diabetes mellitus was distinctly
different from that of healthy persons of the same age as
shown by studies of the correlation between content of
vitamins or their coenzyme forms in blood, excretion of the
vitamins with urine and content of the vitamins in a diet.
These data corroborated once again that in estimation of the
vitamins consumption suitable for ill children, the criteria
of healthy children requirements for vitamins should not be
taken into consideration. Dissimilar metabolism in healthy and
impaired persons may also demonstrate some differences in
consumption of these vitamins. Preliminary data showed that
requirements of the impaired children for vitamin C were
slightly increased, for vitamin B2--similar or slightly
decreased as compared with healthy children. These results
suggest that additional investigations are required for
evaluation of vitamins consumption in children with diabetes
mellitus of the I type.
Spice constituents scavenging free radicals and
inhibiting pentosidine formation in a model system.
Oya T; Osawa T; Kawakishi S
Department of Applied Biological Sciences, Nagoya University,
Japan.
Biosci Biotechnol Biochem (Japan) Feb 1997, 61 (2)
p263-6
Many antioxidants have been found in spices and herbs, and
some of them are well known as strong scavengers of active
oxygen radicals. We have isolated active products, which
markedly inhibited the formation of malondialdehyde (MDA from
2-deoxyribose and the hydroxylation of benzoate with the
hydroxyl radical, from methanol extracts of allspice and
clove. Pimentol from allspice, and biflorin and its isomer,
abbreviated as clove3, from clove were identified as the
active principles. These revealed strong activity as hydroxyl
radical scavengers at a concentration of 2.0 microM. The
antioxidative activities in an in vitro model system involving
the rabbit erythrocyte membrane ghost were as strong as those
of alpha-tocopherol at 200 microM. Such advanced glycation end
products (AGE) as pentosidine are biomarkers of diabetes
mellitus, and active oxygens have been suggested to be
involved in the formation of AGE. The above-mentioned free
radical scavengers effectively inhibited the formation of
pentosidine in a model system of N
alpha-t-butoxycarbonyl-fructoselysine and N
alpha-t-butoxycarbonyl-arginine.
L-Arginine reduces lipid peroxidation in patients
with diabetes mellitus.
Lubec B; Hayn M; Kitzmuller E; Vierhapper H; Lubec G
Department of Paediatrics, University of Vienna,
Austria.
Free Radic Biol Med (United States) 1997, 22 (1-2)
p355-7
A current concept for the development of diabetic long-term
complications is the involvement of oxidative stress, as,
e.g., lipid peroxidation, in the diabetic state. Data
published recently show also oxidative damage to DNA, which
might be one factor for accelerated aging and diabetic
microangiopathy. In our study we tested the hypothesis that
L-arginine can reduce lipid peroxidation in patients with
diabetes. We performed a blind placebo controlled study with
crossing over two treatment periods for 3 months. Thirty
patients with diabetes mellitus were randomly assigned to
treatment group A (first treatment then placebo) and B (first
placebo then treatment). Treatment consisted of two daily
dosages of 1 g L-arginine free base. Lipid peroxidation as
reflected by malondialdehyde was evaluated in urine using a
standard HPLC assay. After 3 months of treatment there was a
significant reduction in malondialdehyde levels in group A (p
< .0032), whereas there was no difference compared to the
baseline values after three months of placebo treatment in
group B (p < .97). After crossing over, there was a
significant reduction in malondialdehyde levels in group B (p
< .0002). Group A showed a significant increase in
malondialdehyde levels (p < .0063) returning to baseline
values. L-Arginine treatment was able to reduce the lipid
peroxidation product malondialdehyde. This provides evidence
that treatment with L-arginine may counteract lipid
peroxidation and thus reduce microangiopathic long-term
complications in diabetes mellitus.
Short-term oral administration of L-arginine
reverses defective endothelium-dependent relaxation and cGMP
generation in diabetes.
Pieper GM; Siebeneich W; Dondlinger LA
Department of Transplant Surgery, Medical College of
Wisconsin, Froedtert Memorial Lutheran Hospital, Milwaukee WI
53226, USA.
