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E m e r g i n g T r e a t m e n t s a n d T e c h n o l o g i e s
O R I G I N A L
Effect of High-Dose Vitamin E on Insulin
Resistance and Associated Parameters in
Overweight Subjects
ATRICK J. MANNING, MMEDSC, FRACP
SYLVIA A. DE JONG
implicated in the pathogenesis of insulin AYNE H.F. SUTHERLAND, PHD
ANNE R. RYALLS
resistance is the free fatty acid (FFA) (7).
OBERT J. WALKER, MD, FRCP
LIZABETH A. BERRY
Although the rate of release of FFAs from HEILA M. WILLIAMS, MSC
individual adipocytes may not be raisedin obesity, the increased amount of adi-pose tissue overall leads to an increase inthe flux of FFAs to the liver and skeletalmuscle, the two tissues most intimately OBJECTIVE — Markers of oxidative stress and plasma alanine transferase (ALT) levels are
increased and circulating antioxidant concentrations are reduced in individuals with insulin FFAs enter target tissues, they are either resistance. Vitamin E improves glycemic control in people with diabetes. We tested the hypoth-esis that vitamin E would decrease markers of oxidative stress and plasma ALT levels and stored as triglycerides or are utilized as a improve insulin sensitivity in overweight individuals.
substrate for oxidation by the cell’s mito-chondria. As a result of the normal pro- RESEARCH DESIGN AND METHODS — Eighty overweight individuals (BMI Ͼ27
cess of oxidation, reactive oxygen species kg/m2) were randomly allocated to receive either 800 IU vitamin E per day or a matching placebo for 3 months. The dose of vitamin E was increased to 1,200 IU per day for a further 3 months.
potentially harmful to cellular functions.
To prevent these harmful effects, the cell RESULTS — Plasma peroxides decreased by 27% at 3 months and by 29% at 6 months in the
group that received vitamin E and were positively correlated with plasma vitamin E concentra- tions at the 6-month time point. At 3 months, fasting plasma glucose and insulin concentrations idant concentrations are reduced in obese were significantly reduced and homeostasis model assessment increased. These changes werenot apparent at 6 months. Plasma ALT concentrations declined significantly throughout the between the production of ROS and anti-oxidant defenses results in oxidative CONCLUSIONS — In conclusion, these findings indicate that vitamin E improves oxidative
stress (10). Although the relationship be- stress and hepatocellular function. Although insulin resistance also improves, this effect appears tween oxidative stress and certain diabe- tes-related complications has been firmlyestablished (11), there is still uncertainty Diabetes Care 27:2166 –2171, 2004
concerning its role in the development ofinsulin resistance.
Theprevalenceofdiabetesisincreas- factorsisalteredintheobeseindividual inglucosehomeostasis,andhepaticinsu-
(3). Diabetes results when, in addition to lin sensitivity is of profound importance in determining fasting glucose concentra- that of obesity, with insulin resistance ex- occurs, leading to relative insulin defi- plaining the link between these two enti- ␥-glutamyl transferase (GGT) predict fu- responsible for insulin resistance remains ture risk of developing diabetes (12).
unclear, it would appear that a number of antioxidant activity. Systemic concentra- ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● From the 1Department of Medical and Surgical Sciences, Dunedin School of Medicine, University of Otago, individuals probably reflect nonalcoholic Dunedin, New Zealand; and the 2Department of Preventive and Social Medicine, Dunedin School of Med- fatty liver disease, which is itself a marker icine, University of Otago, Dunedin, New Zealand.
of insulin resistance (13). Whether anti- Address correspondence and reprint requests to Dr. Patrick J. Manning, Department of Medical and Surgical Sciences, University of Otago, Private bag, Dunedin, New Zealand. E-mail: patrickmanning@ Received for publication 4 April 2004 and accepted in revised form 15 June 2004.
tions in obese individuals is uncertain.
