ArticlePDF Available

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


Abstract and Figures

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.
Content may be subject to copyright.
Journal of Dietary Supplements, Early Online:1–12, 2014
2014 by Informa Healthcare USA, Inc.
Available online at
DOI: 10.3109/19390211.2014.901999
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
(Received 14 June 2013; accepted 3 December 2013)
J Dietary Suppl Downloaded from by on 04/02/14
For personal use only.
2Akbarzadeh et al.
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.
Forty specific pathogen-free male wistar rats weighing 180–250 g were provided
from the Medical Center Animal Research facility at Esfahan University of
J Dietary Suppl Downloaded from by on 04/02/14
For personal use only.
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.
J Dietary Suppl Downloaded from by on 04/02/14
For personal use only.
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
HOMA B=20 ×InsulinμIU
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).
J Dietary Suppl Downloaded from by on 04/02/14
For personal use only.
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.
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.
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
J Dietary Suppl Downloaded from by on 04/02/14
For personal use only.
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
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.
J Dietary Suppl Downloaded from by on 04/02/14
For personal use only.
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
J Dietary Suppl Downloaded from by on 04/02/14
For personal use only.
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,
J Dietary Suppl Downloaded from by on 04/02/14
For personal use only.
Stevia Omentin Visfatin Diabetes 9
group 1 group 2 group 3 group 4 group 5
FBS mg/dl
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,
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).
group 1 group 2 group 3 group 4 group 5
TG mg/dl
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).
J Dietary Suppl Downloaded from by on 04/02/14
For personal use only.
10 Akbarzadeh et al.
group 1 group 2 group 3 group 4 group 5
Omenn ng/ml
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.
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.
This study was supported in part by the The Persian Gulf Tropical Medicine
Research Center, Bushehr University of Medical Sciences, Bushehr, Iran
Declaration of interest: The authors report no conflict of interest. The authors
alone are responsible for the content and writing of this paper.
J Dietary Suppl Downloaded from by on 04/02/14
For personal use only.
Stevia Omentin Visfatin Diabetes 11
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.
Auwerx J, Schoonjans K, Fruchart JC, Staels B. Regulation of triglyceride metabolism by PPARs:
fibrates and thiazolidinediones have distinct effects. J Atheroscler Thromb. 1996;3:81–89.
ao C, Ferreira SR, Giuffrida FM, Ribeiro-Filho FF. The new adipose tissue and adipocy-
tokines. Curr Diabetes Rev. 2006;2:19–28.
Chandran M, Phillips SA, Ciaraldi T, Henry RR. Adiponectin: more than just another fat cell
hormone? Diabetes Care. 2003;26:2442–2450.
Chen TH, Chen SC, Chan P, Chu YL, Yang HY, Cheng JT. Mechanism of the hypoglycemic
effect of stevioside, aglycoside of Stevia rebaudiana. Planta Med. 2005;71:108–113.
Chen J, Jeppesen PB, Nordentoft I, Hermansen K. Stevioside improves pancreatic? cell func-
tion during glucotoxicity via regulation of acetyl-CoA carboxylase. Am J Physiol Endocrinol
Metab. 2007;292:1906–1916.
Eriksson J, Franssila-Kallunki A, Ekstrand A, Saloranta C, Wid´
en E, Schalin C, Groop L. Early
metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus. N
Engl J Med. 1989;321:337–343.
Esteghamati A, Noshad S, Rabizadeh S, Ghavami M, Zandieh A, Nakhjavani M. Comparative
effects of metformin and pioglitazone on omentin and leptin concentrations in patients with
newly diagnosed diabetes: a randomized clinical trial. Regul Pept. 2013;14:1–6. [Epub ahead
of print]
Fallah-Hoseini H, Fakhrzadeh H, Larijani B, Shikhsamani A. Review of anti-diabetic medicinal
plant used in traditional medicine. J Med Plant. 2006;5:1–8.
Fruchart JC, Duriez P. Mode of action of fibrates in the regulation of triglyceride and HDL-
cholesterol metabolism. Drugs Today (Barc). 2006;42(1):39–64.
