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The Effect of Stevia Rebaudiana on Serum Omentin and Visfatin Level in STZ-Induced Diabetic Rats

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ABSTRACT Recently the role of adipocytokines in relationship to incidence of diabetes has been demonstrated. One of the medicinal plants that are used in the treatment of diabetes is stevia. This study investigates the effect of stevia on serum omentin and visfatin levels as novel adipocytokines in diabetic induced rats to find potential mechanisms for the anti hyperglycemic effect of stevia. Forty male wistar rats weighing 180-250 g were induced with diabetes by intraperitoneal injection of streptozotocin (STZ). The animals were divided into 5 groups of 8. Rats in group 1 (non-diabetic control) and group 2 (diabetic control) were treated with distilled water, and the rats in the treated groups, group 3 (T250), group 4 (T500), and group 5 (T750) were treated with stevia, gavaged every day at 9 a.m. in doses of 250, 500, and 750 mg/kg, respectively. At the end of the study significant reductions in fasting blood sugar (FBS), the homeostasis model assessment insulin resistance (HOMA-IR), triglyceride (TG), alkaline phosphatase (ALP), and Omentin level were found in groups 3 and 4 in comparison with group 2. Pancreatic histopathology slides demonstrated that stevia extract did not induce any increase in the number of β-cells. The conclusion is that prescription of stevia in the doses of 250 and 500 mg/kg/d decreases the omentin level indirectly via activating insulin sensitivity and lowering blood glucose in STZ-induced diabetic rats.
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Journal of Dietary Supplements, Early Online:1–12, 2014
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DOI: 10.3109/19390211.2014.901999
ARTICLE
The Effect of Stevia Rebaudiana on Serum Omentin
and Visfatin Level in STZ-Induced Diabetic Rats
Samad Akbarzadeh1, Fatemeh Eskandari2, Hadis Tangestani2, Somaieh
Tangerami Bagherinejad2, Afshar Bargahi1, Parviz Bazzi3, Adel Daneshi4,
Azam Sahrapoor2, William J. O’Connor6, & Ali Reza Rahbar5
1Department of Biochemistry, School of Medicine, Bushehr University of Medical
Sciences, Bushehr, Iran, 2The Student’s Committee Research, School of Medicine,
Bushehr University of Medical Sciences, Bushehr, Iran, 3Department of Anatomy, School
of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran, 4The Persian Gulf
Marine Biotechnology Research Center, Bushehr University of Medical Sciences,
Bushehr, Iran, 5Department of Nutrition, The Persian Gulf Tropical Medicine Research
Center, Bushehr University of Medical Sciences, Bushehr, Iran, 6The UCD School of
Mechanical & Materials Engineering, University College Dublin, Dublin, Ireland
ABSTRACT. Recently the role of adipocytokines in relationship to incidence of dia-
betes has been demonstrated. One of the medicinal plants that are used in the treat-
ment of diabetes is stevia. This study investigates the effect of stevia on serum omentin
and visfatin levels as novel adipocytokines in diabetic induced rats to find potential
mechanisms for the anti hyperglycemic effect of stevia. Forty male wistar rats weigh-
ing 180–250 g were induced with diabetes by intraperitoneal injection of streptozotocin
(STZ). The animals were divided into 5 groups of 8. Rats in group 1 (non-diabetic con-
trol) and group 2 (diabetic control) were treated with distilled water, and the rats in the
treated groups, group 3 (T250), group 4 (T500), and group 5 (T750) were treated with
stevia, gavaged every day at 9 a.m. in doses of 250, 500, and 750 mg/kg, respectively. At
the end of the study significant reductions in fasting blood sugar (FBS), the homeosta-
sis model assessment insulin resistance (HOMA-IR), triglyceride (TG), alkaline phos-
phatase (ALP), and Omentin level were found in groups 3 and 4 in comparison with
group 2. Pancreatic histopathology slides demonstrated that stevia extract did not in-
duce any increase in the number of β-cells. The conclusion is that prescription of stevia
in the doses of 250 and 500 mg/kg/d decreases the omentin level indirectly via activating
insulin sensitivity and lowering blood glucose in STZ-induced diabetic rats.
KEYWORDS. Diabetes, omentin, stevia, visfatin
Address correspondence to: Ali Reza Rahbar, Deputy for Research, Bushehr University of Medical Sciences,
Moallem Street, Bushehr, P.O. Box-3631, I.R. Iran (E-mail: rahbar alireza@yahoo.com).
(Received 14 June 2013; accepted 3 December 2013)
1
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2Akbarzadeh et al.
