Jung et al.

Nutrition & Metabolism 2011, 8:18

http://www.nutritionandmetabolism.com/content/8/1/18

RESEARCH

Open Access

Onion peel extracts ameliorate hyperglycemia

and insulin resistance in high fat diet/
streptozotocin-induced diabetic rats
Ji Young Jung, Yeni Lim, Min Sun Moon, Ji Yeon Kim* and Oran Kwon*

Abstract
Background: Quercetin derivatives in onions have been regarded as the most important flavonoids to improve
diabetic status in cells and animal models. The present study was aimed to examine the hypoglycemic and insulinsensitizing capacity of onion peel extract (OPE) containing high quercetin in high fat diet/streptozotocin-induced
diabetic rats and to elucidate the mechanism of its insulin-sensitizing effect.
Methods: Male Sprague-Dawley rats were fed the AIN-93G diet modified to contain 41.2% fat and intraperitoneally
injected with a single dose of streptozotocin (40 mg/kg body weight). One week after injection, the rats with
fasting blood glucose levels above 126 mg/dL were randomly divided into 4 groups to treat with high fat diet
containing 0 (diabetic control), 0.5, or 1% of OPE or 0.1% quercetin (quercetin equivalent to 1% of OPE) for 8
weeks. To investigate the mechanism for the effects of OPE, we examined biochemical parameters (insulin
sensitivity and oxidative stresses) and protein and gene expressions (pro-inflammatory cytokines and receptors).
Results: Compared to the diabetic control, hypoglycemic and insulin-sensitizing capability of 1% OPE were
demonstrated by significant improvement of glucose tolerance as expressed in incremental area under the curve
(P = 0.0148). The insulin-sensitizing effect of OPE was further supported by increased glycogen levels in liver and
skeletal muscle (P < 0.0001 and P = 0.0089, respectively). Quantitative RT-PCR analysis showed increased expression
of insulin receptor (P = 0.0408) and GLUT4 (P = 0.0346) in muscle tissues. The oxidative stress, as assessed by
superoxide dismutase activity and malondialdehyde formation, plasma free fatty acids, and hepatic protein
expressions of IL-6 were significantly reduced by 1% OPE administration (P = 0.0393, 0.0237, 0.0148 and 0.0025,
respectively).
Conclusion: OPE might improve glucose response and insulin resistance associated with type 2 diabetes by
alleviating metabolic dysregulation of free fatty acids, suppressing oxidative stress, up-regulating glucose uptake at
peripheral tissues, and/or down-regulating inflammatory gene expression in liver. Moreover, in most cases, OPE
showed greater potency than pure quercetin equivalent. These findings provide a basis for the use of onion peel
to improve insulin insensitivity in type 2 diabetes.
Keywords: Onion Peel Extract Quercetin, Type 2 Diabetes, Streptozotocin, Antioxidant

Background
Type 2 diabetes mellitus (T2DM) is one of the worlds
most common chronic diseases as changing lifestyles
lead to reduced physical activity and increased obesity
[1]. Early phenomenon of T2DM is insulin insensitivity,
* Correspondence: jiyn_kim@ewha.ac.kr; orank@ewha.ac.kr
Department of Nutritional Science and Food Management, Ewha Womans
University, 11-1 Daehyeon-dong, Seodeamun-gu, Seoul 120-750, Republic of
Korea

which not only has negative metabolic consequences

[2-5] but also contributes subsequent pancreas b-cell
exhaustion, resulting in the onset of clinical hyperglycemia [6]. Thus, understanding the regulation of the insulin response and identifying the related mechanisms are
important to early treatment and prevention of T2DM.
Several hypotheses have been proposed to explain the
pathogenesis of T2DM, and during last decades, much
attention has been given to the lipid toxicity and low-

2011 Jung et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.

Jung et al. Nutrition & Metabolism 2011, 8:18

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grade inflammation as major causes on insulin insensitivity [7,8].