Fukuhara A, Matsuda M, Nishizawa M, Segawa K, Tanaka M, Kishimoto K, Matsuki Y,
Murakami M, Ichisaka T, Murakami H, Watanabe E, Takagi T, Akiyoshi M, Ohtsubo T, Ki-
hara S, Yamashita S, Makishima M, Funahashi T, Yamanaka S, Hiramatsu R, Matsuzawa Y,
Shimomura I. Visfatin: a protein secreted by visceral fat that mimics the effects of insulin.
Science. 2005;307:426–430.
Gregersen S, Jeppesen PB, Holst JJ, Hermansen K. Antihyperglycemic effects of Stevioside in
Type 2 diabetic subjects. Metabolism. 2004;53:73–76.
Han S, Zhang H, Qin L, Zhai C. Effect of dietary carbohydrate replaced with wild rice (Zizania
latifolia (Griseb) Turcz) on insulin resistance in rats fed with high-fat/cholesterol diet. Nutri-
ents. 2013;5:552–564.
Haider DG, Schindler K, Schaller G, Prager G, Wolzt M, Ludvik B. Increased plasma visfatin
concentrations in morbidly obese subjects are reduced after gastric banding. J Clin Endocrinol
Metab. 2006;91:1578–1581.
J Dietary Suppl Downloaded from by on 04/02/14
For personal use only.
12 Akbarzadeh et al.
Jeppesen PB, Gregersen S, Poulsen CR, Hermansen K. Stevioside acts directly on pancreatic beta
cells to secrete insulin: actions independent of cylcic adenosine monophosphate and adenosine
triphosphate sensitive potassium ion channel activity. Metabolism 2000;49:208–214.
Kujur RS, Singh V, Ram M, Yadava HN, Singh KK, Kumari S, Roy BK. Antidiabetic activity
and phytochemical screening of crude extract of Stevia rebaudiana in alloxan-induced diabetic
rats. Pharmacognosy Res. 2010;2:258–263.
Lailerd N, Saengsirisuwan V, Sloniger JA, Toskulkao C, Henriksen EJ. Effects of stevioside
on glucose transport activity in insulin-sensitive and insulin-resistant rat skeletal muscle.
Metabolism. 2004;53:101–107.
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis
model assessment: insulin resistance and beta-cell function from fasting plasma glucose and
insulin concentrations in man. Diabetologia. 1985;28:412–419.
Mueller M, Beck V, Jungbauer A. PPARαactivation by culinary herbs and spices. Planta Med.
Nunes AP, Ferreira-Machado SC, Nunes RM, Dantas FJ, De Mattos JC, Caldeira-de-Ara ´
A. Analysis of genotoxic potentiality of stevioside by comet assay. Food Chem Toxicol.
Pegorier JP, May CL & Girard J. Control of gene expression by fatty acids. J Nutr.
Posadzki P, Watson LK, Ernst E. Adverse effects of herbal medicines: an overview of systematic
reviews. Clin Med. 2013;13:7–12.
Saravanan R, Vengatashbabu K, Ramachandran V. Effect of Rebaudioside A, a diterpenoid on
glucose homeostasis in STZ-induced diabetic rats. J Physiol Biochem. 2012;68:421–431.
Shibata H, Sawa Y, Oka T, Sonoke S, Kim KK, Yoshioka M. Steviol and steviol glycoside. Glu-
cosyltransferase activities in S. rebaudiana Bertoni. Purification and partial characterization.
Arch Biochem Biophys. 1995;321:390–396.
Shivanna N, Naika M, Khanum F, Kaul VK. Antioxidant, anti-diabetic and renal protective prop-
erties of Stevia rebaudiana. J Diabetes Complicat. 2013;27:103–113.
Soejarto DD, Kinghorn AD, Farnsworth NR. Potential sweetening agents of plant origin.
III. Organoleptic evaluation of Stevia leaf herbarium samples for sweetness. J Nat Prod.
World Health Organization. Geneva: WHO; (2008). Diabetes, Fact sheet no. 312. [Last
cited on 2010 May 23]. Available from:
Yang RZ, Lee MJ, Hu H, et al. Identification of omentin as a novel depot-specific adipokine in
human adipose tissue: possible role in modulating insulin action. Am J Physiol Endocrinol
Metab. 2006;290:E1253–E1261.
