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The respiratory function and the antioxidant capacity of liver mitochondrial
preparations isolated from Goto-Kakizaki non-insulin dependent diabetic rats and
from Wistar control rats, with the age of 6 months, were compared. It was found
that Goto-Kakizaki mitochondrial preparations presented a higher coupling
between oxidative and phosphorylative systems, compared to non-diabetic
preparations. Goto-Kakizaki mitochondria presented a lower susceptibility to
lipid peroxidation induced by ADP/Fe2+, as evaluated by the formation of
thiobarbituric acid substances. The decreased susceptibility to peroxidation in
diabetic rats was correlated with an increase in mitochondrial vitamin E
(alpha-tocopherol) content and GSH/GSSG ratio. Moreover, the glutathione
reductase activity was significantly increased, whereas the glutathione
peroxidase was decreased. Superoxide dismutase activity was unchanged in
diabetic rats. Fatty acid analyses showed that the content in polyunsaturated
fatty acids of Goto-Kakizaki mitochondrial membranes was significantly higher
compared to controls. These results indicate that the lower susceptibility to
lipid peroxidation of mitochondria from diabetic rats was related to their
antioxidant defense systems, and may correspond to an adaptative response of the
cells against oxidative stress in the early phase of diabetes.

Increased oxidative stress, hypofibrinolysis and insulin resistance are present
in obese Type 2 diabetic patients. It is supposed that treatment with
antioxidant alpha-tocopherol (vitamin E) could not only decrease free radical
production, but also ameliorate insulin action. We evaluated the effect of 3
months administration of vitamin E (600 mg daily) on insulin action examined by
hyperinsulinemic clamp in 11 obese Type 2 diabetic patients. Oxidative stress
and fibrinolysis were also determined. The administration of vitamin E caused a
decrease of glucose disposal rate (26.6 9.5 vs 21.3 7.5 micromol/kg/min,
P < 0.02) and of metabolic clearance rate of glucose (3.7 1.6 vs 2.9 0.8
ml/kg/min. P < 0.02). A decrease of insulin receptor number was observed on
erythrocytes after vitamin E (284 84 vs 171 59 pmol/l, P < 0.01).
Significantly higher plasma malondialdehyde (MDA) concentration documented an
increased oxidative stress in diabetic patients as compared with healthy persons
(3.13 0.68 vs 1.89 0.18 micromol/l, P<0.001). An inverse relationship
was found between MDA concentration and insulin sensitivity expressed by glucose
disposal rate (r = -0.73). Vitamin E further worsened the hypofibrinolysis
documented by a decrease of tissue plasminogen activator (P < 0.01) without
changes in its inhibitor PAI-1. In conclusion. our results demonstrate that
higher doses of vitamin E may further deteriorate insulin action and
fibrinolysis in obese Type 2 diabetic patients.

AIMS: Vascular endothelial dysfunction, an early marker of atherosclerosis, has
been demonstrated in Type 2 diabetes mellitus (DM). Vitamin E preserves
endothelial function in animal models of diabetes and reduces cardiovascular
risk. We examined endothelial function and the effect of vitamin E supplements
in uncomplicated Type 2 DM. METHODS: Forty-eight subjects with Type 2 DM and 21
controls had endothelial function assessed using forearm venous occlusion
plethysmography with endothelium-independent (sodium nitroprusside) and
dependent (acetylcholine, bradykinin) vasodilators. Those with diabetes received
1600 i.u. daily oral alpha-tocopherol or placebo, double-blind for 8 weeks, and
had endothelial function reassessed. RESULTS: The diabetic group had higher
HbA1c (6.91.4 vs 4.80.6%; P<0.01) and systolic (14515 vs. 13016 mm
Hg; P<0.01) but not diastolic blood pressure (798 vs. 769 mm Hg; P =
0.15). There was blunted vasodilation to acetylcholine (15 microg/min; P<0.01)
in subjects with diabetes. Vasodilation to sodium nitroprusside and bradykinin
was similar (all P>0.1). Alpha-tocopherol did not affect vasodilation to
nitroprusside (P>0.1), acetylcholine (P>0.1) or bradykinin (P>0.1). CONCLUSIONS:
There may be receptor-specific endothelial dysfunction in subjects with
uncomplicated Type 2 DM. This is not improved by treatment with
alpha-tocopherol.