INTRODUCTION
The number of diabetic patients has been increasing rapidly worldwide, and
prevention of diabetes advancement is a major issue in the 21th century (Zimmet,
Alberti, & Shaw, 2001). The World Health Organization (WHO) estimates that
more than 180 million people worldwide have diabetes and this number will likely
double by 2030 (WHO, 2000). In diabetic patients, chronic increase in blood
glucose concentration leads to insulin resistance and induces complications char-
acteristic of diabetes, such as coronary heart disease, hypertension, renal failure,
serum lipid distortion, etc. For the treatment of diabetes, especially in eastern
countries, in addition to the restriction of energy and the promotion of exercise,
the use of medicinal plants has played an important role. These novel compounds
are used by traditional herbalist for the management of diabetes in several regions
of Iran (Fallah-Hoseini, Fakhrzadeh, Larijani, & Shikhsamani, 2006).
One of the medicinal plants widely used as an alternative medicine in the
treatment the hyperglycemia in diabetes is stevia. Stevia rebaudiana that grows
in South America does not contain useable carbohydrates for humans. It contains
Stevioside, rebaudiosides A, B, C, D, E, and F, dulcoside A, and steviolbioside.
Natural sweet-tasting glycosides, isolated from the herb, are 200–350 times sweeter
than sucrose and have been used as a natural sweetener in Brazil and Japan
for decades (Soejarto, Kinghorn, & Farnsworth, 1982; Lailerd, Saengsirisuwan,
Sloniger, Toskulkao, & Henriksen, 2004; Chen et al., 2005). In addition, the extract
of stevia has shown the ability to decrease the blood glucose level in diabetic
patients (Kujur et al., 2010; Jeppesen, Gregersen, Poulsen, & Hermansen, 2000;
Chen et al., 2005). So far various mechanisms have been reported to be active in
the hypoglycemic property of stevia, such as enhancement of insulin secretion,
activation of glucose utilization, counteracting the glucotoxicity in β-cells and
suppressing the glucagon secretion by α-cell of pancreas (Jeppesen et al., 2000;
Chen et al., 2005, Chen et al., 2007, Shibata et al., 1995).
Recently the role of adipocyte derived cytokine in the incidence of diabetes
has been demonstrated (Bulcao, Ferreira, Giuffrida, & Ribeiro-Filho, 2006; Yang
et al., 2006). Visfatin and omentin are two novel adipocyteokines that are involved
in insulin signal transduction (Yang et al., 2006), glucose homeostasis (Chandran,
Phillips, Ciaraldi, & Henry, 2003) and insulin-mimetic effects (Fukuhara et al.,
2005). There are some clinical trials that studied the relationship between glucose
lowering agents (metformin and resiglitasone) and adipocytokines (Esteghamati
et al., 2013) but to the best of our knowledge there is no published report to show
the effect of stevia consumption, as a novel glucose lowering remedy (FDA ap-
proved), on serum adipocytokines concentration in an animal or human model
study. Therefore we undertook this research to investigate the impact of stevia on
serum omentin and visfatin levels in diabetic induced rats, in order to find other
potential mechanisms involved in the hypoglycemic property of stevia. Further-
more the dose effectiveness dependency of stevia on morphology of the liver and
pancreas as well as lipid and glycemic parameters was evaluated.
MATERIAL AND METHODS
Forty specific pathogen-free male wistar rats weighing 180–250 g were provided
from the Medical Center Animal Research facility at Esfahan University of
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Stevia Omentin Visfatin Diabetes 3
medical sciences. They were housed in micro-filter-top cages at Bushehr Univer-
sity of medical sciences animal house. The animals were allowed to acclimatize for
2 weeks at 22 ±3C with a 12:12-hr light:dark cycle and 60–65% humidity, provided
with rodent chow and water ad libitum. All experimental protocols were followed
under the approval from the Animal Care and Use Committee for Animal Inves-
tigations. The experimental model was conducted in a manner consistent with the
relevant ethical guidelines for animal research. The animals were randomly divided
into 5 groups of 8 members each. After fasting for 12 h, the experimental diabetes
was induced by intraperitoneal injection of a single dose of 60 mg/kg of streptozo-
tocin (STZ) (Alexis Biochemical, Lot-L24553) to the rats in all the groups except
one which was assigned to be the non-diabetic control group. After 5 days of the
STZ injection, blood samples were taken from the tail of the subjects and the glu-
cose level was measured by glucometer (Bionime Rightest GM 300, Switzerland).
Animals with a blood glucose value of >300 mg/dL were assumed to be diabetics
(Heidarian & Soofiniya, 2011) and the others were excluded.
