A review on role of antioxidants in diabetes

Abstract

Diabetes mellitus is a chronic metabolic disease. Oxidative stress plays a major part in the pathogenesis of diabetes. Supplementation with antioxidants and the medicinal plants which possess antioxidants activity have been reported their hypoglycemic activity. The antioxidants are used to treat and reduce the complication of diabetes mellitus. The diet supplementations of antioxidants vitamins are beneficial in the treatment of diabetes. This review article was summarizing the role of antioxidants in diabetes mellitus.

Full text

Vol 11, Issue 2, 2018
Online - 2455-3891
Print - 0974-2441
A REVIEW ON ROLE OF ANTIOXIDANTS IN DIABETES
DEEPA RAJENDIRAN1,2, SUBBULAKSHMI PACKIRISAMY3, KRISHNAMOORTHY GUNASEKARAN4*
1Department of Biochemistry, Research and Development Centre, Bharathiar University, Coimbatore, Tamil Nadu, India. 2Department of
Biochemistry, Madha Dental College and Hospital, Kundrathur, Chennai, Tamil Nadu, India. 3Department of Pharmacology, Meenakshi
Ammal Dental College and Hospital Maduravoyal, Chennai, Tamil Nadu, India. 4Department of Biochemistry, Rajas Dental College and
Hospital, Kavalkinaru Junction, Tirunelveli, Tamil Nadu, India. Email: krishgunabio@gmail.com
Received: 23 October 2017, Revised and Accepted: 15 November 2017
ABSTRACT
Diabetes mellitus is a chronic metabolic disease. Oxidative stress plays a major part in the pathogenesis of diabetes. Supplementation with antioxidants
and the medicinal plants which possess antioxidants activity have been reported their hypoglycemic activity. The antioxidants are used to treat and
reduce the complication of diabetes mellitus. The diet supplementations of antioxidants vitamins are beneficial in the treatment of diabetes. This
review article was summarizing the role of antioxidants in diabetes mellitus.
Keywords: Antioxidants, Diabetes mellitus, Oxidative stress, Medicinal plants.
INTRODUCTION
Diabetes mellitus is an insistent metabolic disorder characterized
by an aberrantly upraised level of blood glucose due to the deficit in
insulin secretion by the β-cells of the pancreas and/or resistance
toward the exploit of hormone insulin associated with disturbances
in the carbohydrates, lipids, and proteins metabolism which leads to
long-term complications. International Diabetes Federation conferring
371 million people affected by diabetes and the number likely to
elevate 552 million by 2030. Based on the previous experimental and
clinical studies recommend that oxidative stress plays a main role in the
pathogenesis of diabetes. This article reviews the role of antioxidants
in diabetes [1].
FREE RADICALS
Free radicals are a molecule with one or more single pair of the electron
that can quickly react with the constituents such as proteins, nucleic
acid, and lipids. The reactive molecule comprises the reactive oxygen
species (ROS) and reactive nitrogen species was derived from oxygen
and nitrogen, respectively. These reactive particles are generated in
cellular membrane, mitochondria, nucleus, lysosome, peroxisome,
endoplasmic reticulum, and cytoplasm. The enhanced generation of the
reactive species associated with hyperglycemia [2].
OXIDATIVE STRESS AND DIABETES
Oxidative stress plays a key role in the development of wide range of
diseases including cancer, cardiovascular disease, diabetes, aging, liver,
and lung diseases. Oxidative stress due to an imbalance between radical
engendering and radical scavenging systems. Previous experimental
studies have been reported overproduction of free radicals and defect
of antioxidants protection involved pathogenesis of diabetes [3]. The
mechanism behind the prooxidant-antioxidant imbalance in diabetes
mellitus is auto-oxidation of glucose, increased the formation of
advanced glycation end products (AGEs), polyol pathway, hexosamine
pathway, and mitochondrial respiratory chain. The enzymatic source of
free radical generation includes nitric oxide synthase, NADPH oxidase,
and xanthine oxidase [4].