BACKGROUND: Diabetes mellitus (DM) is associated with enhanced lipid
peroxidation and persistent platelet activation. We tested the hypothesis that
the in vivo formation of the F2-isoprostane 8-iso-prostaglandin (PG)F2alpha, a
bioactive product of arachidonic acid peroxidation, is enhanced in DM and
contributes to platelet activation. METHODS AND RESULTS: Urine samples were
obtained from 85 diabetic patients and 85 age- and sex-matched healthy subjects
for measurement of immunoreactive 8-iso-PGF2alpha and 11-dehydro-thromboxane B2 (TXM), an in vivo index of platelet activation. Sixty-two had
non-insulin-dependent (NID)DM, and 23 had insulin-dependent (ID) DM. Vitamin E
supplementation, metabolic control, and cyclooxygenase inhibitors were used to
investigate the mechanisms of formation of 8-iso-PGF2alpha in this setting.
Urinary 8-iso-PGF2alpha excretion was significantly higher (P=0.0001) in NIDDM
patients (419208 pg/mg creatinine; range 160 to 1014) than in age-matched
control subjects (20892; 41 to 433). Urinary 8-iso-PGF2alpha was linearly
correlated with blood glucose and urinary TXM. 8-iso-PGF2alpha excretion was
also significantly (P=0. 0001) higher in IDDM patients (400146; 183 to 702)
than in control subjects (19769; 95 to 353). Vitamin E supplementation (600
mg/d for 14 days) was associated with a statistically significant reduction in
both urinary 8-iso-PGF2alpha (by 37%) and TXM (by 43%) in 10 NIDDM patients.
Improved metabolic control was associated with a significant (P=0.0001)
reduction in 8-iso-PGF2alpha and TXM excretion by 32% and 41%, respectively, in
21 NIDDM patients. 8-iso-PGF2alpha was unchanged after 2-week dosing with
aspirin and indobufen despite profound suppression of TXM excretion.
CONCLUSIONS: We conclude that DM is associated with increased formation of
F2-isoprostanes, as a correlate of impaired glycemic control and enhanced lipid
peroxidation. This may provide an important biochemical link between impaired
glycemic control and persistent platelet activation. These results provide a
rationale for dose-finding studies of antioxidant treatment in diabetes.

OBJECTIVE: The present study has examined the effect of vitamin E, the principal
modulator of free radical activity, on electrophysiological parameters in
patients with diabetic peripheral sensorimotor polyneuropathy, matched for
duration of disease and metabolic control. RESEARCH DESIGN AND METHODS: A total of 21 subjects with type 2 diabetes were enrolled in this double-blind
randomized placebo-controlled study (vitamin E, 11 patients; placebo, 10
patients). Patients were randomly assigned to receive either 900 mg vitamin E or
placebo for 6 months. The average dietary vitamin E consumption of the subjects
was similar during the study. The main outcome measure was the
electrophysiological tests assessing nerve conduction. Fasting plasma glucose,
HbA1, postprandial plasma glucose, and electrophysiological parameters in the
basal state and after 6 months of treatment were studied. RESULTS: Glycemic
indexes did not show any significant changes during the study, whereas nerve
conduction improved significantly in 2 of the 12 studied electrophysiological
parameters after 6 months in patients on vitamin E supplementation. The changes
in the electrophysiological parameters were obvious in the median motor nerve
fibers and tibial motor nerve fibers. Nerve conduction velocity in the median
motor nerve fibers (P = 0.0019) and tibial motor nerve distal latency (P =
0.0284) improved significantly after 6 months of vitamin E supplementation.
CONCLUSIONS: This study shows that defective nerve conduction in diabetic
subjects with mild-to-moderate peripheral neuropathy may be improved by
pharmacological doses of vitamin E supplementation. Further studies with a
larger number of patients for longer periods of time are needed.

The effects of alpha-tocopherol nicotinate on blood viscoelasticity and
viscosity and on lipid peroxidation stress in erythrocyte membranes in patients
with Type 2 DM were investigated. Thirteen Type 2 diabetic subjects with
retinopathy were given alpha-tocopherol nicotinate 300 mg tds, after meals, for
3 months. The treatment resulted in significant reductions of blood viscosity at
different shear rates (e.g. -2.23 2.82 p<0.015, gamma = 1.5 s(-1)) and
viscoelasticity (p<0.004); resistance of erythrocyte deformation (p<0.001) and
lipid peroxidation stress in red cell membrane (malondialdehyde or MDA reduced
by 0.17 0.13 nmol l(-1) p<0.005). Plasma viscosity, red cell rigidity, and
HbA1c were unchanged. There were negative linear correlations between the
indices of red cell deformability and the levels of MDA of red cell membrane
both pre- and post-treatment (e.g. R = -0.79, p<0.001; R = -0.78, p<0.002, n =
13; pre- and post-, respectively). We suggest that the improvements of
rheological properties of blood and red cell deformability by alpha-tocopherol
nicotinate are mainly attributed to reducing lipid peroxidation stress on
membrane of red blood cells. The treatment may be useful in slowing
deterioration of microangiopathy in Type 2 DM.