A number of ways to improve insulin sensitivity have
been proposed, because early treatment and prevention
play a pivotal role in reducing the population burden of
diabetes. Lifestyle changes such as losing weight, exercising, and watching the diet are often recommended,
but have been difficult to maintain over a long term.
Benefits of pharmaceutical factors to treat the disease
aggressively early have been recommended, but medications may have unwanted side effects. Thus, there has
been a growing interest in herbal remedies that can be
introduced into the general population with the least
side effects and the maximal preventive outcome [9]. In
this context, flavonoids naturally occurring in plant
foods would be desirable options. Many studies have
shown that diabetes can be delayed or prevented by
intervention with dietary flavonoids. Quercetin is one of
the most common flavonoids in foods and has been
reported to improve diabetic status by decreasing oxidative stress [10-12] or by reducing the disturbance of
hepatic gene expressions [13]. However, most of the studies are generally carried out using highly purified quercetin rather than food extracts enriched in quercetin.
Onion bulbs have been recognized as the richest source
of dietary flavonoids. At least 25 different flavonoids have
been characterized and quercetin and its glycosides are
the most important ones [14]. Especially higher concentrations of quercetin occur in the outer dry layers of
onion bulb [15]. In the previous study, our team showed
that outer dry layers of onion bulb have strong antioxidant activity and proposed quercetin as the major component responsible for this activity [16]. Although there
are a few studies presented antidiabetic effects of onion
skin extract in vivo [17,18], more evidence is needed to
support its insulin-sensitizing capabilities. Therefore the
present study was performed to evaluate the effectiveness
of OPE in modulating hyperglycemia and insulin-insensitivity by using a high fat diet (HFD)/streptozotocin
(STZ)-induced diabetic rat model. The effect of OPE on
the plasma concentration of FFAs, the biomarkers of oxidative stress and inflammation in liver, the insulin receptor (INSR) and glucose transporter type 4 (GLUT4)
expressions in skeletal muscle were also investigated.

Materials and methods

Preparation of OPE

The OPE was kindly provided by the Center for Changnyeong Onion Bioindustry (Changwon, Korea). Briefly,
outer dry layers of onion bulbs (Allium cepa L.) were
extracted with 60% ethanol adjusted to pH 5.5 at 50C
for 3 hours. The extract was concentrated and then
freeze-dried. The amount of total polyphenol and quercetin were 618.10 14.51 mg/g and 101.28 6.95 mg/g

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as determined by methods of Folin-Ciocalteu [19] and

Hertog et al. [20], respectively. Pure quercetin was purchased from Wako Pure Chemical Industries, Ltd.
(Osaka, Japan).
Animals, induction of diabetics, and diets

Male Sprague-Dawley rats aged 8 weeks were purchased

from Orient Bio Inc. (Seoul, Korea). The rats were housed
at a temperature of 23 1C with 12/12 h light/dark cycles
and 45 5% humidity with access to water and chow diet
for a week prior to the experiment. The experimental protocols were approved by the Institutional Animal Care and
Use Committee (IACUC) of the Ewha Womans University.
For the experiments, a diabetic state was induced by feeding AIN 93G diet modified to contain 41.2% fat (HFD) for
2 weeks, followed by a single intraperitoneal injection of
STZ (Sigma Chemical Co., St. Louis, MO, USA) at a low
dose (40 mg/kg body weight, dissolved in 0.05 M citrate
buffer, pH 4.5, immediately before use). One week after
injection, fasting blood glucose (FBG) levels were determined from tail blood using an Accu-Check (Roche Diagnostics, Manheim, Germany). The rats with FBG levels
above 126 mg/dL were randomly divided into 4 groups
(n = 7 for each group): one group was fed with a HFD only
(diabetic control group), two groups with a HFD containing
0.5 or 1% of OPE respectively, and the other group with a
HFD containing 0.1% of quercetin (matched with the 1% of
OPE-treated group) for 8 weeks. The rats consumed diet
and tap water ad libitum during the experimental period.
Oral glucose tolerance tests (OGTTs) were performed
from the tail vein at the last week of the experimental period. The rats were sacrificed under anesthesia and blood,
liver, and skeletal muscle was immediately collected.
Oral glucose tolerance test