Stevia was supplied from the north of Iran. Sample specimens were authenti-
cated by the herbarium of the research center of Agriculture and Natural Resources
of Bushehr Province, Iran. The voucher was deposited in the Herbarium of Bushehr
University of Medical Sciences. The aqueous extract of stevia plant was obtained
by boiling aerial parts for 30 min in distilled water at a ratio of 1:100 w/v, and in-
cubated overnight at 40C with slow shaking on an orbital shaker (Stuart Scientific
Orbital Shaker, UK). The hydrosoluble part was centrifuged (6000 g,10min)and
insoluble precipitate was discarded. The supernatant was filtered by Whatman No.
1 paper. The filtrate was concentrated under reduced pressure at 40C using a ro-
tary evaporator (Laborota 4000, Heildolph, Germany) and finally freeze-dried to
get the stevia extract. The resulting sample was powdered and plastic sealed for
future use.
Rats in group 1 [non-diabetic control group (N-DC)] and group 2 [diabetic con-
trol group (DC)] were treated with distilled water, and the rats in group 3 (T250),
group 4 (T500), and group 5 (T750) were treated with stevia, gavaged every day at
9 a.m. in corresponding doses of 250, 500, and 750 mg/kg, respectively. The rats in
all groups continued to consume their usual diet while taking the stevia or distilled
water. The rat diet included brown rice, oats, wheat, soy, and fish meal, Calcium
Carbonate, Yeast Culture Dehydrated, Flax Seed Meal (Linseed), Inulin, Mono-
calcium Phosphate, Soy Oil and needed vitamins and minerals (Table 1).
At the end of the 30th day of the study, after 12 hr nocturnal fasting, the rats
were given a lethal overdose of isoflorane by inhalation. Subsequently the blood
TABLE 1. Analysis of the Nutrients Contained in Rat Diet
Crude carbohydrate 58.00%
Crude protein 15.00%
Crude fat 4.00%
Crude fiber 7.00%
Moisture 10.00%
Calcium 1.20%
Phosphorous 0.80%
Premium Ingredients: Brown Rice, Oats and Wheat, Soy and Fish Meal.
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4Akbarzadeh et al.
samples were taken from the heart into a syringe and placed on ice; all blood sam-
ples were promptly centrifuged at 3000 gfor5minat4
C, the serum was separated,
and it was kept at 80C for further analysis. Analyses were carried out at the lab-
oratory of the Persian Gulf Tropical Medicine Research Center on the day of the
blood collection. Serum glucose, triglycerides (TGs), total cholesterol, and HDL
cholesterol were determined using the enzymatic method (Pars Azemon Co, Iran)
by an auto analyzer, selectra-2 (vital science, spankeren, Netherlands). Insulin was
measured using ELISA (Alpco Insulin ELISA kit). Homeostasis model assessment
insulin resistance (HOMA.IR) of fasting blood sugar (FBS) and homeostasis model
assessment insulin-B cells (HOMA-B) were calculated by the following formulae
(Matthews et al., 1985):
HOMA IR =InsulinμIU
ml ×FBS mmol
ml
22.5
HOMA B=20 ×InsulinμIU
ml
FBS mmol
ml 3.5
Serum omentin concentrations were measured using rat omentin ELISA kit
[ELISA kit, Cat. No: CK-E11073. China]. The detection limit of the assay and sen-
sitivity were 2–600 ng/L, and 1.12 ng/L properly. The intra and inter-assay coeffi-
cients of variance were less than 10% and 20%, respectively. To detect visfatin in
the serum samples, a commercially available (Cat. No.V0523EK) enzyme-linked
immunosorbent assay kit (Adipo-Gen, Seoul, Korea) was used following the man-
ufacturer’s instructions. The assay sensitivity for visfatin was 0.10 ng/mL; the intra
and inter-assay coefficients of variance were 3.8–5.5% and 6.4–9.5%, respectively.
To evaluate the histopathology changes in the pancreatic β-cells and in the liver
of STZ-induced diabetic rats, pancreatic and liver biopsies were taken on the 30th
day of the study. The samples were fixed and dehydrated by formaldehyde and
alcohol properly. Subsequently the fixed samples were molded and embedded by
paraffin and finally they were cut in 3-micron thickness and stained (H and E stain-
ing) for evaluation by light microscopy. Light and electron micrographs of samples
which obtained through light microscopy were carefully studied and evaluated for
morphological changes.