Yan P, Li L, Yang M, Liu D, Liu H, Boden G, Yang G. Effects of the long-acting human glucagon-
like peptide-1 analog liraglutide on plasma omentin-1 levels in patients with type 2 diabetes
mellitus. Diabetes Res Clin Pract. 2011;92:368–374.
Yilmaz Y, Yonal O, Kurt R, Alahdab Y, Eren F, Ozdogan O, Celikel C, Imeryuz N, Kalayci
C, Avsar E. Serum levels of omentin, chemerin and adipsin in patients with biopsy-proven
nonalcoholic fatty liver disease. Scand J Gastroenterol. 2011;46:91–97.
Utzschneider KM, Kahn SE. Review: the role of insulin resistance in nonalcoholic fatty liver
disease. J ClinEndocrinol Metab. 2006;91:4753–4761.
Zhang H, Xie H, Zhao Q, Xie GQ, Wu XP, Liao EY, Luo XH. Relationships between serum
adiponectin, apelin, leptin, resistin, visfatin levels and bone mineral density, and bone bio-
chemical markers in post-menopausal Chinese women. J Endocrinol Invest. 2010;33:707–711.
Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature.
J Dietary Suppl Downloaded from by on 04/02/14
For personal use only.
... In addition, daily oral administration of another stevia glycoside, rebaudiana A, at the dose of 50-500 mg kg −1 BW, significantly reduced fasting blood glucose and insulin resistance. It protected β-cells in STZ-induced diabetic rats [37,38]. On the contrary, Dyrskog et al. [18] mentioned that daily oral administration of rebaudiana A at a dose of 25 mg kg −1 BW for 8 weeks did not improve blood glucose, serum insulin, and glucose tolerance in spontaneously diabetic rats. ...
... A slight reduction in SIL was observed in DR+SU as a non-significant effect compared to the NR group. An improvement was shown when Stevia-based sweeteners or rebaudiana A were orally taken, as mentioned by Dyrskog et al. [18] and Akbarzadeh et al. [37]. ...
... Although the concentration of ALT and AST increased dramatically in the STZ-DR group compared to NR, SU did not affect the concentrations of ALT and AST in NR+SU and NR+SU+ST groups. Akbarzadesh et al. [37] reported that the daily oral administration of S. rebaudiana A (250, 500, and 750 mg kg −1 BW) did not significantly affect the AST and ALT. ...
Full-text available
Numerous food organizations have identified excessive calorie consumption and accompanying ailments as significant health risks associated with high sugar consumption. Administering stevioside (ST), sucralose (SU), and the two synergically (SU+ST) affected normal rats’ weight gain. In the current study, SU showed the highest undesired effect. Indeed, administering the three treatments to diabetic rats (DR) did not improve the rats’ weight gain. Although, insulin injection synergically with the treatments improved the weight gain, as recorded after three weeks. The best-improving rate was observed in the ST group. After the administration of ST and ST+SU to the DR, the blood glucose level (GL) was positively affected, with SU having no effects on reducing the GL. A considerable reduction in serum insulin (SIL) was noted in the DR+SU group. On the contrary, ST did not negatively affect the SIL, rather an improvement was recorded. In addition, giving SU did not significantly affect the ALT level in the DR or normal rats (NR). A significant improvement in total bilirubin (TBILI) was observed when insulin was injected with ST or SU in DR groups. Further, triglycerides (TG) after administering ST, SU, or ST+SU to NR had no significant difference compared to the control group (NR). Although, the three treatments markedly but not significantly lowered TG in the DR. For total cholesterol (CHO), both DR and NR had no significant effect after the three treatments. No histopathological alterations were recorded in the NR group. Diffuse and severe atrophy of the islands of Langerhans due to depletion of their cells and mild papillary hyperplasia of the pancreatic ducts were represented by a slightly folded ductal basement membrane and newly formed ductules in STZ-DR. Simultaneous atrophy and absence of the cells of islands of Langerhans besides ductal hyperplasia were evident in DR+SU. Hyperplastic ductal epithelium and atrophic Langerhans cells were seen in DR+SU+In. Degeneration and mild atrophy were observed in the islands of Langerhans structures. There was essentially no noticeable change after utilizing ST. A slight shrinkage of the Langerhans’ islets was detected in DR+ST. In DR+ST+In, no histopathological alterations in the islands of Langerhans were recorded. Congestion in the stromal blood vessels associated with degenerative and necrotic changes in the cells of the islands of Langerhans in DR+SU+ST was observed. In NR+SU, congestion of the blood vessels associated with mild atrophy in the islands of Langerhans and dilatation in stromal blood vessels was noticed. In conclusion, ST is safe, and SU should be taken cautiously, such as mixing with ST and/or taken at a very low concentration to avoid its drastic effect on the human body.
