Effects of 8-Week Vitamin E (α Tocopherol) Supplementation on

Reduced Insulin Resistance in Non-diabetic Obese Subjects



Erlina Marfianti

, Isnatin Miladiyah

Internal Medicine Department, Faculty of Medicine, Universitas Islam Indonesia, Sleman Yogyakarta, Indonesia

Pharmacology Department, Faculty of Medicine, Islamic Universitas Islam Indonesia, Sleman Yogyakarta, Indonesia

Keywords: Vitamin E, Obesity, Non-Diabetic, Insulin Resistance

Abstract: Obesity is a risk factor for diabetes mellitus (DM) and coronary heart disease. In obesity, oxidative stress and

adipokine hormone increase, leading to insulin resistance (IR) which can develop into DM. Vitamin E is an

antioxidant that is expected to lower IR. This study aims to determine the effects of 8-week supplementation

of vitamin E on reducing IR in non-diabetic obese subjects. The design was PROBE (Prospective Randomized

Open Blinded End-point). The subjects were ≥18 years old with ≥25 kg/m

body mass index and HOMA-IR

value >2.7 The exclusion criteria were DM patients and those taking metformin or antioxidants. Twenty

subjects in group A received 800 IU Vitamin E supplementation while 20 subjects in group B received

placebo, both for 8 weeks. Reduced IR was measured from the decreasing HOMA-IR value after 8 weeks.

The difference in decreasing HOMA-IR value between both groups was analyzed using independent t-test.

The mean in group A was 0.199 ± 0.336, while group B had - 0.078 ± 0.271. The between both groups was

statistically significant, with p = 0.004, 95% CI (0.096-0.457. Supplementation of 800 UI Vitamin E for 8

weeks could decrease IR in obese non-diabetic subjects.

1 INTRODUCTION

The prevalence of obesity has increased rapidly due

to lifestyle and diet changes, making it a global

problem in developed and developing countries.

Obesity is a complex, multifactorial, and mostly

preventable disease. The population with obesity and

overweight problems currently reaches more than a

third of the world's population. If secular trends

continue, it is estimated that 38% of the world's adult

population will be overweight, and another 20% will

be obese by 2030 (Chooi et al., 2019). Obesity

represents a significant health challenge because it

substantially increases the risk of diseases, such as

type-2 diabetes mellitus, fatty liver disease, and

cardiovascular disease, thereby contributing to a

decline in quality of life and life expectancy

(González-Muniesa et al., 2017). The risk of type-2

diabetes mellitus will increase significantly and

progressively in line with the increase in body mass

index and the duration of obesity (Cederberg &

Laakso, 2014).

https://orcid.org/0000-0001-8473-2820

https://orcid.org/0000-0003-1630-7130

World Health Organization (WHO) defines

overweight as BMI (body mass index) of 23-24.9

kg/m

and obesity as BMI of ≥25 kg/m

in the Asia-

Pacific population

(Purnamasari et al., 2014). In

obesity, oxidative stress and adipokines increase, and

they are responsible for the incidence of insulin

resistance (Hurrle & Hsu, 2017). A previous study

found that the prevalence of insulin resistance in

obese people was 59.6%. Insulin resistance, a process

of decreasing insulin sensitivity, is determined using

HOMA-IR (Homeostatic Model Assessment of

Insulin Resistance) values of >2.7. Insulin resistance

is a metabolic disorder with a negative impact of

underlying diabetes mellitus and cardiovascular

disorders (Reynolds & He, 2005). In obese people, an

increase in non-esterified fatty acids, glycerol,

adipokine hormones, cytokines, pro-inflammatory

markers, and other substances are associated with

insulin resistance.

Epidemiological, clinical, and animal studies have

reported the role of oxidative stress in the

pathogenesis of obesity and its associated related

104

Marﬁanti, E. and Miladiyah, I.

Effects of 8-Week Vitamin E ( Tocopherol) Supplementation on Reduced Insulin Resistance in Non-diabetic Obese Subjects.