Statistical Analysis
The distribution of variables was studied using probability plots and the Shapiro-
Wilks test. Due to the χ2distribution of the variables, nonparametric tests
were used to analyze the data. The differences after intervention between
groups in omentin, visfatin, lipidemic, and glycemic parameters were analyzed by
Kruskal–Wallis. Mann–Whitney Uwas used wherever there was a main effect in
order to compare variables between each group separately. A value of p<.05 was
accepted as significant. Statistical analysis was performed using the SPSS 15 statis-
tical software package (SPSS Inc., Chicago, IL).
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Stevia Omentin Visfatin Diabetes 5
FIGURE 1. Photomicrographs of liver and pancreatic images of STZ- induced diabetic rats.
Group 1 [Control: the non-diabetic control group], group 2 [Diabet, the diabetic control
group], group 3 (fed 250 mg/d stevia], group 4 [fed 500 mg/d stevia], group 5 [fed 750 mg/d
stevia] (H and E staining, ×400 magnification). Stevie extract administration did not induce
any increase in the number of β-cells of pancreatic islets in all of the treated groups. In
addition no sign of liver tissue deterioration was seen following stevia prescription.
RESULTS
After STZ injection the FBS in the animals in the study were 318.00 ±131.78 which
showed that all the rats were induced with diabetes. The FBS and weight of the
diabetic rats confirmed that the groups were well matched for all entry criteria (data
not shown) and that there were no significant differences between the groups.
After 30 days of stevia consumption, a significant reduction in FBS in group 3
(T250) (p=.03), as well as in group 4 (T500) (p=.03) was seen in comparison with
group 2 (DC). The HOMA-IR also decreased in group 3 (T250) (p=.04) and in
group 4 (T500) (p=.01) sequel stevia prescription. A significant decrease in the
TG level was observed in group 3 (T250) (p=.02) and in group 4 (T500) (p=.02)
in comparison with group 2 (DC) at the end of the study. The decline in omentin
was also significant in group 3 (T250) (p=.01) and in group 4 (T500) (p=.01)
compared to group 2 (DC). The ALP level at the end of the study decreased in
group 3 (T250) (p=.010) as well as in group 4 (T500) (p=.01) after intervention.
The stevia supplementation of 750 mg/kg/d showed no significant changes in any
biochemical parameters between the groups (Table 2).
The difference in the fasting insulin concentrations, HOMA-B, visfatin, choles-
terol, and HDL-C were not significant between the treated groups and group 1
(N-DC) and 2 (DC).
The pancreatic and hepatic histopathology slides of all the groups were prepared
on the 30th day of study. As shown in Figure 1 the stevia extract did not induce any
increase in the number of β-cells of pancreatic islets in any of the treated groups.
In addition no sign of liver tissue deterioration was seen in histopathology slides
after the stevia treatment in the diabetic rats.
DISCUSSION
Omentin as a novel adipocytokine has been known to modulate blood glucose.
In our study the level of omentin showed a significant reduction with increas-
ing doses of stevia prescription in diabetic rats. Esteghamati et al., in agreement
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TAB LE 2 . Differences of Variables at the End of the Study Following Intervention Between Groups
Group 1 (N-DC) Group 2 (DC) Group 3 (T250)Group4(T
500)Group5(T
750)
Omentin (ng/mL) 110.67 ±11.29 124.85 ±11.24∗∗ 101.63 ±23.6199.98 ±20.17106.55 ±16.87
Visfatin (ng/mL) 10.03 ±6.39 10.17 ±5.77 6.89 ±4.35 10.65 ±4.87 7.47 ±3.55
FBS (mg/dL) 137.79±23.22 526.16 ±180.8∗∗ 142.57 ±128.06144.50 ±84.78290.86 ±187.54
HOMA-IR 3.44 ±2.22 18.47 ±10.67∗∗ 2.82 ±4.045.53 ±6.228.32 ±9.87
HOMA-B 41.84 ±17.62 12.21 ±9.23∗∗ 21.82 ±7.16 33.66 ±15.825.41 ±26.15
Insulin (u/L) 9.43 ±5.41 14.02 ±7.42 4.86 ±4.42 13.46 ±9.94 11.02 ±8.23
TG (mg/dL) 49.67 ±8.9191.16 ±25.30∗∗ 36.29 ±21.0738.33 ±14.9653.71 ±36.67
Chol (mg/dL) 76.17 ±11.72 91.33 ±15.64 104.22 ±35.16 103.00 ±29.31 85.29 ±24.27
HDL-C (mg/dL) 41.10 ±5.88 52.93 ±7.54 54.06 ±16.67 52.33 ±17.07 44.09 ±9.45
ALP 353.33 ±46.62 1272.00 ±481.48∗∗ 758.86 ±324.78943.50 ±324.481084 ±728.58
Weight (g) 250.33 ±38.05 252.42 ±37.55 254.42 ±23.45 255.83 ±42.75 223.85 ±30.33
Mean ±SD. Kruskal–Wallis was used to assess treatment effects between groups. Mann-Whitney correction was used wherever there was a main effect. Significantly changes for each of
the three treatment groups relative to the group 2 (diabetic control group). ∗∗Significantly differences for group 2 (diabetic control group) relative to the group 1 (non-diabetic control group).