... To cool, store in a refrigerator at 4 • C until further analysis. To prepare the supplemented cupcake samples, sugar was replaced by BPP, CLP, SLP, and mixed SLP-BPP and SLP-CLP (1:1 w/w) at different levels (20,40,60, and 80%), which represented 4, 8, 12, and 16% from the total formula of the cupcake. Table 1 presents the formulations of the cupcake samples supplemented with 12% agro-wastes and Stevia powder, representing the highest amount that could be added with the lowest changes in sensory attributes. ...
... Both of these actions could help improve the body's enzymes that break down carbohydrates and restore normal blood glucose levels [59]. Stevia rebaudiana leaves' extract has been found to reduce random and fasting blood glucose levels in rats by reviving the β-cells of the pancreas, reactivating the glycogen synthase system, enhancing insulin secretion, and increasing liver glycogen level [60]. Table 7 presents the results of a study on the effects of cupcake samples containing Stevia and agro-wastes on serum liver functions, ALT, AST, and albumin of alloxan-induced diabetic rats. ...
Full-text available
One potential solution to enhance the nutritional value of food while addressing environmental concerns is to use bioactive extracts from agro-waste in the food industry. This study aimed to investigate the effects of replacing sucrose with powders made from Stevia leaves (SLP), banana peels (BPP), and carrot leaves (CLP), as well as their mixtures, in cupcakes. Additionally, the study aimed to determine the impact of these substitutes on alloxan-induced diabetic rats fed the cupcakes. Sensory evaluation revealed that up to 60% of sucrose in the cupcake formula could be replaced without significant changes in sensory attributes. Substituting agro-wastes and SLP increased the protein content from 12.86% to 14.26% and the dietary fiber content from 3.65% to 5.60% compared to the control sample. The treated diabetic groups, particularly those fed cupcakes containing SLP-CLP mixture, showed increased body weight gain % and feed intake, reducing serum glucose levels from 427.5 to 180.8 mg/dL after 28 days. The mix of CLP-SLP had the highest additive effect, indicating a significant reduction in various biochemical parameters, including ALT, AST, albumin, urea, uric acid, creatinine, total cholesterol, triglyceride, and LDL, compared to the positive control. No histopathological alterations were detected in the pancreas and liver of diabetic rats fed cupcakes supplemented with SLP-CLP. However, moderate degenerations were observed in the hepatocytes of diabetic rats fed cupcakes fortified with SLP-BPP.
... Hence, many studies have tried to address how to protect beta cells from metabolic insults [5][6][7][8][9]. In this regard, Stevia rebaudiana Bertoni (Stevia), a native plant to the northeast of Paraguay, mainly known for its sweetener properties, has recently been shown to have beneficial effects in several models of disease and cellular dysfunction, including diabetes and beta cells [10][11][12][13][14][15][16][17][18][19]. Stevia leaf extracts represent, in fact, a unique Natural Complex Substance, thanks to the presence of steviol glycosides, phenolic acids, flavonoids, alkaloids, water-soluble chlorophylls, xanthophylls, hydroxycinnamic acids, minerals, and vitamins [20]. ...