Abbreviations: ALT, alanine transferase; AST, aspartate aminotransferase; CRP, C-reactive protein; FFA,
free fatty acid; GGT, ␥-glutamyl transferase; HOMA, homeostasis model assessment; IL, interleukin; ROS, to improve insulin signaling in vitro (14) reactive oxygen species; TNF, tumor necrosis factor.
and improves glycemic control in individ- A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion 2004 by the American Diabetes Association.
DIABETES CARE, VOLUME 27, NUMBER 9, SEPTEMBER 2004 Manning and Associates
correlation coefficients were used to test insulin sensitivity and/or the other meta- for relationships between variables.
resistance. This study was designed to in- RESULTS — Six subjects dropped out
agnostic Laboratories, Dunedin Hospital.
from the study for personal reasons before RESEARCH DESIGN AND
METHODS — Eighty-six healthy sub-
characteristics of the remaining 80 partic- jects, aged 31– 65 years, with a BMI Ͼ27 cant differences existed in any variables (IL)-6 and tumor necrosis factor (TNF)-␣ centrations at baseline were Ͼ35 IU/l in 10, 7, and 14 subjects, respectively. Self- supplements, serious illness, and clinical that 55% of participants did not drink al- ric, health, and lifestyle information was collected. Participants gave informed and method is based on the cleavage of perox- the initial 3 months but gave blood at all ides by horseradish peroxidase, leading to randomization with stratification for sex count indicated that 84% of subjects dur- calibrator (Roche Diagnostics). As deter- Ͻ25 kg/m2) is 27.2 (21.7–48.5) pmol/l. during the study.
creased significantly in participants who cebo for a further 3 months. Subjects were ␣-tocopherol concentration was mea- were randomized to vitamin E treatment and did not change significantly in those receiving placebo (Fig. 1). Despite an in- the same assay to reduce interassay varia- crease in vitamin E dosage in the final 3 months of the study, circulating vitamin E plasma insulin, CRP, IL-6, TNF-␣, perox- searcher (W.H.F.S.), who did not interact index of insulin sensitivity was calculated (fasting glucose ϫ fasting insulin).
tion was carried out in blocks of six. Par- lifestyle changes during the study. Assess- Values are given as median (interquartile glucose, insulin, and peroxide concentra- tions were significantly less than zero and significantly greater than zero. Plasma tri- that accounted for the underlying covari- ance structure in the data and adjusted for the baseline measures was used to analyze variables were significantly different from for all variables, the results being reported tubes, the tubes were then centrifuged at 1,500g for 15 min at 4°C, and plasma and DIABETES CARE, VOLUME 27, NUMBER 9, SEPTEMBER 2004 Vitamin E and insulin resistance
Table 1—Characteristics of the subjects at baseline
39). After lipid standardization, the re-sults remained unchanged, although thecorrelation between baseline vitamin E statistically significant (r ϭ Ϫ0.120, CONCLUSIONS — Oxidative stress
studies but not all (20), antioxidant ther- type 2 diabetes (15,16). In addition, anti- reduced in individuals at increased risk of antioxidant therapy improves insulin sen- sitivity in nondiabetic individuals who are obese. Our results suggest that vitamin E improves insulin sensitivity and the asso- Data are median (interquartile range).
the magnitude of this improvement in in-sulin sensitivity, as indicated by fastinginsulin levels, depends on the magnitude of the increase in plasma vitamin E. It is was significantly correlated with the in- well established that fasting insulin and at 6 months (r ϭ Ϫ0.404, P ϭ 0.01, n ϭ sulin sensitivity and correlate well with 95% CIs, for plasma ALT, GGT, and ASTconcentrations at 3 months and 6 monthsare shown in Fig. 3. The differences forplasma ALT at 3 and 6 months were sig-nificantly different from zero. The corre-sponding differences for plasma GGT andAST were close to attaining statistical sig-nificance from zero.
body weight (P ϭ 0.77), BMI (P ϭ 0.87),blood pressure, and plasma concentra-tions of cholesterol, HDL cholesterol,HbA1c, CRP, IL-6, and TNF-␣ did notchange significantly in subjects receivingvitamin E compared with placebo duringthe study.