FBS =fasting blood sugar; TG =triglyceride; ALP =alkaline phosphatase; HOMA.IR =homeostasis model assessments for insulin resistance; HOMA-B =homeostasis model assessments
for b-cells.
6
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Stevia Omentin Visfatin Diabetes 7
with our findings, reported a significant reduction in omentin level after ad-
ministration of the herbal and artificial hypoglycemic medication (metformin
and resiglitasone) in type 2 diabetic patients (Esteghamati et al., 2013). In our
study and also in the research by Esteghamati et al., FBS similar to omentin
decreased following consumption of the medication by the study subjects. In
contrast, there are several reports showing an increase in the level of omentin
following serum glucose reduction in diabetic individuals (Yan et al., 2011).
To try to account for this discrepancy, we should address the mechanisms
which are involved in modulating the blood glucose level by stevia compared
to omentin. The biochemical pathways attributed to stevia in lowering blood
glucose [suppression of hepatic glucose release, attenuation of glucagon secre-
tion, and decrease of peripheral insulin resistance] are independent of the path-
ways attributed to omentin [3-kinase, Akt, or S160] (Saravanan, Vengatashbabu,
& Ramachandran, 2012; Shibata et al., 1995; Chen, Jeppesen, Nordentoft, &
Hermansen, 2007; Yang et al., 2006). If insulin sensitivity as well as regulation
of blood glucose is restored via stevia dependent mechanisms, independently of
omentin mechanisms, it could be concluded that the level of omentin is suppressed
or at least attenuated after stevia prescription.
Therefore, stevia suppresses the level of serum omentin via amelioration of
insulin resistance per se. In other words, stevia reduces omentin level indirectly
via negative feedback. Additionally, declining serum omentin levels following ste-
via administration could be explained through the relationships between omentin
and non-alcoholic fatty liver disease (NAFLD). There is a well-established as-
sociation between increased omentin level and the incidence of NAFLD. It has
been reported that the level of omentin is an independent predictor for disruption
of microtubules and necrosis of hepatocyte in NAFLD (Yilmaz et al., 2011). On
the other hand, the association between NAFLD and diabetes is very well estab-
lished (Utzschneider & Kahn, 2006). If NAFLD, which is a hepatic manifestation
of metabolic syndrome and is characterized by insulin resistance (Utzschneider &
Kahn, 2006), is treated by stevia administration, it will regulate not only blood glu-
cose but also omentin levels. It should also be noted that the effect of stevia on
liver has been accompanied by protective properties (Saravanan et al., 2012). In
summary it could be concluded that the ability of stevia to lower omentin levels
might be primarily attributed to its hepatic protective functions, while acknowl-
edging that other mechanisms are also involved.
In the current study the level of fasting plasma glucose decreased in those rats
which consumed stevia in comparison with the control group. The hypoglycemic
effect of stevia is recognized and could be found elsewhere (Gregersen, Jeppesen,
Holst, & Hermansen, 2004), although the mechanisms involved are not fully elu-
cidated. Some reports have indicated that the hypoglycemic effect of stevia could
attributed to the enhancement of insulin secretion (Jeppesen et al., 2000), the cor-
rection of liver gluconeogenic enzymes abnormalities (Saravanan et al., 2012), the
suppression of glucagon secretion by the α-cell of the pancreas (Shibata et al., 1995;
Chen et al., 2007) and finally by augmentation of glucose utilization in peripheral
tissues and muscles (Chen et al., 2005). Analysis of the data from the present study
showed no significant changes in insulin level following stevia prescription. Accord-
ingly HOMA-B did not changed throughout the study and analyzing the pancreatic
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8Akbarzadeh et al.
biopsy samples of treated rats demonstrated no increase in B-cell in comparison to
untreated groups (Figure 1). Sustained HOMA-B accompanied by a significant re-
duction in HOMA-IR, following stevia prescription, together lead us to assume that
stevia decreases blood glucose via enhancing insulin binding capacity. In agreement
with our findings, Chen et al. suggested stevioside is able to regulate blood glucose
level by enhancing insulin utilization in insulin-deficient rats. He concluded that
this property of stevia is due to decreased protein levels of phosphoenol pyruvate
carboxykinase (PEPCK) and PEPCK mRNA which simultaneously slow down glu-
coneogenesis in rat liver (Chen et al., 2005). More studies are likely warranted to
elucidate the ambiguities which have surrounded the mechanisms involved in the
role of stevia in modulating blood glucose at the cellular levels.