Full-text available
Aims Stevia rebaudiana Bertoni leaf extracts have gained increasing attention for their potential protection against type 2 diabetes. In this study, we have evaluated the possible beneficial effects of Stevia rebaudiana leaf extracts on beta-cells exposed to lipotoxicity and explored some of the possible mechanisms involved. Methods Extracts, deriving from six different chemotypes (ST1 to ST6), were characterized in terms of steviol glycosides, total phenols, flavonoids, and antioxidant activity. INS-1E beta cells and human pancreatic islets were incubated 24 h with 0.5 mM palmitate with or without varying concentrations of extracts. Beta-cell/islet cell features were analyzed by MTT assay, activated caspase 3/7 measurement, and/or nucleosome quantification. In addition, the proteome of INS-1E cells was assessed by bi-dimensional electrophoresis (2-DE). Results The extracts differed in terms of antioxidant activity and stevioside content. As expected, 24 h exposure to palmitate resulted in a significant decrease of INS-1E cell metabolic activity, which was counteracted by all the Stevia extracts at 200 μg/ml. However, varying stevioside only concentrations were not able to protect palmitate-exposed cells. ST3 extract was also tested with human islets, showing an anti-apoptotic effect. Proteome analysis showed several changes in INS-1E beta-cells exposed to ST3, mainly at the endoplasmic reticulum and mitochondrial levels. Conclusions Stevia rebaudiana leaf extracts have beneficial effects on beta cells exposed to lipotoxicity; this effect does not seem to be mediated by stevioside alone (suggesting a major role of the leaf phytocomplex as a whole) and might be due to actions on the endoplasmic reticulum and the mitochondrion.
... 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]. ...
Full-text available
Background: The currently therapy of type 2 diabetes is unsatisfactory. Nowadays, there is a great interest in using the medicinal plants for treatment of diabetes. Therefore, we studied the efficacy of stevia extract alone and in combination with commonly used sulfonylureas ”glimepiride” in a trial to introduce a new effective therapeutic regimen for type 2 diabetes mellitus. Methods: Nicotinamide (230 mg/kg, IP) followed by streptozotocin (65 mg/kg, IP) were injected for induction of type 2 diabetes in male rats. The diabetic groups were treated for 21 days as the following, the first with stevia extract (300 mg/kg), the second with glimepiride (1 mg/kg), and the third with a combination of glimepiride and stevia extract. Many parameters were measured to evaluate the alleviation of the toxic effect of streptozotocin by stevia and/or glimepiride. Immunohistochemical expression of endothelial nitric oxide (eNOS) was assessed in renal tissues. Results: The stevia extract reduced the blood glucose, triglycerides, cholesterol, ALT, AST, urea, creatinine, tumour necrosis factor (TNFα) levels and malondialdehyde concentration compared to control diabetic group. Stevia treatment improved insulin and adiponectin levels. Stevia reduced eNOS expression in renal tissues compared to the diabetic rats. All these changes were more significant with combined treatment. Conclusion: Stevia and glimepiride may be a new putative therapeutic regimen for management of type 2 diabetes and its complications.
The placenta provides maternal–fetal nutrient transport. The primary source of energy for fetus development is glucose and maternal–fetal glucose transport occurs through glucose transporters (GLUTs). Stevioside, a component of Stevia rebaudiana Bertoni, is used for medicinal and commercial purposes. We aim to determine the effects of stevioside on GLUT 1, GLUT 3, and GLUT 4 proteins expressions in diabetic rat placentas. The rats are divided into four groups. A single dose of streptozotocin (STZ) is administered to form the diabetic groups. Pregnant rats receive stevioside to form the stevioside and diabetic + stevioside groups. According to immunohistochemistry results, GLUT 1 protein is found in both the labyrinth and junctional zones. GLUT 3 protein is limited in the labyrinth zone. GLUT 4 protein is detected in trophoblast cells. According to Western blotting results, on the 15th and 20th days of pregnancy, there is no difference in the expression of GLUT 1 protein between groups. On the 20th day of pregnancy, the expression of GLUT 3 protein in the diabetic group is statistically higher compared to the control group. On the 15th day and 20th day of pregnancy, the expression of GLUT 4 protein in the diabetic group is statistically lower compared to the control group. Insulin levels in blood samples derived from rat abdominal aorta are determined by the ELISA method. According to the ELISA results, there is no difference in insulin protein concentration between groups. Stevioside treatment reduces GLUT 1 protein expression under diabetic conditions.