After overnight fasting for 12 hours, the animals were

administered a glucose (1 g/kg of body weight) dissolved
in water by gavage. Blood glucose concentrations were
determined from the tail vein with an Accu-check at 0,
30, 60, 90, and 120 min. The incremental area under
the curve (IAUC) was calculated using the method of
Thomas MS Wolever et al. [21].
Measurement of plasma insulin and free fatty acid

Plasma insulin and FFAs were measured using commercial kits (Rat insulin ELISA kit, Mercodia, Uppsala, Sweden; FFA quantification kit, Biovision, Mountain view,
CA, USA). All procedures were performed in accordance with the manufacturers instructions. Homeostasis
model assessment-insulin resistance (HOMA-IR) was
calculated to measure the insulin sensitivity of the rats
fed the experimental diets by the following formula
[22,23]: [Fasting plasma insulin (g/L) Fasting blood
glucose (mg/dL)]/22.5.

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Measurements of glycogen synthesis

Glycogen in liver and skeletal muscle was determined

using the method described by LO et al [24]. Briefly,
samples were homogenized in KOH solution and incubated in boiling water for 30 min. After addition of 90%
ethanol, they were incubated overnight at 4C, followed
by the centrifugation at 1,000 g for 30 min at 4C
(H50A-8 centrifuge, Hanil, Seoul, Korea). Water, 5%
phenol reagent, and H2SO4 solution were added to standard and samples. Bovine liver glycogen (Sigma Chemical Co., St. Louis, MO, USA) was used as a standard.
Absorbance at 490nm was determined using a spectrophotometer (Genesys 10UV, Thermo Electron Co.,
Madison, WI, USA).
Measurements of liver markers of oxidative stress

Liver malondialdehyde (MDA) and superoxide dismutase (SOD) activity were measured using a commercial
kit purchased from Cayman Chemical (Ann Arbor, MI,
USA) and Dojindo Lab (Kumamoto, Japan) respectively.
For MDA, liver was homogenized in 250 l of radioimmunoprecipitation buffer containing protease inhibitor
and sonicated for 15 sec at 40 V. After centrifugation at
1,600 g for 10 min at 4C, the supernatant was collected
to measure MDA concentration according to the manufacturers instructions. For SOD activity, liver was
homogenized in 10 volumes (w/v) of 50 mM phosphate
- 0.25 M sucrose - 0.5 mM EDTA buffer (pH 7.4). The
homogenate was centrifuged at 10,000 g for 20 min at
4C. Five milliliters of the supernatant was ultrasonicated twice for 30 sec. Next, 2 ml of solution containing
five volumes of chloroform with three volumes of ethanol was added and mixed strongly for 2 min. The mixture was centrifuged at 20,000 g for 20 min at 4C. The
final supernatant was collected and measured for SOD
activity according to the manufacturers instructions.
Western blotting

Equal amounts of liver whole lysate were separated by

SDS-polyacrylamide gel electrophoresis, transferred to
polyvinylidene difluoride membranes, incubated in blocking buffer, and treated with primary antibodies: anti-tumor
necrosis factor (TNF)-a (Abcam, Cambridge, UK), antiinterleukin (IL)-6 (Abcam, Cambridge, UK), and anti-atubulin (Cell Signaling Technology, Danvers, MA, USA).
Appropriate secondary antibodies were used, and the
bands were visualized using ChemiDoc XRS System and
analyzed using Quantity One software (Bio-Rad, CA, USA).
Quantitative real-time reverse transcription-polymerase
chain reaction (RT-PCR) analysis

Total RNA was extracted from liver or skeletal muscle

using TRIZOL reagent (Invitrogen Co., Carlsbad, CA,
USA). RNA concentration and quality were measured

Page 3 of 8

by a BioSpec-nano (Shimadzu Corp., Tokyo, Japan).

cDNA was constructed using high capacity RNA with a
cDNA kit (Applied Biosystems, Foster City, CA, USA).
The expression of mRNA was measured by PCR using the
TaqMan method and an ABI StepOne Plus system
(Applied Biosystems, Foster City, CA, USA). The primer
sets for target genes in the rats were INSR [Insr;
Rn01637243_m1], GLUT-4 [Slc2a4; Rn00562597_m1],
TNF-a [Tnf; Rn99999017_m1], IL-6 [Il6; Rn01410330_
m1], and b-actin [Actb; Rn00667869_m1]. The relative
amounts of these mRNAs were normalized to the amount
of b-actin.
Statistical analysis

All results are presented as the mean standard error

(SE). Statistical analyses were conducted by using SAS
9.2 (SAS Institute, Cary, NC, USA). Data analyses were
performed by one-way analysis of variance (ANOVA)
with post hoc Dunnets multiple comparison test. Statistical significance was indicated by P < 0.05.