Eur J Pharmacol (Netherlands) Dec 19 1996, 317 (2-3)
p317-20
In the present study, we evaluated whether acute dietary
supplementation with L-arginine in vivo could reverse the
defective endothelium-dependent relaxation in diabetic blood
vessels assessed ex vivo. At 8 weeks of diabetes,
streptozotocin-induced diabetic rats were given 1.25%
L-arginine in drinking water 3 days prior to isolation of
aortic rings for evaluation ex vivo. Plasma arginine
concentration was reduced by diabetes but restored to normal
in diabetic rats receiving dietary L-arginine. In
norepinephrine-contracted rings, relaxation to acetylcholine
but not to nitroglycerin was reduced by diabetes. Dietary
treatment with L-arginine restored relaxation to acetylcholine
without altering relaxation to nitroglycerin and restored the
defect in acetylcholine-stimulated cGMP generation. These data
suggest that the substrate for nitric oxide synthesis by the
endothelium is likely to be limited in diabetes but can be
overcome by dietary supplementation with L-arginine.
A diet enriched in protein accelerates diabetes
manifestation in NOD mice.
Schneider K; Laube H; Linn T
Department of Internal Medicine, Justus Liebig University,
Giessen, Germany.
Acta Diabetol (Germany) Sep 1996, 33 (3) p236-40
Diet modifies the development of insulin-dependent diabetes
mellitus in animals and in humans. We examined female
non-obese-diabetic (NOD) mice, a diabetes-prone mouse strain
with 70% spontaneous diabetes incidence and metabolic
abnormalities in non-overtly diabetic litters. They were fed a
diet containing 55% (n = 27) or 15% (n = 26) protein,
respectively, after weaning. At an age of 30 weeks,
non-diabetic NOD mice were submitted to an intravenous glucose
tolerance test (0.5 g/kg body weight; blood samples were taken
after 2, 4, 8, 10, 15, 20 and 30 min) and to perfusion of the
pancreas (stimulation media were Krebs-Ringer-Hepes buffer
with 5 mmol/l glucose, 30 mmol/l glucose and 5 mmol/l glucose
plus 19 mmol/l arginine). Diabetic mice were removed from the
experiment. Serum glucose concentration and body weight were
monitored weekly. Food ingestion was checked at an age of 11
weeks. On average, the onset of diabetes was diagnosed in mice
on a high-protein diet (19.7 +/- 1.3 weeks) 4 weeks earlier
than in mice on a low-protein diet (23.5 +/- 1.1 weeks; P <
0.05). Non-diabetic NOD mice on a high-protein diet showed
significantly better glucose tolerance (as determined by the
glucose disappearance rate) and mean insulin secretion (at 30
mmol/l glucose). No difference in the serum glucose
concentration between non-diabetic mice on the low-protein
diet or high-protein diet could be proved. In non-diabetic
mice on the high-protein diet the body weight and food
ingestion exceeded those of mice on the low-protein diet (P
< 0.05). High insulin secretion and glucose tolerance in
non-diabetic mice may reflect the capacity of beta-cells to
adapt; however, beta-cells tend to be destroyed under such
circumstances. Thus, a high-protein diet promoted the onset of
diabetes, but it did not increase significantly the incidence
of the disease.
Metformin improves hemodynamic and rheological
responses to L-arginine in NIDDM patients.
Marfella R; Acampora R; Verrazzo G; Ziccardi P; De Rosa N;
Giunta R; Giugliano D
Department of Geriatrics and Metabolic Discases, Second
University of Naples, Italy.
Diabetes Care (United States) Sep 1996, 19 (9)
p934-9
OBJECTIVE: The endothelium plays a pivotal role in the
regulation of vascular tone by releasing nitric oxide (NO).
Increased availability of L-arginine, the natural precursor of
NO, induces vasodilatation and inhibits platelet activity. We
studied the effect of metformin on hemodynamic and rheological
responses to L-arginine in patients with NIDDM.