DOI: 10.5220/0010488501040108

In Proceedings of the 1st Jenderal Soedirman International Medical Conference in conjunction with the 5th Annual Scientiﬁc Meeting (Temilnas) Consortium of Biomedical Science Indonesia

(JIMC 2020), pages 104-108

ISBN: 978-989-758-499-2

conditions, including insulin resistance. Obesity can

also induce systemic oxidative stress through

multiple biochemical mechanisms, such as

superoxide generation from NADPH oxidases

(NOX), oxidative phosphorylation, glyceraldehyde

auto-oxidation, and protein kinase C (PKC) activation

(Savini et al., 2013). Other factors contributing to

oxidative stress due to obesity include increased free

fatty acid, hyperleptinemia,

tissue dysfunction,

low

antioxidant defence, and chronic inflammation

(Serra

et al., 2013). In obesity, free fatty acids that enter the

target organs are stored as triglycerides or used as a

substrate for the oxidation of mitochondrial cells to

produce ROS (Reactive Oxygen Species). Reactive

Oxygen Species causes oxidative stress which has the

potential to damage cellular functions. To prevent

these damaging effects, the cells create a complex

antioxidant system to eliminate ROS (Serra et al.,

2013). In obese people, however, antioxidants'

concentration decreases, causing an imbalance in

ROS production and antioxidants that prevent

oxidative stress (Manna & Jain, 2015). Deficiencies

in vitamins and minerals can also contribute to the

development of an impaired antioxidant defence in

obesity. Increased BMI is found to be correlated with

lower levels of carotenoids, vitamin C, and vitamin

E. In obesity, oxidative stress is thought to be one of

the factors causing insulin resistance and developing

diabetes mellitus (McMurray et al., 2016).

Vitamin E is a major fat-soluble component in the

cell's antioxidant defence system and is obtained

exclusively from food. It has many essential roles in

the metabolic system due to its antioxidant activity.

Vitamin E is also a potent chain-breaking antioxidant

that inhibits molecules of reactive oxygen species'

production when fat is oxidized

(Rizvi et al., 2014).

Such antioxidant is known to have the effect of

preventing free radicals that can adversely affect and

damage cells (Han, 2016)

Previous studies of vitamin E's effects to reduce

insulin resistance have been controversial as the

results were inconsistent. A study by Manning et al.

(2004) showed that the effects of high doses of

vitamin E are associated with decreased insulin

resistance and several inflammatory parameters,

including FFA, in the overweight population

(Manning et al., 2004). Another study by Balbi et al.

(2018) found that Vitamin E correlates with a

significant reduction in blood glucose and glycated

hemoglobin compared to placebo in Type-2 DM

patients (Balbi et al., 2018). A previous study

indicated that the combination of vitamins C, E, and

β-carotene during an 8-week supplementation

moderately reduces HOMA-IR values in overweight

young adults. Oxidative stress also decreases and may

become a potential mechanism underlying such

favorable changes in cardiovascular disease and

precursors of diabetes

(Vincent et al., 2009). Several

studies, however, do not support the role of vitamin E

in improving insulin sensitivity. An animal study

found that vitamin E supplementation in obese

rodents does not improve insulin sensitivity but

changes mitochondrial biogenesis and mitochondrial

protein expression (Picklo & Thyfault, 2015). Since

vitamin E's role in insulin resistance remains unclear,

this study aims to determine the effects of vitamin E

on reduced insulin resistance in the obese population

without diabetes mellitus.

2 MATERIAL AND METHODS

2.1 Research Design

This study was conducted with a clinical trial design

of prospective randomized open and blinded endpoint

evaluation (PROBE). In PROBE, the researcher

knows the patients' medication but not the patients'

final evaluation (laboratory results).

2.2 Subjects and Methods

Forty subjects aged 18-65 with a BMI of ≥25 kg/m2

and HOMA-IR of >2.7 (insulin resistance) were

recruited from community populations using an open

recruitment method. The exclusion criteria were

diabetes mellitus patients and candidates using

metformin or TZD drugs and antioxidant

supplements during the last one month. The

independent variable was the vitamin E therapy, and

the dependent variable was HOMA-IR. The required

number of subjects was calculated using the formula

for unpaired numerical analytic research (Dahlan,

2010).

The subjects received a clinical examination,

and the anthropometric, health, and lifestyle

information was collected. The participants agreed

and signed informed consent, and they were

randomized into two groups, namely group A that

received 800 IU Vitamin E supplementation, and

group B, that received placebo.

The subjects were instructed to take vitamin E

and placebo with meals. Vitamin E at a dose of 800

IU was given twice a day in a capsule form containing

Vitamin E (alpha-tocopherol) maleate. The placebo

used was a capsule containing flour with a shape

similar to a capsule containing Vitamin E and also

given twice a day. The supplementation was carried

Effects of 8-Week Vitamin E ( Tocopherol) Supplementation on Reduced Insulin Resistance in Non-diabetic Obese Subjects

105

out for 8 weeks, and HOMA-IR was measured before

and after 8 weeks of 800 IU Vitamin E

supplementation or placebo. The participants were

instructed not to make lifestyle changes during the

study. In the course of the supplementation, the

participants reported their conditions and complaints

to the researcher.