Besides the hypoglycemic effects, our findings also point to a hypolipidemic role
for stevia. The published sources about the impact of stevia in lipid profiles are
scarce. In this study the TG level has decreased significantly after stevia adminis-
tration. The hypo lipidemic property of stevia might be explained by interaction
between stevia consumption and activation of peroxisome proliferators-activated
receptors (PPARs). Recently a working model was developed, at the gene tran-
scriptional level, which involves PPARs as a regulatory factor in lipogenesis pro-
cess (Pegorier, May, & Girard, 2004). Some studies indicated that PPARs could ac-
tivate the expression of the lipoprotein lipase (LPL) and apo C-II genes as well as
the hepatic uptake and esterification of free fatty acids, along with increasing mito-
chondrial free fatty acid oxidation (Fruchart & Duriez, 2006; Auwerx, Schoonjans,
Fruchart, & Staels, 1996). Mueller et al. concluded that stevia can activate PPARα
and identified this property as a possible mechanism involved in the hypotriglyc-
eridemic effect of stevia (Mueller, Beck, & Jungbauer, 2011).
It should also be mentioned that the reduction of TG, FBS, ALK, and omentin
did not appear in a dose dependent manner. With increasing dosage of stevia the
beneficial impact was reduced. The U-shaped relationship between the stevia doses
and the fasting blood glucose, the TG as well as the omentin levels in this study
leads us to conclude that the impact of stevia on blood lipids glucose, liver enzyme,
as well as on omentin has a saturation limit, beyond which further increase of ste-
via consumption has significant beneficial effect (Figures 2–4). It could therefore
be concluded that here are therapeutic limits for this agent, beyond which not only
are the beneficial characteristics eliminated but toxic implications appear. There
are some reports indicating that the medium lethal dose (LD50) for stevia is more
than 5 g/kg/d, although lower doses have revealed no significant changes in the
animal behavior, such as in alertness, motor activity, breathing, restlessness, diar-
rhea, convulsions, coma, and appearance. No death was also observed up to the
dose of 5 g/kg body weight (Kujur et al., 2010). The toxicity of herbal medicine
has been always a subject of debate. The hepatic insult following herbal medicine
treatment has been reported by several studies (Posadzki, Watson, & Ernst, 2013;
Nunes et al., 2007). In our study histopathology analysis of samples of liver biopsy
showed no lesions at the dosage level applied in the study when compared to those
of the control group (Figure 1). Shivanna et al. believed that stevia has renal and
hepatic protective properties which are manifested by attenuation of malondialde-
hyde (MDA) and improvement of the antioxidant status of the liver. They believed
that this characteristic is due to the antioxidant component of stevia (Shivanna,
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Stevia Omentin Visfatin Diabetes 9
0
100
200
300
400
500
600
group 1 group 2 group 3 group 4 group 5
FBS mg/dl
Groups
FIGURE 2. Effect of stevia on FBS. Prescription of stevia in doses of 250 mg/kg/d in the
group 3 and 500 mg/kg/d in the group 4 decreased FBS significantly in respect to the group
2 (diabetic control group). No significant change in FBS was seen following prescription of
stevia in doses of 750 mg/kg/d a in group 5 in comparison with group 2 (n=8, mean ±SD,
p<.05).
Naika, Khanum, & Kaul, 2013). In the current study also a significant reduction in
the hepatic ALP was found which confirms the hepatic protective role of stevia up
to a dose of 250–500 mg/kg/d.
In the present study the visfatin level did not change following stevia prescrip-
tion. Some studies have reported inconsistent and conflicting results regarding as-
sociations between visfatin and diabetes (Eriksson et al., 1989; Zhang et al., 2010).
0
20
40
60
80
100
120
group 1 group 2 group 3 group 4 group 5
TG mg/dl
Groups
FIGURE 3. Effect of stevia on TG. Prescription of stevia in doses of 250 mg/kg/d in group
3 and 500 mg/kg/d in group 4 decreased TG significantly in respect of group 2 (diabetic
control group). No significant change in FBS was seen following prescription of stevia in
doses of 750 mg/kg/d in group 5 in comparison with group 2 (n=8, mean ±SD, p<.05).
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10 Akbarzadeh et al.