RESEARCH DESIGN AND METHODS: Ten newly diagnosed NIDDM
patients with mild fasting hyperglycemia (7.5 +/- 0.3 mmol/l)
and without evidence of both micro- and macrovascular
complications were investigated. They received an intravenous
infusion of L-arginine (1 g/min for 30 min) with evaluation of
plasma glucose and insulin, systolic (sBP) and diastolic (dBP)
blood pressure, heart rate and plasma catecholamines, platelet
aggregation, and blood viscosity and filterability. The
L-arginine test was repeated after an 8-week treatment with
metformin (850 mg b.i.d.).
RESULTS: Metformin treatment significantly reduced basal
fasting plasma glucose, HbA1c, and platelet aggregation to ADP
(P < 0.05); the other parameters did not change. During
pretreatment test, L-arginine infusion decreased sBP (from 137
+/- 4.1 to 129 +/- 4.5 mmHg, P < 0.01) and dBP (from 79 +/-
1.9 to 75 +/- 1.2 mmHg, P < 0.01) without affecting heart
rate or plasma catecholamines. Both platelet aggregation and
blood viscosity showed significant decrements after
L-arginine, while blood filterability did not change. After
metformin treatment, the decrease in blood pressure after
L-arginine infusion was significantly enhanced, with a maximal
decrease of sBP of 12 +/- 3.4 mmHg (8 +/- 2.5 mmHg
pretreatment, P < 0.05) and dBP of 9.5 +/- 2.4 mmHg (4.5
+/- 1.9 mmHg pretreatment, P < 0.01). Heart rate, plasma
norepinephrine levels, and blood filterability also rose
significantly (P < 0.05-0.01). The decrease in both
platelet aggregation and blood viscosity after L-arginine was
significantly amplified after metformin.
CONCLUSIONS: We conclude that L-arginine infusion in newly
diagnosed NIDDM patients without vascular complications
produces relevant hemodynamic and theological changes, which
are amplified by an 8-week treatment with metformin. Whether
these vascular effects of metformin will improve the poor
cardiovascular outlook of the diabetic patient is still
unknown.
Impairment of coronary blood flow regulation by
endothelium-derived nitric oxide in dogs with alloxan-induced
diabetes.
Matsunaga T; Okumura K; Ishizaka H; Tsunoda R; Tayama S;
Tabuchi T; Yasue H
Division of Cardiology, Kumamoto University School of
Medicine, Japan.
J Cardiovasc Pharmacol (United States) Jul 1996, 28 (1)
p60-7
Diabetes mellitus is a major cause of ischemic coronary
artery disease. Endothelial dysfunction is implicated in the
pathogenesis of diabetic vascular disease. To examine coronary
blood flow (CBF) regulation with endothelium-derived nitric
oxide (EDNO) in the diabetic state, we compared the effects of
both acetylcholine (ACh) and adenosine (Ado) on left
circumflex coronary artery (LCX) blood flow in 12
vehicle-treated and 21 dogs made diabetic with alloxan
anesthetized with pentobarbital. All dogs were pretreated with
aspirin to inhibit endogenous prostaglandins. None of the
hemodynamic parameters were significantly different in the two
groups. The percent change in coronary vascular resistance
(CVR) after ACh (100 ng/kg) infusion was significantly
attenuated in diabetic dogs (-56.5 +/- 1.4%) as compared with
vehicle-treated dogs (-64.5 +/- 1.2%) (p < 0.01), whereas
the effect of Ado (1 microgram/kg) was not different between
the two groups (-71.1 +/- 1.5% in vehicle, -67.0 +/- 1.3% in
diabetes). After infusion of incremental doses of
NG-nitro-L-arginine methyl ester (L-NAME) 10(-5)-10(-3)M, the
effect of ACh was progressively inhibited in both groups and
was different no longer between the two groups after the
maximal dose. L-Arginine (L-ARG), but not D-ARG, significantly
restored the effect of ACh in diabetic dogs but did not affect
vehicle-treated dogs. The effect of Ado did not change after
L- and D-ARG administration. Cu, Zn-superoxide dismutase (Cu,
Zn-SOD) had no effect on any of the effects of ACh and Ado in
diabetic dogs. Regulation of CBF with EDNO is impaired in dogs
with alloxan-induced diabetes, and this impairment is
partially restored by L-ARG.