Full-text available
Full-text available
Stevia (Stevia rebaudiana Bertoni) is a natural herb with biological activities such as anticancer, antidiabetic, anticardiovascular disease, anti-inflammatory, and antimicrobial. The current systematic review and meta-analysis of previously published data were performed to assess the antidiabetic effect of stevia leaves. Three electronic databases (PubMed, CENTRAL, and DOAJ) had been used for searching articles published before September 2020. Meta-analysis via random-effect model had been performed to assess the effects of different doses of stevia on blood glucose level (BGL) and studies were weighted according to an estimate of the standard mean difference (SMD). Overall, 16 eligible studies were selected for qualitative analysis and 9 were included for quantitative analysis. The results of the meta-analysis for BGL showed that at the doses of 200, 300, and 400 mg/kg of stevia leaves there was a significant difference in means of BGL between the intervention and control group and the dose of 500 mg/kg showed no significance (Standard mean difference (SMD): −3.84 (−9.96, 2.27); p =.22). Based on the duration of intervention, subgroup analysis of articles showed a significant difference between the groups (p <.001). The results of the meta-analysis support the hypothesis that stevia leaf has an antihyperglycemic effect and reduces the blood glucose level at doses of 200, 300, and 400 mg/kg. Therefore, more clinical trials on animals and humans have to be done to investigate the antidiabetic and antihyperglycemic effects along with the efficacy and safety of these medicinal leaves. © 2022 The Authors. Food Science & Nutrition published by Wiley Periodicals LLC.
Objective To examine the effects of D-tagatose or stevia preloads on carbohydrate metabolism markers after an oral glucose load, as well as subjective and objective appetite in women with insulin resistance (IR). Research Design and Methods Randomized controlled crossover study. Women with IR without T2DM (n=33; aged 23.4 ± 3.8; BMI 28.1 ± 3.4 kg×m⁻²) underwent three oral glucose loads (3 hours each) on three different days. Ten min before oral glucose load, volunteers consumed a preload of 60 mL water (control), 60 mL water with stevia (15.3 mg), or D-tagatose (5000 mg). Serum glucose and C-peptide were evaluated at -10, 30-, 60-, 90-, 120-, and 180-min. Subjective appetite was determined with a visual analog scale. Food intake was measured at ad libitum buffet after 180 minutes. Results C-peptide iAUC was significantly higher for stevia (median (IQR): 1033 (711-1293) ng×min×L⁻¹) vs. D-tagatose (794 (366-1134) ng×min×L⁻¹; P=0.001) or control (730 (516-1078) ng×min×L⁻¹; P = 0.012). At 30- and 60-min serum glucose was higher for stevia vs other conditions (P<0.01). Volunteers reported greater satiety for stevia and D-tagatose vs. control at 60 min and greater desire to eat for stevia vs. control at 120- min (all P<0.05). Objective appetite did not vary by condition (P=0.06). Conclusions Our findings suggest that these NNS are not inert. Stevia intake produced an acute response on C-peptide release while increased serum glucose at earlier times. It is possible that NNS affects subjective but not objective appetite. This trial is registered at as NCT04327245. Clinical Trial Registry NCT04327245.