0
20
40
60
80
100
120
140
group 1 group 2 group 3 group 4 group 5
Omenn ng/ml
Groups
FIGURE 4. Effect of stevia on serum omentin level. Prescription of stevia in doses of
250 mg/kg/d in group 3 and 500 mg/kg/d in group 4 decreased omentin, significantly in
comparison with group 2 (diabetic control group). No significant change in omentin was
seen following prescription of stevia in doses of 750 mg/kg/d in group 5 in comparison with
group 2 (n=8, mean ±SD, p<.05).
The original work describing visfatin binding to IR has been withdrawn (Fukuhara
et al., 2005).There are several reports that show significant correlation between
plasma visfatin concentrations and the amount of visceral fat (Fukuhara et al., 2005;
Haider et al., 2006). Han et al. found significant increase in visfatin level among
obese compared to non-obese rats, which confirms the strong association between
obesity and increased visfatin in animal models (Han, Zhang, Qin, & Zhai, 2013).
In our study the weight of the animals did not change throughout the study and this
could be considered a potential reason for non-significant changes in visfatin level
in the treated groups.
CONCLUSION
It is concluded that prescription of stevia in a dose of 250 and 500 mg/d p.o. de-
creases the omentin level indirectly via activating insulin sensitivity and lowering
blood glucose in STZ-induced diabetic rats. It is worth mentioning that we did not
evaluate the effects of ether extract and methanolic extract of stevia on the adipocy-
tokines level in diabetic rats. A future study of this area would be worthwhile.
ACKNOWLEDGMENTS
This study was supported in part by the The Persian Gulf Tropical Medicine
Research Center, Bushehr University of Medical Sciences, Bushehr, Iran
(DP/8703277330,14/9/2010).
Declaration of interest: The authors report no conflict of interest. The authors
alone are responsible for the content and writing of this paper.
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Stevia Omentin Visfatin Diabetes 11
ABOUT THE AUTHORS
Samad Akbarzadeh and Afshar Bargahi, Department of Biochemistry, School
of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran. Fatemeh
Eskandari, Hadis Tangestani, Somaieh Tangerami Bagherinejad, and Azam
Sahrapoor, The student’s committee research. School of Medicine, Bushehr
University of Medical Sciences, Bushehr, Iran. Parviz Bazzi, Department of
Anatomy, School of Medicine, Bushehr University of Medical Sciences, Bushehr,
Iran. Adel Daneshi, The Persian Gulf Marine Biotechnology Research Center,
Bushehr University of Medical Sciences, Bushehr, Iran. Ali Reza Rahbar,De-
partment of Nutrition, The Persian Gulf Tropical Medicine Research Center,
Bushehr University of Medical Sciences, Bushehr, Iran. William J O’Connor, The
UCD School of Mechanical & Materials Engineering, University College Dublin,
Belfield Campus, Dublin 4, Ireland.
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... Similary, combined treatment of diabetic rats with stevia extract (300 mg/kg/day) and glimepiride (1 mg/kg/day) for a similar period caused a more decrease in the BGLs in a comparison to diabetic rats treated with glimepiride alone. This finding is collaborated with the previous results that approved potential benefits of stevia plant on hyperglycemia on diabetic animals [22][23][24]. ...
... The extract has also been shown to decrease serum low-density lipoprotein cholesterol (LDLcholesterol), total cholesterol, and triglyceride (TG) (Ahmad et al., 2018;Park & Cha, 2010) and prevent fat accumulation in the liver cells (Holvoet et al., 2015). It was also found to decrease liver function enzymes, namely, alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) (Akbarzadeh et al., 2015;Shivanna, Naika, Khanum, & Kaul, 2013). Such beneficial effects have been attributed to the antioxidant and antiinflammatory properties of Stevia (Ramos-Tovar et al., 2019;Scaria et al., 2017). ...
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Aims: To assess the effects of two commonly used oral hypoglycemic medications metformin and pioglitazone on serum concentrations of omentin and leptin in patients with newly diagnosed type 2 diabetes. Methods: In a clinical trial setting (NCT01593371), patients were randomly allocated to either metformin 1000mg daily (n=41), or pioglitazone 30mg daily (n=50). Serum concentrations of omentin and leptin were measured at baseline and after 12weeks. Patients' weight, waist circumference, blood pressure, fasting plasma glucose, fasting insulin, HbA1c, highly sensitive C-reactive protein, and serum lipids were also measured at the two visits. Results: Baseline concentrations of omentin and leptin were not different between the two arms of the trial. After three months, metformin decreased both omentin and leptin concentrations in women, and leptin concentrations only in men. On the other hand, pioglitazone reduced both adipokines only in women, but not men. Univariate and multivariate ANCOVA models revealed that both interventions are equally effective in reducing omentin concentration (p=0.497 for women and 0.344 for men in multivariate models controlling for the effects of confounding variables). Similarly, neither medication was more effective in reducing leptin concentrations after three months (p=0.822 for women and 0.441 for men in multivariate models). Conclusions: Metformin and pioglitazone at pharmacologic doses are equally effective in alteration of serum omentin and leptin concentrations in patients with diabetes, albeit sex differences in response to medications exist. Implication of these findings on long term management and complication prevention of diabetes needs to be elucidated.