Involvement of the L-arginine-nitric oxide pathway
in hyperglycaemia-induced coronary artery dysfunction of
isolated guinea pig hearts.
Wascher TC; Bachernegg M; Kickenweiz A; Stark G; Stark U;
Toplak H; Graier WF
Diabetic Angiopathy Research Group, University of Graz,
Austria.
Eur J Clin Invest (England) Aug 1996, 26 (8)
p707-12
The effects of hyperglycaemia and L-arginine on
flow-induced reduction of coronary artery resistance were
investigated in isolated guinea pig hearts. In the presence of
indomethacin, hyperglycaemia caused an increase in
flow-induced vasodilatation (P < 0.05). Hyperosmotic
controls failed to mimic this effect. Addition of L-arginine
strongly enhanced this effect. Addition of D-arginine failed
to mimic the effects of L-arginine. The effect of L-arginine
was abolished by co-administration of NG-nitro-L-arginine. In
the absence of indomethacin and L-arginine, the effect of
hyperglycaemia was blunted, suggesting the formation of
vasoconstrictive prostanoids. Addition of L-arginine again
resulted in a significant increase in flow-induced
vasodilatation. In conclusion our results suggest that
increased flow-induced vasodilatation under hyperglycaemic
conditions depends on an adequate supply of L-arginine to
maintain sufficient formation of nitric oxide.
Deficient nitric oxide responsible for reduced
nerve blood flow in diabetic rats: effects of L-NAME,
L-arginine, sodium nitroprusside and evening primrose
oil.
Omawari N; Dewhurst M; Vo P; Mahmood S; Stevens E; Tomlinson
DR
Department of Pharmacology, Queen Mary and Westfield College,
London.
Br J Pharmacol (England) May 1996, 118 (1)
p186-90
1. This study examined the potential role of impaired
nitric oxide production and response in the development of
endoneurial ischaemia in experimental diabetes. Rats were
anaesthetized (Na pentobarbitone 45 mg kg-1, diazepam 2 mg
kg-1) for measurement of sciatic nerve laser Doppler flux and
systemic arterial pressure. Drugs were administered into the
sciatic endoneurium via a microinjector attached to a glass
micropipette.
2. In two separate studies comparing diabetic rats
(streptozotocin-induced; 8-10 wk duration) with controls,
nerve Doppler flux in diabetic rats (Study 1, 116.6 +/- 40.4
and Study 2, 90.1 +/- 34.7 (s.d.) in arbitrary units) was
about half that measured in controls (219.6 +/- 52.4 and 212.8
+/- 95.5 respectively; P < 0.005 for both). There were no
significant differences between the two in systemic arterial
pressure.
3. Inhibition of nitric oxide production by microinjection
of 1 nmol L-NAME into the endoneurium halved flux in controls
(to 126.3 +/- 41.3 in Study 1 and 102.1 +/- 38.9 in Study 2;
both P < 0.001), with no significant effect in diabetic
rats, indicating markedly diminished tonic nitric oxide
production in the latter. D-NAME was without effect on nerve
Doppler flux.
4. L-Arginine (100 nmol), injected after L-NAME, markedly
increased flux in controls (by 65.8% (P < 0.03) and 97.8%
(P < 0.01) in the two studies) and by proportionally
similar amounts in diabetic rats [75.8% (P < 0.001) and
60.2% (P < 0.02)]. The nitro-donor, sodium nitroprusside
(SNP; 10 nmol) had similar effects to L-arginine in both
groups (increases of 66.0% in controls and 77.5% in diabetics;
both P < 0.002).
5. A second diabetic group, treated with evening primrose
oil performed exactly like control rats in respect of
responses to L-NAME, L-arginine and SNP.
6. These findings implicate deficient nitric oxide in nerve
ischaemia of diabetes and suggest correction thereof as a
mechanism of action of evening primrose oil.
Interactions between essential fatty acid,
prostanoid, polyol pathway and nitric oxide mechanisms in the
neurovascular deficit of diabetic rats.