CHEMICAL CAUSES OF DIABETES
In most of the animal research, the chemicals or drug is used for the
induction of diabetes. The well-known chemical compound used in
diabetic research is alloxan; it is a toxic compound which destroys the
beta-cells of the pancreas. In previous research, alloxan used to induce
type 1 diabetes in animals such as rat, mice, and rabbits. Nowadays,
instead of alloxan, streptozotocin used for induction of Types 1 and 2
diabetes due to their toxicity and instability [5].
Streptozotocin is a glucosamine nitrosourea compound has a chemical
name of 2-deoxy-2(methyl nitrosamino)carbonyl)amino)-D-glucose
derived from a fermentation broth of Streptomyces achromogenes. It
is toxic glucose analog generally used to induce experimental diabetes.
Rakieten et al. [6] were the first to demonstrate that STZ-induced
diabetes in an animal model. Based on the previous experimental
model, it is frequently used single intravenous dose between 40 and
60 mg/kg of body weight [7].
The streptozotocin enters into the beta-cells of pancreas through
glucose transporter 2 (GLUT 2). The mechanism behind the
streptozotocin action in the beta-cell is DNA alkylation due to the
presence of methyl nitrosourea moiety. Transfer of methyl group
from streptozotocin to DNA cause damage, resulting in the formation
of DNA fragmentation [8]. However, the synergistic action of nitric
oxide and ROS it may contribute beta-cell destruction. The damage to
DNA activates poly ribosylation; it leads to depletion of NAD and ATP
eventually may lead to beta-cell death [9].
ANTIOXIDANTS
Antioxidants are substances able to slow or inhibit the oxidation of
other molecules. Recently, the medicinal field focused the antioxidants
therapy in the management of numerous diseases, especially diabetes.
Preceding experimental studies and clinical trials have suggested
the efficacy of antioxidants in preventing diabetes complication. The
therapeutic strategy uses the antioxidants as a substrate, combined
drug, synthetic antioxidants, and drug with antioxidants activity. In
general, the medicinal plants with antioxidants activity are considered
for the treatment of diabetes mellitus [10].
ROLE OF ANTIOXIDANTS IN DIABETES
The antioxidants therapy defends the beta-cell against oxidative stress-
induced apoptosis and preserves the function of the beta-cell. Data
from earlier studies show the antioxidants diminish diabetic-related
complication and recover insulin sensitivity. Epidemiological studies
© 2018 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons.
org/licenses/by/4. 0/) DOI: http://dx.doi.org/10.22159/ajpcr.2018.v11i2.23241
Review Article

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revealed a strong association between the dietary antioxidants intake
and protection against diabetes.
Vitamin E
It is naturally occurring lipophilic antioxidant exists as tocopherol
and tocotrienol. It defends the cell against oxidative damage. It is
believed Vitamin E playing a key role in controlling hyperglycemia,
and the combined antioxidants therapy also considered for control and
prevention of diabetic complication. The studies in an animal model
have shown supplementation of Vitamin E decreases the hepatic lipid
peroxide level in streptozotocin-induced diabetes [11]. However, the
increased level of lipid peroxide due to change of antioxidant status in
the diabetic rat.
Dietary vitamin and administration of Vitamin E positively associated
with glucose concentration. The level of glucose significantly decreased
and the OGGT improved in diabetic condition by supplementation of
Vitamin E [12]. During diabetic condition, the antioxidant enzymes SOD,
CAT, and GPX decreased. However, the oral administration of Vitamin E
(440 mg/kg of body weight, once a week for 30 days) significantly
increased SOD and GSH-Px activity and decreased the hydroperoxide
level due to an improvement of glycemia [13].
During diabetic condition, the excess glucose attached to hemoglobin to
produce glycosylated hemoglobin. It is an important marker for diabetes
which is prevented Vitamin E treated rat in diabetic condition [14].