Results
Eight-week OPE administration showed insulin sensitizing
effects in HFD/STZ-induced diabetic rats

To determine the insulin sensitizing effects of OPE,

OGTT was performed at the last week of treatment. As
compared to the diabetic control, the OPE treated
groups showed consistent improvement in OGTT at all
time points in a dose-dependent manner, although the
differences did not reach statistical significance (Figure
1A). The difference between the diabetic control and
the 1% OPE treated group was marginally significant at
time points 60 min (P = 0.0597). As shown in Figure
1B, in comparison to the diabetic control, rats with 1%
OPE administration showed significantly decreased
IAUC (P = 0.0148), whereas the quercetin equivalent
group showed no significant reduction. HOMA-IR, FBG
and insulin secretion showed insignificant reduction in
all treatments (Figure 2). There were also no differences
in body weight, food intakes, and organ weights among
groups (data not shown).
To support insulin sensitizing effect of OPE further,
glucose uptake and utilization in peripheral tissues were
determined. In liver, both 1% OPE and quercetin
induced significant increases in glycogen levels, as compared to the diabetic control (P < 0.005, Figure 3A).
Similar effect was shown in skeletal muscle, but the difference between the diabetic control and the quercetin
equivalent was not significant (P = 0.2186, Figure 3B).
Oxidative stress and metabolic dysregulation of FFAs in
diabetic condition were alleviated by OPE administration

Oxidative stress status was assessed by measuring the

MDA formation and SOD activity in liver. Compared

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A
350

25

20

HOMA-IR

Blood glucose (mg/dL)

300

250

15

10

200
0

OPE 0

OPE 0
OPE 0.5
OPE 1.0
Q 0.1

150

OPE 0.5

OPE 1.0

Q 0.1



B

100
30

60

90

200

120

Fasting blood glucose (mg/dL)

Time (min)


B


150

100

50

OPE 0

OPE 0.5

OPE 1.0

Q 0.1

Figure 1 Hypoglycemic effect of OPE or quercetin on the OGTT

test. After 8 week administration of each experimental diet in HFD/
STZ induced diabetic rats, OGTTs were performed in the fasting
state (A) and then IAUCs were calculated (B). Data are expressed as
means SE (n = 7 for each group). Comparisons were done among
the IAUC of each group by Dunnets multiple comparison test.
*Different from control, P < 0.05

with diabetic control, MDA formation was suppressed

by quercetin as well as all 2 doses of OPE administration (P < 0.05, Figure 4A), whereas SOD activity was
significantly increased only in the 1% OPE-treated rats
(P = 0.0393, Figure 4B). Plasma FFA levels were
decreased in a dose-dependent manner and one percent of OPE administration showed significant lower
level compared with the diabetic control (P = 0.0148).
However quercetin administration showed no change
(Figure 4C).

Plasma insulin (Pg/L)

3.0
2.5
2.0
1.5
1.0
0.5
0.0

OPE 0

OPE 0.5

OPE 1.0

Q 0.1

Figure 2 Effects of OPE or quercetin on HOMA-IR (A), FBG (B),

and insulin secretion (C) in HFD/STZ-induced diabetic rats.
Parameters were measured after 8 week administration of 0, 0.5, 1%
OPE or 0.1% quercetin. Data are expressed as means SE (n = 7 for
each group). Comparisons were done between the control group
and each individual treated group by Dunnets multiple comparison
test.

The OPE modified gene expressions related to

inflammation and glucose uptake in the liver

In comparison to the diabetic control, quercetin

administration significantly suppressed mRNA expression of IL-6 gene in liver. In line with this RT-PCR
result, IL-6 protein was also decreased significantly by
quercetin administration. One percent of OPE

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B


C

Figure 3 Glycogen levels in liver (A) and skeletal muscle (B).