Cameron NE; Cotter MA; Hohman TC
Department of Biomedical Sciences, University of Aberdeen,
Scotland, UK.
Diabetologia (Germany) Feb 1996, 39 (2) p172-82
Impaired omega-6 essential fatty acid metabolism and
exaggerated polyol pathway flux contribute to the
neurovascular abnormalities in streptozotocin-diabetic rats.
The potential interactions between these mechanisms were
examined by comparing the effects of threshold doses of aldose
reductase inhibitors and evening primrose oil, alone and in
combination, on neurovascular deficits. In addition, high-dose
aldose reductase inhibitor and evening primrose oil treatment
effects were challenged by co-treatment with the
cyclo-oxygenase inhibitor, flurbiprofen, or the nitric oxide
synthase inhibitor, NG-nitro-L-arginine. Eight weeks of
diabetes caused an 18.9% reduction in sciatic motor conduction
velocity (p < 0.001). This was only modestly ameliorated by
a 0.1% dietary supplement of evening primrose oil or the
aldose reductase inhibitors ZD5522 (0.25 mg.kg-1.day-1 and
WAY121 509 (0.2 mg.kg-1.day-1 for the final 2 weeks. However,
joint treatment with primrose oil and ZD5522 or WAY121 509
caused marked 71.5 and 82.4% corrections, respectively, of the
conduction deficit. Sciatic nutritive blood flow was 43.1%
reduced by diabetes (p < 0.001) and this was corrected by
67.8% with joint ZD5522 and primrose oil treatment (p <
0.001). High-dose WAY121 509 (10 mg. kg-1.day-1 and primrose
oil (10% dietary supplement) prevented sciatic conduction
velocity and nutritive blood flow deficits in 1-month diabetic
rats (p < 0.001). However, these effects were abolished by
flurbiprofen (5 mg.kg(-1).day-1 and NG-nitro-L-arginine (10
mg.kg-1.day-1) co-treatment (p < 0.001). Thus, the data
provide evidence for synergistic interactions between polyol
pathway/nitric oxide and essential fatty acid/cyclo-oxygenase
systems in the control of neurovascular function in diabetic
rats, from which a potential therapeutic advantage could be
derived.
Effects of vanadyl sulfate on carbohydrate and
lipid metabolism in patients with non-insulin-dependent
diabetes mellitus.
Boden G; Chen X; Ruiz J; van Rossum GD; Turco S
Division of Endocrinology/Diabetes/Metabolism and the General
Clinical Research Center, Temple University Schools of
Medicine and Pharmacy, Philadelphia, PA, USA.
Metabolism (United States) Sep 1996, 45 (9)
p1130-5
The safety and efficacy of vanadyl sulfate (VS) was tested
in a single-blind, placebo-controlled study. Eight patients
(four men and four women) with non-insulin-dependent diabetes
mellitus (NIDDM) received VS (50 mg twice daily orally) for 4
weeks. Six of these patients (four men and two women)
continued in the study and were given a placebo for an
additional 4 weeks. Euglycemic-hyperinsulinemic clamps were
performed before and after the VS and placebo phases. VS was
associated with gastrointestinal side effects in six of eight
patients during the first week, but was well tolerated after
that. VS administration was associated with a 20% decrease in
fasting glucose concentration (from 9.3 +/- 1.8 to 7.4 +/- 1.4
mmol/L, P < .05) and a decrease in hepatic glucose output
(HGO) during hyperinsulinemia (from 5.0 +/- 1.0 pre-VS to 3.1
+/- 0.9 micromol/kg x min post-VS, P < .02). The
improvement in fasting plasma glucose and HGO that occurred
during VS treatment was maintained during the placebo phase.
VS had no significant effects on rates of total-body glucose
uptake, glycogen synthesis, glycolysis, carbohydrate (CHO)
oxidation, or lipolysis during euglycemic-hyperinsulinemic
clamps. We conclude that VS at the dose used was well
tolerated and resulted in modest reductions of fasting plasma
glucose and hepatic insulin resistance. However, the safety of
larger doses and use of vanadium salts for longer periods
remains uncertain.