Vitamin E has been shown to controls hyperglycemia and lowering
the HbA1c by inhibiting the sequence of oxidative stress in diabetic
rats [15]. The mechanism by which antioxidants reduced the glucose
levels not yet clear, but the plasma glucose level decreased by increasing
the glucose metabolism in peripheral tissues [16]. Supplementation
of Vitamin E (1800IU/day) showed that the serum level of Vitamin E
increases in Type 1 diabetes and control rats, whereas the retinal blood
flow significantly increased and elevated baseline creatinine clearance
normalized, but the HbA1C level not affected in the same experiment. It is
achieved by unchanged glycemic control and normalization of DAG/PKC
pathway through activation of DAG kinase in diabetic patients [17].
In synergy with β-carotene and Vitamin C, it is reduced the risk of
diabetes and cancer. The antioxidant property of Vitamin E associated
with the prevention of hyperglycemia and minimizes the macrovascular
and microvascular complications in individuals with diabetes [18].
Vitamin C
It is powerful antioxidants scavenging free radicals in aqueous
compartment. It is essential to convert Vitamin E free radicals to
Vitamin E, as a cofactor required for hydroxylation reaction in human.
The most important function of Vitamin C is key chain-breaking
antioxidants in the aqueous phase. It provides stability to the cell
membrane.
The research conducted by Yazd Diabetes Research Center, Iran, has
been reported that totally 84 diabetic patients received 500 mg or
1000 mg of ascorbic acid daily for 6 weeks. The daily consumption of
1000 mg of Vitamin C may be beneficial in reducing blood glucose level
and lipids, whereas 500 mg not significantly made any change during
the parameter studied [19].
Eriksson and Kohvakka studied the effect of Vitamin C supplementation
(2 g/day for 90 days) in 56 diabetic patients; the result has shown the
high-dose supplementation reduced the level of fasting blood glucose,
HbA1c and improve glycemic control [20]. Frequent intake of Vitamin C
dietary source was found to decrease the risk of Type 2 diabetes in a
population-based study [21].
Administration of Vitamin C and E (100 mg/kg of body weight of rat)
significantly reduced the blood glucose level [22]. However, lowered
level of ascorbic acid and SOD observed in the diabetic subject when
compared to the non-diabetic person [23]. The increased level of
Vitamin C in diabetes may due to increased utilization in trapping the
oxyradicals. Some of the studies have been reported that diabetes may
result in decreased plasma Vitamin C and E due to increased oxidative
stress [24].
The mechanism behind the treatment of diabetes is not clear. However,
it diminishes the microalbuminuria, erythrocyte sorbitol levels and
plays a chief role in ameliorating insulin resistance of diabetic patients
due to its antioxidant function [25,26].
Alpha-lipoic acid
A potent antioxidant, it is also known as 1, 2-dithiolane-3-pentanoic
acid or thioctic acid.
Alpha-lipoic acid fights cellular injuries triggered by free radicals, those
unstable, highly reactive molecules that are derivatives of both normal
and frazzled cell activity. It has a capability to restore endogenous
antioxidants such as glutathione, Vitamin E, and Vitamin C. It is effective
in many pathological conditions such as cardiovascular disease,
diabetes mellitus, and liver disease [27,28].
Alpha-lipoic acid has been reported to progress glucose metabolism
in Type 2 diabetes mellitus patient by directly activate lipid, tyrosine,
and serine/threonine kinases in target cells, due to these mechanisms
which stimulate glucose uptake and glycogenesis. In vitro studies have
reported that the alpha-lipoic acid increases the translocation of GLUT1
and GLUT4 to the plasmatic membrane of adipocytes and skeletal
muscle. It is related to an improved activity of proteins of insulin
signaling pathway [29].
Budin et al. [30] had reported that the intake of ALA reduced the
glucose level and total cholesterol in STZ-induced diabetes in rats. It
also regenerates the other antioxidants such as Vitamin C, Vitamin E,
and SOD in diabetic condition. The same results have been previously
reported in experimental animals [31].