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Obesity is a well-known risk factor for the development of insulin resistance, type 2 diabetes, dyslipidemia, hypertension, and cardiovascular disease. Rather than the total amount of fat, central distribution of adipose tissue is very important in the pathophysiology of this constellation of abnormalities termed metabolic syndrome. Adipose tissue, regarded only as an energy storage organ until the last decade, is now known as the biggest endocrine organ of the human body. This tissue secretes a number of substances - adipocytokines - with multiple functions in metabolic profile and immunological process. Therefore, excessive fat mass may trigger metabolic and hemostatic disturbances as well as CVD. Adipocytokines may act locally or distally as inflammatory, immune or hormonal signalers. In this review we discuss visceral obesity, the potential mechanisms by which it would be related to insulin resistance, methods for its assessment and focus on the main adipocytokines expressed and secreted by the adipose tissue. Particularly, we review the role of adiponectin, leptin, resistin, angiotensinogen, TNF-α , and PAI-1, describing their impact on insulin resistance and cardiovascular risk, based on more recent findings in this area.
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Background: Stevia rebaudiana Bertoni has been used for the treatment of diabetes in, for example, Brazil, although a positive effect on antidiabetic and its complications has not been unequivocally demonstrated. This herb also has numerous therapeutic properties which have been proven safe and effective over hundreds of years. Streptozotocin is a potential source of oxidative stress that induces genotoxicity. Objective: We studied the effects of stevia leaves and its extracted polyphenols and fiber on streptozotocin induced diabetic rats. We hypothesize that supplementation of polyphenols extract from stevia to the diet causes a reduction in diabetes and its complications. Design/methods: Eighty Wistar rats were randomly divided into 8 groups; a standard control diet was supplemented with either stevia whole leaves powder (4.0%) or polyphenols or fiber extracted from stevia separately and fed for one month. Streptozotocin (60 mg/kg body weight, i.p) was injected to the diabetic groups on the 31st day. Several indices were analyzed to assess the modulation of the streptozotocin induced oxidative stress, toxicity and blood glucose levels by stevia. Results: The results showed a reduction of blood glucose, ALT and AST, and increment of insulin level in the stevia whole leaves powder and extracted polyphenols fed rats compared to control diabetic group. Its feeding also reduced the MDA concentration in liver and improved its antioxidant status through antioxidant enzymes. Glucose tolerance and insulin sensitivity were improved by their feeding. Streptozotocin was also found to induce kidney damage as evidenced by decreased glomerular filtration rate; this change was however alleviated in the stevia leaves and extracted polyphenol fed groups. Conclusion: The results suggested that stevia leaves do have a significant role in alleviating liver and kidney damage in the STZ-diabetic rats besides its hypoglycemic effect. It might be adequate to conclude that stevia leaves could protect rats against streptozotocin induced diabetes, reduce the risk of oxidative stress and ameliorate liver and kidney damage.
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Rebaudioside A (Reb A), a major constituent of Stevia rebaudiana, was recently proposed as an insulinotropic agent. The aim of this investigation was to evaluate the antihyperglycemic effect of Reb A on the activities of hepatic enzymes of carbohydrate metabolism in streptozotocin (STZ)-induced diabetic rats. Diabetes was induced in adult male Albino Wistar rats, weighing 180-200 g, by a single intraperitoneal injection at a dose of STZ (40 mg/kg body weight). Diabetic rats showed significant (P<0.05) increase in the levels of plasma glucose and glycosylated hemoglobin and significant (P<0.05) decrease in the levels of plasma insulin and hemoglobin. Activities of gluconeogenic enzymes such as glucose-6-phosphatase and fructose-1,6-bisphosphatase were significantly (P<0.05) increased while hexokinase and glucose-6-phosphate dehydrogenase were significantly (P<0.05) decreased in the liver along with glycogen. Oral treatment with Reb A to diabetic rats significantly (P<0.05) decreased blood glucose and reversed these hepatic carbohydrate metabolizing enzymes in a significant manner. Histopathology changes of pancreas confirmed the protective effects of Reb A in diabetic rats. Thus, the results show that Reb A possesses an antihyperglycemic activity and provide evidence for its traditional usage in the control of diabetes.