Contraction and relaxation of aortas from diabetic
rats: effects of chronic anti-oxidant and aminoguanidine
treatments.
Archibald V; Cotter MA; Keegan A; Cameron NE
Department of Biomedical Sciences, University of Aberdeen,
Marischal College, Scotland, UK.
Naunyn Schmiedebergs Arch Pharmacol (Germany) Apr 1996, 353
(5) p584-91
We examined whether chronic treatment with the free radical
scavengers butylated hydroxytoluene (1 g kg-1 day-1) and
N-acetyl-L-cysteine (250 mg kg-1 day-1), or the inhibitor of
advanced glycosylation reactions, aminoguanidine (1 g kg-1
day-1), could prevent the development of relaxation and
contraction abnormalities in aorta from 2 month
streptozotocin-diabetic rats. Diabetes caused a 24% deficit in
maximal endothelium-dependent relaxation to acetylcholine for
phenylephrine precontracted aortas (P < 0.01). This was
unaffected by tissue-bath glucose concentration (5.5 or 40
mM), or by addition of 1 mM L-arginine. Butylated
hydroxytoluene, N-acetyl-L-cysteine and aminoguanidine
treatments gave substantial protection, maximum relaxation
remaining in the non-diabetic range. Neither diabetes nor
treatment affected endothelium-independent relaxation to
glyceryl trinitrate. To test the suggestion that
aminoguanidine could act as an inhibitor of constitutive
nitric oxide synthase, acute aminoguanidine effects on
endothelium-dependent relaxation to acetylcholine were also
examined. No inhibition was noted. A modest increase in
phenylephrine sensitivity with diabetes (P < 0.05) was
unaffected by butylated hydroxytoluene or N-acetyl-L-cysteine,
but partially prevented by aminoguanidine (P < 0.05). The
data, therefore, provide evidence for the involvement of
reactive oxygen species and the advanced glycosylation process
particularly for impaired endothelium-dependent relaxation in
experimental diabetes.
[Erythrocyte and plasma antioxidant activity in
diabetes mellitus type I]
Ndahimana J; Dorchy H; Vertongen F
Service de Chimie medicale, Universite Libre de Bruxelles,
Belgique.
Presse Med (France) Feb 10 1996, 25 (5) p188-92
OBJECTIVES: Some biologic parameters involved in cell
defence against oxygen radicals (plasmatic vitamins C and E,
erythrocyte glutathione peroxidase, glutathione reductase and
superoxide dismutase) were measured in single blood samples
from 119 diabetic infants, adolescents and young adults.
METHODS: Data were studied in relation to residual insulin
secretion determined by C peptide, level of metabolic control
appreciated by glycosylated haemoglobin, lipid abnormalities
and subclinical complications (retinopathy, neuropathy and
nephropathy).
RESULTS: There was no change in antioxidant parameters with
insulin secretion. Patients with poor glycaemic control and
high plasma lipids had higher levels of plasma vitamin E.
Patients with nephropathy had lower plasma vitamin C levels
and those with neuropathy showed lower erythrocyte glutathione
peroxidase activity. Plasma vitamin C concentrations and
erythrocyte glutathione reductase activities were negatively
correlated with the age of the patients and the duration of
the disease.
CONCLUSION: Higher transport capacity of vitamin E probably
explains the elevated levels of vitamin E observed in patients
with high lipid levels and long lasting illness. The lower
levels of vitamin C in the presence of nephropathy may be due
to an increased renal excretion of this vitamin. The reduction
of glutathione peroxidase, glutathione reductase activities
and vitamin C levels confirms the existence of an oxidative
stress in type I diabetes.
Hyperglycemia-induced latent scurvy and
atherosclerosis: the scorbutic-metaplasia hypothesis.
Price KD; Price CS; Reynolds RD
University of Illinois at Chicago, College of Medicine 60612,
USA.
Med Hypotheses (England) Feb 1996, 46 (2)
p119-29
Latent scurvy is characterized by a reversible
atherosclerosis that closely resembles the clinical form of
this disease. Acute scurvy is characterized by microvascular
complications such as widespread capillary hemorrhaging.