Glycogen levels were measured in liver and skeletal muscle after 8
week administrations of 0, 0.5, 1% OPE or 0.1% quercetin in HFD/
STZ-induced diabetic rats. Data are expressed as means SE (n = 7
for each group). Comparisons were done between the control
group and each individual treated group by Dunnets multiple
comparison test. *Different from control, P < 0.05, ***different from
control, P < 0.005

administration significantly suppressed IL-6 protein in

liver (P = 0.0025), whereas showing little suppression
on mRNA expression of IL-6 gene, compared with the
diabetic control. Although mRNA levels of TNF-a
were decreased significantly by quercetin administration (P < 0.05), neither quercetin nor 1% OPE administration significantly affected TNF-a protein in liver
compared with the diabetic control (Figure 5). In addition, hepatic mRNA expressions of both INSR and
GLUT4 significantly increased in 1% OPE or quercetin
administration compared with the diabetic control (P <
0.05, Figure 6).

Figure 4 Effect of OPE or quercetin on MDA formation (A),

SOD activity (B), and plasma FFAs (C) in HFD/STZ-induced
diabetic rats. MDA formation, SOD activity and plasma FFAs were
measured in liver and skeletal muscle after 8 week administrations
of 0, 0.5, 1% OPE or 0.1% quercetin in HFD/STZ-induced diabetic
rats. Data are expressed as means SE (n = 7 for each group).
Comparisons were done between the control group and each
individual treated group by Dunnets multiple comparison test. *
Different from control, P < 0.05

Discussion
This study was designed to investigate the modulating
effects of OPE on hyperglycemia and insulin-insensitivity in HFD/STZ-induced diabetic rats. To induce
T2DM, a single low dose of STZ at 40 mg/kg body

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Figure 5 Immunoblot analysis of protein levels (A) and gene

expression levels (B) of TNF-a and IL-6 in liver of HFD/STZinduced diabetic rats. Levels of TNF-a protein and IL-6 protein
were measured normalized against a-tublin, and expressed as fold
of control. The mRNA expression levels were determined by
quantitative RT-PCR, normalized against b-actin, and plotted relative
to those of diabetic control rats. Data are expressed as means SE,
(n = 7 for each group). Comparisons were done between the
control group and each individual treated group by Dunnets
multiple comparison test. *Different from control, P < 0.05,
***different from control, P < 0.005.

weight was injected combined with HFD. High doses of

STZ (>45 mg/kg body weight) is well known to be
taken by pancreatic b-cells via GLUT2 and to induce
severe damages of pancreatic b-cells, mimicking T1DM
[25]. On the contrary, the combination of HFD and low
doses of STZ resulted in characteristic of T2DM; HFD
induces insulin resistance and low doses of intraperitoneal STZ induce moderate impairment of insulin secretion [26-30]. In this study, OGTT, insulin secretion, and
peripheral glucose utilization were assessed, along with
the plasma FFAs, the biomarkers relating to oxidative
stress and inflammation in liver, and the expressions of
GLUT4 and INSR genes in skeletal muscle. In all cases,
the effects of 1% OPE were compared with those of
pure quercetin equivalent.
Liver and skeletal muscle is the primary site of glucose
disposal in the insulin-stimulated state [31]. The

Figure 6 Effects of OPE or quercetin on the mRNA expression

of the INSR and GLUT 4 in skeletal muscle of HFD/STZ-induced
diabetic rats. Expression levels for INSR and GLUT4 were
determined by quantitative RT-PCR, normalized against b-actin, and
plotted relative to those of diabetic control rats. Data are expressed
as means SE (n = 7 for each group). Comparisons were done
between the control group and each individual treated group by
Dunnets multiple comparison test. *Different from control, P < 0.05,
**different from control, P < 0.01.