The presence of conventional risk factors cannot sufficiently account for the
excess risk of atherosclerosis in patients with non-insulin-dependent diabetes
mellitus (NIDDM). Oxidative modification of LDL has been implicated in the
pathogenesis of coronary atherosclerosis. Thirty-five patients with NIDDM, 20
nondiabetic, hypertriglyceridemic subjects (HTG-control), and 21 diabetic,
normotriglyceridemic subjects (NTG-control) were enrolled in this study.
Oxidative susceptibility of LDL was determined by monitoring formation of
conjugated dienes. Mean lag time of LDL oxidation and vitamin E/lipid peroxide
of LDL was lower in patients with NIDDM (43.2 3.9 minutes and 1.6 1.3)
than in HTG-control (48.8 3.2 minutes and 2.3 1.2, respectively) and
NTG-control subjects (54.2 6.1 minutes and 3.0 1.8, respectively). Mean
LDL particle size in patients with NIDDM and HTG-control subjects (24.4 0.9
and 24.7 0.7 nm, respectively) was smaller than in NTG-control subjects
(25.9 1.0 nm). Multiple stepwise regression analyses ascertained that the
vitamin. E/lipid peroxide of LDL is a major determinant of LDL oxidation lag
time. These results suggest that LDL in patients with NIDDM is more susceptible
to oxidative modification primarily because of a reduced level of vitamin
E/lipid peroxide of LDL. The enhanced susceptibility of LDL to oxidation may be
a pivotal factor underlying the increased incidence of vascular disease in
patients with NIDDM.

Persons with diabetes are at increased risk for developing coronary heart
disease (CHD): although the standard risk factors are also applicable, there are
other major nontraditional risk factors for these persons. For example,
oxidation of lipoproteins may play an important role in the development of
atherosclerosis. Another risk factor is the presence of small, dense low-density
lipoprotein (LDL), which may have enhanced atherogenicity because it enters the
arterial wall more readily and is more easily oxidized. Both of these factors
may be particularly important in persons with non-insulin-dependent diabetes
mellitus (NIDDM), because these persons may have greater rates of lipid
oxidation in vivo than do nondiabetic persons and also have an increased
prevalence of small, dense LDL. I describe potential dietary and pharmacologic
regimens in patients with NIDDM to decrease in vivo lipid peroxidation, and the
susceptibility of LDL and dense LDL subfractions to oxidative modification. In
nearly all NIDDM patients, reducing dietary saturated fat helps lower plasma
cholesterol and reduces the risk for CHD. There is, however, some controversy as
to whether dietary saturated fat should be replaced by carbohydrates or by
monounsaturated fatty acids (MUFAs) in NIDDM. Recent studies showed reduced
susceptibility to oxidation of LDL in subjects consuming MUFA-enriched diets,
thus adding another dimension to the ongoing debate over the most appropriate
diet for NIDDM patients. Additionally, supplemental antioxidants such as
probucol and vitamin E alone or in combination with MUFA-enriched diets have
shown promise in protecting LDL from oxidation when given to nondiabetic
populations. I also present recent results from an antioxidant trial in NIDDM
subjects.

OBJECTIVE--To investigate whether low vitamin E status is a risk factor for
incident non-insulin dependent diabetes mellitus. DESIGN--Population based
follow up study with diabetes assessed at baseline and at four years.
SETTING--Eastern Finland. SUBJECTS--Random sample of 944 men aged 42-60 who had no diabetes at the baseline examination. INTERVENTION--Oral glucose tolerance
test at four year follow up. MAIN OUTCOME MEASURES--A man was defined diabetic
if he had either (a) a fasting blood glucose concentration > or = 6.7 mmol/l, or
(b) a blood glucose concentration > or = 10.0 mmol/l two hours after a glucose
load, or (c) a clinical diagnosis of diabetes with either dietary, oral, or
insulin treatment. RESULTS--45 men developed diabetes during the follow up
period. In a multivariate logistic regression model including the strongest
predictors of diabetes, a low lipid standardised plasma vitamin E (below median)
concentration was associated with a 3.9-fold (95% confidence interval 1.8-fold
to 8.6-fold) risk of incident diabetes. A decrement of 1 mumol/l of
uncategorised unstandardised vitamin E concentration was associated with an
increment of 22% in the risk of diabetes when allowing for the strongest other
risk factors as well as serum low density lipoprotein cholesterol and
triglyceride concentrations. CONCLUSIONS--There was a strong independent
association between low vitamin E status before follow up and an excess risk of
diabetes at four years. This supports the theory that free radical stress has a
role in the causation of non-insulin dependent diabetes mellitus.

Vitamin E supplementation for four months produced a significant improvement in glucose utilization and hepatic response to insulin in normal and diabetic
subjects.