The most common causes of morbidity and mortality are cardiovascular diseases (CVDs), which are typically associated with stress, insufficient exercise, poor diet, and overweight. CVDs can be prevented by modifying certain risk factors, such as cholesterol and blood sugar levels and body weight. Natural sugars from fruits and honey have long been part of the human diet. However, although sucrose was the main sweetener during the 20th century, it is gradually being replaced by artificial sweeteners. These are many times sweeter than natural sugar and as they often have no calories, they may be used for weight control. Some papers indicate that natural sweeteners such as stevia (obtained from Stevia rebaudiana Bertoni) may be safer alternatives for prophylaxis of CVDs. Therefore, this mini-review provides an overview of existing knowledge about the effects of stevia and its secondary metabolites on cardiovascular risk factors, particularly its antihyperlipidemic properties; however, only a few studies have evaluated the effects of stevia in humans, and they tend to be of low quality. For example, only one experiment has confirmed that stevia extract has antihyperlipidemic action in women with hypercholesterolemia, and another indicates that stevioside can manage blood pressure in patients with mild hypertension. Additionally, the concentrations of the bioactive components of stevia leaves have no clear correlation with their biological properties, especially in human models. Therefore, future research should be focused on in vivo studies evaluating the effects of regular consumption of stevia products on the cardiovascular system and CVD risk factors, both in healthy individuals and those with diabetes. Further studies are needed to clarify the mechanism of action behind the functional effects of stevia preparations, including those of two major secondary metabolites: stevioside and rebaudioside A.
Full-text available
Stevia is a unique ingredient rising in the world, valued for being calorie-free as it helps reduce energy intake and added sugar in food. Like all other natural sugars, Stevia is plant-based, belonging to the Asteraceae Family. The leaves of stevia are mainly used as a sweetener and flavor enhancer in the food and beverage industry. The chemical compound obtained from stevia is considered to be the best alternative source of sugar especially for diabetes and obese patients. Several studies have shown that steviosides and similar substances, such as rebaudioside A and isosteviol, may have therapeutic benefits in addition to its sweetness. These benefits include anti-hyperglycemic, anti-hypertensive, anti-inflammatory, anti-tumor, anti-diarrheal, antibacterial, diuretic, antiseptic, anti-inflammatory, anti-fertility, hypotensive, and immunomodulatory actions. The use of Stevia prevents hypertension, acts as a bactericidal agent, and stimulates insulin production and utilization which in turn helps to control type-II diabetes and obesity. The drying temperature affects the quality of the stevia product; high temperatures reduce the medicinal and economic value. Multiple worldwide regulatory authorities have concluded that consuming high-quality stevia products in specified amounts is safe for everyone.
Full-text available
Diabetes is a type of body metabolic derangement that leads to high blood sugar level following low action or lack of insulin. Several type of antidiabetic drugs are used for treatment of high blood sugar level. But due to lack of effective treatment, dietary modification and other alternative intervention is fundamental to successful treatment of diabetes whether it is type I or II. Epidemiological evidence indicates strong correlation between the processed food diet habits and incidence of diabetes. However the reestablishing a traditional diet and lifestyle as well as alternative treatment of diabetes may reduce the incidence and late complication of type II diabetes. Herbal preparation are used by diabetic patients in all societies even in industrialized countries especially among unsuccessfully treated patients and those who are candidate for insulin therapy. As most of the physicians advice their patients not to use herbal medicine, the diabetic patients will use it without knowledge of their physicians. This type of herbal therapy may lead to drug interaction or false and unstable blood glucose level monitoring. The present review covers advance knowledge of herbal medicine including: Allium cepa L., Allium sativum L. Mamordica charantia L., Gymnema sylvestre L., Trigonella foenum graecum L., Atriplex halimus L., Vaccinium myrtillus L., Ginkgo biloba L., Silybum marianum L. Gaertn., Citrullus colocynthis (L.) Schrad, Securigera securidaca L. Camellia sinensis L. and some flavanoids in the management of diabetes.
Full-text available
Wild rice (WR) is a very nutritious grain that has been used to treat diabetes in Chinese medicinal practice. City diet (CD) is based on the diet consumed by Asian area residents in modern society, which is rich in saturated fats, cholesterol and carbohydrates. The present study was aimed at evaluating the effects of replacing white rice and processed wheat starch of CD with WR as the chief source of dietary carbohydrates on insulin resistance in rats fed with a high-fat/cholesterol diet. Except the rats of the low-fat (LF) diet group, the rats of the other three groups, including to high-fat/cholesterol (HFC) diet, CD and WR diet, were fed with high-fat/cholesterol diets for eight weeks. The rats fed with CD exhibited higher weight gain and lower insulin sensitivity compared to the rats consuming a HFC diet. However, WR suppressed high-fat/cholesterol diet-induced insulin resistance. WR decreased liver homogenate triglyceride and free fatty acids levels, raised serum adiponectin concentration and reduced serum lipocalin-2 and visfatin concentrations. In addition, the WR diet potently augmented the relative expressions of adiponectin receptor 2, peroxisome proliferator-activated receptors, alpha and gamma, and abated relative expressions of leptin and lipocalin-2 in the tissues of interest. These findings indicate that WR is effective in ameliorating abnormal glucose metabolism and insulin resistance in rats, even when the diet consumed is high in fat and cholesterol.