previous study demonstrated that glycogen storage was

impaired in diabetic animals [32]. In the present study,
1% OPE administration showed hypoglycemic effects
compared to the diabetic control, as evidenced by significant decrease in IAUC. In the meantime, glycogen
levels were significantly increased in liver and skeletal
muscles in response to 1% OPE administration. In addition, both 1% OPE and its quercetin equivalent induced
up-regulation of INSR and GLUT4 gene expressions in
skeletal muscle. The rapid insulin action to stimulate
glucose uptake and metabolism in peripheral tissues is a
fundamental mechanism for the maintenance of glucose
homeostasis [33]. Glucose uptake is triggered by a cascade of events from insulin binding to its cell surface
receptors, then the ability of insulin to increase glucose
transport in muscle tissue via GLUT4 [33]. Therefore, it
is proposed that OPE improves insulin sensitivity by upregulating expressions of insulin receptor and glucose
transporter as well as by promoting metabolism of glucose in peripheral tissues in diabetic rats. Interestingly,
potency of 1% OPE was generally higher than that of
pure quercetin equivalent. Onion bulbs contain more
than 20 flavonoids other than quercetin [14]. According
to our analysis, OPE was found to be composed of polyphenols at the level 60%. Of these, 16% was quercetin.
Therefore, it was postulated that the higher potency of
OPE might be attributed to the additive or synergistic
effect of an array of phytochemicals.
Several studies suggested that impaired blood lipids
are characteristic of subjects with insulin resistance,
especially circulating FFAs [34-36]. These observations
were supported by recent evidence that FFAs directly
activate macrophage to secrete pro-inflammatory

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cytokines that render muscle cells insulin resistant [37].

Meanwhile the role for pro-inflammatory cytokines in
regulating insulin sensitivity has been suggested by several lines of evidence. For example, subjects with T2DM
exhibited higher serum levels of pro-inflammatory cytokines such as TNF-a, IL-1b, and IL-6 [38]. In addition,
FFAs contribute to the increased production of reactive
oxygen species and lead to the activation of stress-sensitive signaling pathways under hyperglycemic status [39].
In this study, the measurement of oxidative/inflammatory stresses was focused on the liver. Because dietary
quercetin is metabolized in liver, inhibiting liver injury
induced by diabetes may be particularly effective, consequently [13]. The results indicated that plasma FFA
levels in diabetic rats were significantly decreased in
response to OPE administration. Hepatic oxidant stress
was reduced by 1% OPE, as assessed by increasing SOD
activity and blocking MDA formation. Moreover, hepatic expressions of TNF-a and IL-6 were suppressed by
either 1% OPE or quercetin. These results are in agreement with previous reports, in which quercetin had
anti-oxidative and anti-inflammatory activities [12].
Therefore, although detailed mechanisms of action await
further investigation, it is proposed that OPE leads to
improved insulin sensitivity, at least in part, through
enhancing lipid metabolism, reducing oxidative stress,
or modulating pro-inflammatory cytokines in diabetic
rats.
In conclusion, the present study has demonstrated the
potency of OPE to ameliorate hyperglycemia and insulin
resistance in diabetic rats. The OPE modulates glucose
uptake and metabolism in peripheral tissues via INSR
and GLUT4 gene expression in skeletal muscle. Furthermore, OPE lowered plasma FFA levels and suppressed
oxidative and inflammatory stress in liver. These findings provide a basis for the use of onion peel and also
have important implications for the prevention and
early treatment of T2DM.
Acknowledgements
We are grateful to Professor Yong-Jun Cha of Changwon National University
for kindly providing OPE and for useful discussions. This project was
supported by the Ministry of Knowledge & Economy (RITD program, Project
No. 70004683) and the Ministry of Education, Science and Technology (Brain
Korea 21, Project No. 2006-0519-4-7).
Authors contributions
JYK and OK designed this research; JYJ, YL, and MSM conducted research;
JYJ, JYK and OK wrote the paper; and JYK and OK had primary responsibility
for final content. All authors read and approved the final manuscript.
Competing interests
The authors declare that they have no competing interests.
Received: 17 January 2011 Accepted: 28 March 2011
Published: 28 March 2011

Page 7 of 8

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doi:10.1186/1743-7075-8-18
Cite this article as: Jung et al.: Onion peel extracts ameliorate
hyperglycemia and insulin resistance in high fat diet/streptozotocininduced diabetic rats. Nutrition & Metabolism 2011 8:18.

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