concentration was significantly correlatedwith the increase in plasma vitamin Econcentration during the initial 3 monthsof the study (r ϭ Ϫ0.235, n ϭ 80, P ϭ0.04). Plasma peroxide concentrationswere correlated significantly with plasmavitamin E concentration at baseline (r ϭ Figure 1—Plasma concentration of vitamin E in participants receiving vitamin E (f) or placebo Ϫ0.272, P ϭ 0.015, n ϭ 80). The de- (Ⅺ) during the study. Values are mean Ϯ SE. DIABETES CARE, VOLUME 27, NUMBER 9, SEPTEMBER 2004 Manning and Associates
dylinositol 3-kinase– catalyzed phos-phorylation of tyrosine residues in theseproteins, which is required for effectiveinsulin action. Recent evidence (28) sug-gests that vitamin E may influence the ac-tivity of these enzymes by decreasing thecurvature of plasma membranes.
glucose and insulin metabolism. It is themain site of insulin clearance from theblood (29). Animal studies (30) showthat genetic knockout of hepatic insulinreceptors results in severe insulin resis- tance, hyperinsulinemia, glucose intoler- ance, and severe hepatic dysfunction.
ated with hepatic insulin resistance (31) HOMA at 3 (Ⅺ) and 6 (f) and elevated levels of hepatic enzymes in the blood. Furthermore, in nondiabeticindividuals, plasma ALT is associated with percentage of body fat, hepatic insu- lin resistance, and hepatic glucose output in insulin sensitivity in elderly subjects protection by regulating intracellular lev- the cellular level that are not dependent on its antioxidant activity and may poten- output is the main determinant of fasting tially contribute to improved insulin ac- blood glucose levels. High-dose vitamin E onstrating this effect in obese nondiabetic els of plasma hepatic enzymes in patients with nonalcoholic fatty liver disease (33).
ates diacylglycerol kinase activity, thereby decreasing levels of diacylglycerol, which cose levels by decreasing cellular oxidant is an allosteric activator of protein kinase stress, altering membrane properties, and C (26). Increased protein kinase C activity possible that the concomitant decrease in fasting insulin and glucose levels may be phosphorylating serine or threonine resi- due to, at least in part, improved hepato- insulin resistance and glucose output.
in the chemical-physical state of plasmamembranes as a result of a decrease inoxidative stress. Red cell membrane fluid-ity decreased in association with a de-crease in the ratio of serum oxidized toreduced glutathione and concomitantlywith an increase in insulin sensitivity dur-ing 4 months of vitamin E treatment inelderly subjects (22). In addition, in-creased vitamin E may enhance the en-dogenous cellular antioxidant defensesystem and reduce levels of ROS that areproduced by mitochondria. IncreasedFFA levels may overload the mitochon-drial oxidation process, leading to accel-erated production of ROS (7) andincreased oxidant stress in obese individ- Figure 3—Treatment-placebo differ- uals (10). Peroxides are ROS and interfere ence and 95% CIs for plasma ALT, GGT, with insulin signaling (24). In the present and AST activities at 3 (Ⅺ) and 6 (f) DIABETES CARE, VOLUME 27, NUMBER 9, SEPTEMBER 2004 Vitamin E and insulin resistance
cient evidence to exclude a clinically im- portant effect of vitamin E, and a larger sulin resistance. Studies from our labora- study is required to clarify this issue.
incidence of type 2 diabetes with lifestyle described as being associated with insulin intervention or metformin. N Engl J Med346:393– 403, 2002 5. Tuomilehto J, Lindstrom J, Eriksson JG, associations have given rise to the meta- jects in this study did not necessarily meet the effects of vitamin E on its component tion, during vitamin E supplementation.
tes mellitus by changes in lifestyle among These findings suggest that changes in in- an improvement in insulin sensitivity, we subjects with impaired glucose tolerance.
N Engl J Med 344:1343–1350, 2001 triglycerides at 3 months. This effect had 6. Buchanan TA, Xiang AH, Peters RK, Kjos sitivity noted during vitamin E treatment.
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