2.3 Blood Sampling

Fasting blood samples were collected using a catheter

from an antecubital vein into heparinized vacutainer

tubes before and after supplementation. The blood

samples were then analyzed for glucose, insulin,

cholesterol, and triglycerides of pre-supplementation

and glucose and insulin of post-supplementation. All

of the samples were batched within each subject and

run in the same assay. The homeostasis model

assessment (HOMA) was calculated from the fasting

glucose (G

) and insulin (I

) concentrations using the

following formula: (G

X I

)/ 22.5.

2.4 Statistics

All of the data were expressed in mean ± standard

error (SE) and analyzed using a Statistical Package

for Social Sciences. The differences in the mean

reduced HOMA-IR values (insulin resistance

reduction) after 8 weeks of treatment in the two

groups were analyzed using the independent t-test

with a significance level of p <0.05. and a 95%

confidence level.

2.5 Ethical Consideration

This study kept the confidentiality of the patients and

performed all procedures according to the study

ethics. The research approval was obtained from the

ethical review committee of Faculty of Medicine

Universitas Islam Indonesia for biomedical studies

involving human subjects and written informed

consent was taken from the subjects.

3 RESULTS

Forty subjects who met the inclusion and exclusion

criteria were randomized into two groups: twenty

subjects in group A (Vitamin E) and 20 subjects in

group B (placebo). The subjects consisted of 17 men

and 23 women. Table 1 shows the baseline

characteristics of the 40 subjects in this study. No

significant differences existed in the variables of age,

weight, BMI, systolic blood pressure, diastolic blood

pressure, fasting glucose levels, fasting insulin levels,

HOMA-IR, and cholesterol levels between the two

groups at the baseline.

Table 2 shows the HOMA-IR levels before and

after supplementation in the two groups. HOMA IR-

values after the supplementation of 800 IU vitamin E

for 8 weeks decreased significantly (p = 0.04).

Meanwhile, Group B had increased HOMA-IR after

receiving the placebo, although it was not significant

with p = 0.08. A decrease in HOMA-IR values

indicates insulin resistance reduction. Table 3 shows

the mean HOMA-IR reduction differences after 800

IU vitamin E and placebo supplementation for 8

weeks between the two groups.

Table 3 indicates a significant difference in the

decreased HOMA-IR values between group A

receiving vitamin E supplementation and group B

receiving placebo. In Group B, the HOMA-IR value

increased as opposed to the baseline. This significant

difference in decreased HOMA-IR values indicates

that Vitamin E supplementation can lower insulin

resistance than placebo.

4 DISCUSSION

Oxidative stress has been implicated in the

development of insulin resistance, and in some

studies, antioxidant therapy has proved to reduce

ROS and improve glycemic control in people with

type-2 diabetes. Besides, antioxidant concentrations

significantly decrease in individuals with obesity

(Manning et al., 2004)

Table 2: HOMA-IR Levels before and after Supplementation Vitamin E and Placebo

Variable

Group A (Vitamin E) Group B (Plasebo)

Before Afte

* Before Afte

HOMA IR

3.070±0.630

2.871±0.430

0,04

3.081±0.856

3.158±0.534

0,08

* anal

sis of differences in the mean levels before and after thera

usin

aired t-test

JIMC 2020 - 1’s t Jenderal Soedirman International Medical Conference (JIMC) in conjunction with the Annual Scientiﬁc Meeting

(Temilnas) Consortium of Biomedical Science Indonesia (KIBI )

106

However, it remains unknown whether

antioxidant therapy improves insulin sensitivity in

non-diabetic obese individuals. Our results suggest

that 800 IU vitamin E supplementation for 8 weeks

can reduce insulin resistance condition in obese

people in conjunction with decreased HOMA-IR.

This study is in line with some findings of

previous studies. Research by Manning et al. (2004)

showed the effects of high doses of vitamin E on

reducing insulin resistance and several inflammatory

parameters, including FFA in the overweight

population. The reduced insulin resistance after the

administration of high doses of vitamin E has an 18%

difference from placebo treatment. A meta-analysis

study by Balbi et al. (2018) indicated that Vitamin E

is associated with a significant decrease in blood

glucose as well as glycated hemoglobin compared to

placebo. Supplementation of vitamin E can be a

valuable strategy for controlling diabetes

complications and enhancing antioxidant capacity.