Recent studies of obesity show that fat tissue fulfills an endocrine function by producing a variety of secreted proteins, called adipocytokines, that may play key metabolic roles. The present investigators have isolated a newly identified adipocytokine, visfatin, from visceral fat of both mice and humans. Expression of visfatin in the plasma increases as obesity develops. This substance corresponds to a protein identified as preB cell colony-enhancing factor (PBEF), a cytokine expressed in lymphocytes. In a study of 101 human males and females, plasma levels of PBEF correlated closely with the amount of visceral fat as estimated by computed tomography. Correlation with the amount of subcutaneous fat was weak. Significant elevations of PBEF mRNA were also found in KKAy mice, which serve as a model for obesity-related type 2 diabetes. These mice become obese at age 6 to 12 weeks and, at the same time, plasma PBEF levels increase significantly, as do levels of PBEF mRNA in visceral fat. Levels in subcutaneous fat change very little. Mice fed a high-fat diet had higher plasma PBEF concentrations than those fed normal chow. When recombinant visfatin was administered intravenously to c57BL/6J mice, plasma glucose decreased within 30 minutes in a dose-dependent manner. The same effect was noted in insulin-resistant obese KKAy mice, mimicking the effect of insulin injection. Visfatin also had insulin-like effects on cultured cells. In both strains of mice, chronic exposure to visfatin, using adenovirus, significantly lowered plasma levels of both glucose and insulin. Visfatin was found to bind to—and activate—the insulin receptor but in a way different from insulin. These studies indicate that visfatin shares properties of insulin both in vitro and in vivo. In addition to helping to understand glucose and lipid homeostasis and adipocyte proliferation, visfatin may prove to be a useful target when developing drug treatments for diabetes.
This overview of systematic reviews (SRs) aims to evaluate critically the evidence regarding the adverse effects of herbal medicines (HMs). Five electronic databases were searched to identify all relevant SRs, with 50 SRs of 50 different HMs meeting our inclusion criteria. Most had only minor weaknesses in methods. Serious adverse effects were noted only for four HMs: Herbae pulvis standardisatus, Larrea tridentate, Piper methysticum and Cassia senna. The most severe adverse effects were liver or kidney damage, colon perforation, carcinoma, coma and death. Moderately severe adverse effects were noted for 15 HMs: Pelargonium sidoides, Perna canaliculus, Aloe vera, Mentha piperita, Medicago sativa, Cimicifuga racemosa, Caulophyllum thalictroides, Serenoa repens, Taraxacum officinale, Camellia sinensis, Commifora mukul, Hoodia gordonii, Viscum album, Trifolium pratense and Stevia rebaudiana. Minor adverse effects were noted for 31 HMs: Thymus vulgaris, Lavandula angustifolia Miller, Boswellia serrata, Calendula officinalis, Harpagophytum procumbens, Panax ginseng, Vitex agnus-castus, Crataegus spp., Cinnamomum spp., Petasites hybridus, Agave americana, Hypericum perforatum, Echinacea spp., Silybum marianum, Capsicum spp., Genus phyllanthus, Ginkgo biloba, Valeriana officinalis, Hippocastanaceae, Melissa officinalis, Trigonella foenum-graecum, Lagerstroemia speciosa, Cnicus benedictus, Salvia hispanica, Vaccinium myrtillus, Mentha spicata, Rosmarinus officinalis, Crocus sativus, Gymnema sylvestre, Morinda citrifolia and Curcuma longa. Most of the HMs evaluated in SRs were associated with only moderately severe or minor adverse effects.
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.
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.
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.
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.