Jacob et al. have been reported that the administration of 500 mg of ALA
in Type 2 diabetes patients for 10 days shown a significant increase of
insulin-stimulated glucose disposal (30%) and no changes observed in
fasting plasma glucose level or insulin. In the clinical study, 20 patients
received 500 mg, it able to improve insulin resistance in NIDDM [32].
Same results were obtained by chronic administration (100 mg/kg) of
antioxidant in type 2 diabetes mellitus [33].
In another study, the oral supplementation ALA (600 mg twice daily for
4 weeks) treatment which increases the plasma insulin sensitivity [34].
According to Packer et al., ALA is capable to scavenge ROS produced
during the lipid peroxidation and guards the cell structure against
damage. The continued supplementations of the LA in diabetic rats
were associated with diminution of both hyperglycemia and diabetic
nephropathy [35].
Selenium
It is important trace element, naturally present in many foods. It exists
in organic and inorganic forms. Selenomethionine and selenocysteine
belong to organic form; selenate and selenite are inorganic forms.
Mostly the inorganic selenite presents in the soil. Selenium plays a major
role in thyroid hormone metabolism and immune functions. Based on
previous experimental and clinical studies, selenium focused on the
prevention of many diseases due to their antioxidant activity [36].
Previously, selenium was found as a toxic component due to Se
poisoning in animals and humans, thereafter, it was recognized as
essential element since selenium deficiency considered a major
problem in animal and human [37]. The supplementation of selenium
with low doses has a beneficial effect on glucose metabolism, which
mimics insulin-like actions in the animal experimental model. While
the mechanism behind the mimicking insulin is not clear, however, the
previous report showed that Se activates the key protein responsible
for insulin signal cascade [38].

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The inorganic selenium compound sodium selenate and sodium
selenite involved in insulin signaling cascade by activation of kinases. In
animal experimental studies shown selenate stimulate glucose uptake
and involved phosphorylation of insulin receptor and insulin receptor
substrate 1 [39,40] and the oral administration or intraperitoneal
injection of daily doses of selenate for 3-8 weeks in streptozotocin-
induced diabetic rat, the result shown that the raised glucose level to
be reduced [41,42].
In another study stated the above-mentioned insulin-like activity of
selenium due to increased glucose tolerance and alteration in the
activity of gluconeogenic and glycolytic maker enzyme. In the same
way, selenomethionine also studied their antioxidant activity in a
diabetic animal, supplementation of selenomethionine, Vitamin E
plus selenomethionine in type I diabetic rat for 24 weeks effectively
decreased the glucose and glycosylated hemoglobin level [43].
Numerous studies have reported that Vitamin E, C, and alpha-lipoic
acid and selenium frequently used antioxidants in the management
of diabetes. Nowadays, the antioxidants-based formulation developed
for the treatment of various diseases. Table 1 summarizes antioxidants
efficacy of vitamins in diabetes.
MEDICINAL PLANTS IN DIABETES
Medicinal plants are tremendous in the treatment of numerous
diseases due to their antioxidant activity. All parts of medicinal plants
are effective in the treatment of disease and help to discover new kind
of drug. The plants contribute a potential source of hypoglycemic drugs
due to their phytoconstituents [44].
The active constituents responsible for hypoglycemic activity may
include polysaccharides, sterol, triterpenoid, alkaloids, flavonoids, fat,
coumarins, phenolics, and peptides. It stimulates the beta-cell to restore
the function of pancreatic tissue [45]. The insulin secretion in beta-cell
increased and the uptake of glucose increased by adipose tissue and
muscle in plant treated rat, at same the time the absorption of glucose
decreased and hepatic glucose production decreased by inhibiting the
enzymes [46]. Some of the antidiabetic plants possess antioxidants
activity include Nerium oleander Linn. [47], Annona squamosa [48],
Cynodon dactylon [49], Padina boergesenii [50], and Tectona grandis
Linn. [51]. Table 2 summarizes antidiabetic plants which possess
antioxidants activity. Medicinal plants have a long history in the
treatment of diseases majorly in diabetes; therefore, it focused mainly
due to its curative property with fewer side effects.