Supplementation of vitamin E in obesity and type-

2 diabetes mellitus can significantly impact the

parameters of antioxidant status and glycemic

control, which may positively benefit patients. The

beneficial effects of vitamin E can be explained by

the reduced damaging effects of free radicals on the

structural and functional components of cells and

vessel walls. Type-2 diabetes mellitus patients have a

high risk of experiencing microvascular and

macrovascular complications, and daily vitamin E

supplementation provides an alternative strategy for

metabolic control, in addition to the combination of

diet, exercise, and medication (Balbi et al., 2018).

A previous study also showed that a combination

of vitamins C, E, and β-carotene during an 8-week

supplementation period moderately reduces HOMA-

IR values in overweight young adults (Vincent et al.,

2009). In animal subjects studies, vitamin E

supplementation can improve adipose tissue

expansion through a reduction in the fibrotic process.

This improvement, in turn, reduces steatosis and

inflammation, thereby restoring insulin sensitivity.

The mechanism may involve, although not

exclusively, vitamin E antioxidant activity, thus

reducing ROS-mediated collagen deposition and

inflammation (Alcalá et al., 2015). A review by

Wong et al. (2017) summarized the findings in animal

and human studies of the effects of vitamin E and

articulated the contrasting potential of vitamin E in

preventing the medical conditions associated with

obesity and metabolic syndrome. It suggests that

vitamin E may be a promising agent for attenuating

obesity and metabolic syndrome (Wong et al., 2017).

These previous studies support our findings that

vitamin E has a potential mechanism in vitamin E-

induced metabolic improvement, including insulin

resistance reduction in obesity.

However, some previous research had different

results, such as a study by Picklo et al. (2015) which

showed that vitamin E and vitamin C

supplementation in obese rodents do not modify

exercise-induced insulin sensitivity improvement.

Changes in mitochondrial biogenesis and

mitochondrial protein expression may be modified by

antioxidant supplementation (Picklo & Thyfault,

2015). A study of obese adolescents by Hendarto et

al. (2019) found that vitamin E supplementation at a

dose of 400 IU/day for two months does not

significantly affect lipid profiles and adiponectin

levels (Hendarto et al., 2019).

This study has limitations in terms of a limited

number of subjects and design. In addition, the

confounding factors that could affect the level of

HOMA-IR in the study samples were not fully

controlled, thereby suggesting the importance of

performing a study with a larger number of samples

and a better study design. We strongly recommend

that further well-designed, large-scale, long-term,

head-to-head controlled trials and meta-analyses be

carried out to demonstrate the effects of vitamin E

supplementation on non-diabetes mellitus obesity.

Further studies should also be conducted to

strengthen this evidence, especially for defining the

appropriate doses and regimen of vitamin E and

supporting its use in daily practice.

5 CONCLUSION

The supplementation of 800 UI Vitamin E for 8

weeks can reduce insulin resistance in obese people

without diabetes mellitus. This finding may represent

a step forward in disease management.

ACKNOWLEDGEMENTS

We want to thank the Faculty of Medicine, the

Islamic University of Indonesia for supporting this

research.

Table 3:Mean levels of reduction in plasma HOMA-

IR after supplementation

Group A

(

Vitamin E

)

Group B

(

Plasebo

)

HOMA IR 3.070±0.630 2.871±0.430 0,04

*analysis using independent t test

Effects of 8-Week Vitamin E ( Tocopherol) Supplementation on Reduced Insulin Resistance in Non-diabetic Obese Subjects

107

REFERENCES

Alcalá, M., Sánchez-Vera, I., Sevillano, J., Herrero, L.,

Serra, D., Ramos, M. P., & Viana, M. (2015). Vitamin

E reduces adipose tissue fibrosis, inflammation, and

oxidative stress and improves metabolic profile in

obesity. Obesity. https://doi.org/10.1002/oby.21135

Balbi, M. E., Tonin, F. S., Mendes, A. M., Borba, H. H.,

Wiens, A., Fernandez-Llimos, F., & Pontarolo, R.

(2018). Antioxidant effects of vitamins in type 2

diabetes: A meta-analysis of randomized controlled

trials. Diabetology and Metabolic Syndrome.

https://doi.org/10.1186/s13098-018-0318-5

Cederberg, H., & Laakso, M. (2014). Obesity and type 2

diabetes. In Handbook of Obesity: Epidemiology,

Etiology, and Physiopathology, Third Edition.

https://doi.org/10.4236/jdm.2011.14012

Chooi, Y. C., Ding, C., & Magkos, F. (2019). The

epidemiology of obesity. Metabolism: Clinical and

Experimental.

https://doi.org/10.1016/j.metabol.2018.09.005

Dahlan, M. S. (2010). Besar Sampel dan Cara Pengambilan

Sampel dalam Penelitian Kedokteran dan Kesehatan. In

Salemba Medika.