Vitamin C (ascorbate) is required for the synthesis of
collagen, the protein most critical in the maintenance of
vascular integrity. We suggest that in latent scurvy, large
blood vessels use modified LDL--in particular
lipoprotein(a)--in addition to collagen to maintain
macrovascular integrity. By this mechanism, collagen is spared
for the maintenance of capillaries, the sites of gas and
nutrient exchange. The foam-cell phenotype of atherosclerosis
is identified as a mesenchymal genetic program, regulated by
the availability of ascorbate. When vitamin C is limited, foam
cells develop and induce oxidative modification of LDL,
thereby stabilizing large blood vessels via the deposition of
LDL. The structural similarity between vitamin C and glucose
suggests that hyperglycemia will inhibit cellular uptake of
ascorbate, inducing local vitamin C deficiency. (136
Refs.)
Oral vanadyl sulfate improves insulin sensitivity
in NIDDM but not in obese nondiabetic subjects.
Halberstam M; Cohen N; Shlimovich P; Rossetti L; Shamoon
H
Department of Medicine, Diabetes Research Center, Albert
Einstein College of Medicine, Bronx, NY 10461, USA.
Diabetes (United States) May 1996, 45 (5)
p659-66
We compared the effects of oral vanadyl sulfate (100
mg/day) in moderately obese NIDDM and nondiabetic subjects.
Three-hour euglycemic-hyperinsulinemic (insulin infusion 30 mU
/ m / min) clamps were performed after 2 weeks of placebo and
3 weeks of vanadyl sulfate treatment in six nondiabetic
control subjects (age 37 +/- 3 years; BMI 29.5 +/- 2.4 kg/m2 )
and seven NIDDM subjects (age 53 +/- 2 years; BMI 28.7 +/-1.8
kg/m2). Glucose turnover ([3-3 H]glucose), glycolysis from
plasma glucose, glycogen synthesis, and whole-body
carbohydrate and lipid oxidation were evaluated. Decreases in
fasting plasma glucose (by approximately 1.7 mmol/l) and HbAlc
(both P < 0.05) were observed in NIDDM subjects during
treatment; plasma glucose was unchanged in control subjects.
In the latter, the glucose infusion rate (GIR) required to
maintain euglycemia (40.1 +/- 5.7 and 38.1 +/- 4.8 micromol /
kg fat-free mass FFM / min) and glucose disposal (Rd) (41.7
+/- 5.7 and 38.9 +/-4.7 micromol / kg FFM / min were similar
during placebo and vanadyl sulfate administration,
respectively. Hepatic glucose output (HGO) was completely
suppressed in both studies. In contrast, in NIDDM subjects,
vanadyl sulfate increased GIR approximately 82% (17.3 +/- 4.7
to 30.9 +/- 2.7 micromol / kg FFM / min, P < 0.05); this
improvement in insulin sensitivity was due to both augmented
stimulation of Rd (26.0 +/-4.0 vs. 33.6 +/- 2.22 micromol / kg
FFM / min, P < 0.05) and enhanced suppression of HGO (7.7
+/- 3.1 vs. 1.3 +/- 0.9 micromol / kg FFM / min, P < 0.05).
Increased insulin-stimulated glycogen synthesis accounted for
>80% of the increased Rd with vanadyl sulfate (P <
0.005), but plasma glucose flux via glycolysis was unchanged.
In NIDDM subjects, vanadyl sulfate was also associated with
greater suppression of plasma free fatty acids (FFAs) (P <
0.01) and lipid oxidation (P < 0.05) during clamps. The
reduction in HGO and increase in Rd were both highly
correlated with the decline in plasma FFA concentrations
during the clamp period (P < 0.001). In conclusion, small
oral doses of vanadyl sulfate do not alter insulin sensitivity
in nondiabetic subjects, but it does improve both hepatic and
skeletal muscle insulin sensitivity in NIDDM subjects in part
by enhancing insulin's inhibitory effect on lipolysis. These
data suggest that vanadyl sulfate may improve a defect in
insulin signaling specific to NIDDM.
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