Table 1: Antioxidant efficacy of vitamins and supplements in diabetes
Antioxidants Dosage Diabetogen Efficacy Reference
Vitamin E 500 mg/kg on the day 1, 4,
7, 11, 14.21, 24, 27
Streptozotocin (single dose
60 mg/kg body weight)
Lowered lipid peroxide level
in the liver of the diabetic rat
Seven et al. (2004)
Vitamin C 500 mg twice a day Type 1 and 2 diabetic
patients
Supplementation of Vitamin C
with metformin reduces FBS,
PMBG and improves HbA1c.
Ganesh et al. (2011)
Vitamin E + Vitamin C Vitamin C 60 mg daily and
Vitamin E 200 mg twice a
week for 5 weeks
STZ (single dose 75 mg/Kg
body weight)
Reduced hepatic lipid peroxide,
normalized Vitamin C, and
raised Vitamin E above the
normal level.
Madhu et al. (2000)
Alpha-lipoic acid 300 mg daily Type 2 diabetic patients Decreased FBS and IR Hasti et al. (2011)
Selenium
(sodium selenite)
0.5 µg/day STZ (55 mg/kg body weight) Selenium reduced oxidative
stress associated diabetes
Mukherjee et al. (1998)
Plants name Extract Dose Efficacy Reference
Allium sativum L. Ethanolic
extract of the
bulb
500 mg/kg body
weight of rat
Significantly
decreased the blood
sugar level
Shakya et al. (2010)
Aloe vera (L.) Aqueous extract
of leaves
500 mg/kg body
weight of mice
Hypoglycemic and
hepatoprotective
effect
Sharma et al. (2013)
Table 2: Shows the antidiabetic plants which possess antioxidants activity
(Contd...)

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Plants name Extract Dose Efficacy Reference
Syzygium cumini Walp. (Eugenia jambolana) Seed powder 500 and 1000 mg/kg
body weight of rat
Hypoglycemic
activity
Sridhar et al. (2005)
Mimosa pudica Thottal vadi
choornam
(Leaves and
roots)
100 and 200 mg/kg
body weight of rat
Hypoglycemic
activity
Vishwanathan et al. (2013)
Momordica charantia Alcoholic
extract of bitter
melon
0.5-1.5 g/kg body
weight of rabbits.
Hypoglycemic
activity
Vangoori et al. (2013)
Psidium guajava Ethanolic
extract of leaf
250 mg/kg of body
weight of rat
Hypoglycemic
activity
Mukhtar et al. (2004)
Mangifera indica Ethanolic
extract of seed
kernels
300 mg/kg of body
weight of rat
Hypoglycemic
activity
Gupta and Gupta (2011)
Andrographis paniculata Ethanolic
extract. (Aerial
part)
0.1, 0.2, and 0.4 g/body
weight of rat.
Hypoglycemic and
hypotriglyceridemic
effect
Zhang et al. (2000)
Table 2: (Continued)

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CONCLUSION
Among the antioxidants, the diet-derived antioxidants are important
in the prevention and management of various diseases. Over the past
decades, antioxidant-based experimental research emerged in the
production of a new drug. However, many drugs are in clinical trials
which possess antioxidants activity.
Based on the review, supplementation of antioxidants such as
Vitamin E, C, alpha-lipoic acid, and selenium shows their hypoglycemic
and hepatoprotective effect, but some of the studies have been reported
that vitamin supplementation does not affect glucose level. In diabetic
condition, the low level of vitamin reported in the previous study. The
mechanism behind the antioxidant is undefined, most of the study
reported it prevent and minimize the complication of diabetes.
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