González-Muniesa, P., Mártinez-González, M. A., Hu, F.

B., Després, J. P., Matsuzawa, Y., Loos, R. J. F.,

Moreno, L. A., Bray, G. A., & Martinez, J. A. (2017).

Obesity. Nature Reviews Disease Primers.

https://doi.org/10.1038/nrdp.2017.34

Han, C. Y. (2016). Roles of reactive oxygen species on

insulin resistance in adipose tissue. Diabetes and

Metabolism Journal, 40(4), 272–279.

https://doi.org/10.4093/dmj.2016.40.4.272

Hendarto, A., Alhadar, A. K., & Sjarif, D. R. (2019). The

Effect of Vitamin E Supplementation on Lipid Profiles

and Adiponectin Levels in Obese Adolescents: A

Randomized Controlled Trial. Acta Medica

Indonesiana.

Hurrle, S., & Hsu, W. H. (2017). The etiology of oxidative

stress in insulin resistance. In Biomedical Journal.

https://doi.org/10.1016/j.bj.2017.06.007

Manna, P., & Jain, S. K. (2015). Obesity, Oxidative Stress,

Adipose Tissue Dysfunction, and the Associated Health

Risks: Causes and Therapeutic Strategies. Metabolic

Syndrome and Related Disorders, 13(10), 423–444.

https://doi.org/10.1089/met.2015.0095

Manning, P. J., Sutherland, W. H. F., Walker, R. J.,

Williams, S. M., De Jong, S. A., Ryalls, A. R., & Berry,

E. A. (2004). Effect of high-dose vitamin E on insulin

resistance and associated parameters in overweight

subjects. Diabetes Care, 27(9), 2166–2171.

https://doi.org/10.2337/diacare.27.9.2166

McMurray, F., Patten, D. A., & Harper, M. E. (2016).

Reactive Oxygen Species and Oxidative Stress in

Obesity—Recent Findings and Empirical Approaches.

In Obesity. https://doi.org/10.1002/oby.21654

Picklo, M. J., & Thyfault, J. P. (2015). Vitamin E and

vitamin C do not reduce insulin sensitivity but inhibit

mitochondrial protein expression in exercising obese

rats. Applied Physiology, Nutrition and Metabolism.

https://doi.org/10.1139/apnm-2014-0302

Purnamasari, D., Badarsono, S., Moersadik, N., Sukardji,

K., & Tahapary, D. (2014). Identification, Evaluation

and Treatment of Overweight and Obesity in Adults:

Clinical Practice Guidelines of the Obesity Clinic,

Wellness Cluster Cipto Mangunkusumo Hospital,

Jakarta, Indonesia. Journal of the ASEAN Federation of

Endocrine Societies.

https://doi.org/10.15605/jafes.026.02.06

Reynolds, K., & He, J. (2005). Epidemiology of the

metabolic syndrome. American Journal of the Medical

Sciences. https://doi.org/10.1097/00000441-

200512000-00004

Rizvi, S., Raza, S. T., Ahmed, F., Ahmad, A., Abbas, S., &

Mahdi, F. (2014). The role of Vitamin E in human

health and some diseases. Sultan Qaboos University

Medical Journal, 14(2), 157–165.

Savini, I., Catani, M. V., Evangelista, D., Gasperi, V., &

Avigliano, L. (2013). Obesity-associated oxidative

stress: Strategies finalized to improve redox state. In

International Journal of Molecular Sciences.

https://doi.org/10.3390/ijms140510497

Serra, D., Mera, P., Malandrino, M. I., Mir, J. F., & Herrero,

L. (2013). Mitochondrial fatty acid oxidation in obesity.

In Antioxidants and Redox Signaling.

https://doi.org/10.1089/ars.2012.4875

Vincent, H. K., Bourguignon, C. M., Weltman, A. L.,

Vincent, K. R., Barrett, E., Innes, K. E., & Taylor, A.

G. (2009). Effects of antioxidant supplementation on

insulin sensitivity, endothelial adhesion molecules, and

oxidative stress in normal-weight and overweight

young adults. Metabolism: Clinical and Experimental.

https://doi.org/10.1016/j.metabol.2008.09.022

Wong, S. K., Chin, K.-Y., Suhaimi, F. H., Ahmad, F., &

Ima-Nirwana, S. (2017). Vitamin E As a Potential

Interventional Treatment for Metabolic Syndrome:

Evidence from Animal and Human Studies. Frontiers

in Pharmacology, 8, 444.

https://www.frontiersin.org/article/10.3389/fphar.2017

.00444

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