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Effects of estrogen on hyperglycemia and liver dysfunction in diabetic male rats

Article  in  International Journal of Physiology, Pathophysiology and Pharmacology · October 2012

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Int J Physiol Pathophysiol Pharmacol 2012;4(3):156-166
www.ijppp.org /ISSN:1944-8171/IJPPP1207003

Original Article
Effects of estrogen on hyperglycemia and liver dysfunction
in diabetic male rats
Marwa A Ahmed1, Khaled M A Hassanein2
1Department of Physiology Faculty of Medicine, Assiut University, Assiut 71526, Egypt; 2Department of Pathology and
Clinical Pathology, Faculty of Veterinary Medicine, Assiut University, Assiut 71526, Egypt

Received July 7, 2012; accepted August 28, 2012; Epub September 20, 2012; Published September 30, 2012

Abstract: Objective: To study the possible beneficial effect of estrogen (17β-estradiol E2) on hyperglycemia, oxidative
stress and liver dysfunctions in STZ-induced diabetic rats. A total of 40 albino male rats were randomly divided into
four groups: a control group (I), a diabetic group (II), a group given 17β estradiol (E2) for 15 days (III), and a diabetic
group given E2 for 30 days (IV). Diabetes was induced in the rats by 65 mg/kg streptozosin (STZ) via an intraperito-
neal (i.p.) injection. E2 was given in a dose of 500ug/kg/day by oral gavage. Results: E2 administration significantly
lowered plasma glucose levels, increased plasma insulin levels, and improved glucose tolerance of groups III and IV.
In addition, E2 enhanced glutathione peroxidase (GPX) and reduced lipid peroxidation in the hepatic tissues (as com-
pared to diabetic rats). E2 caused significant decrease of plasmatic phosphatase alkaline (PAL), lactate dehydro-
genase (LDH), aspartate and lactate transaminases (AST and ALT) activities of group III and IV compared to group II.
Moreover, E2 restored the histological structure of the liver and pancreas of treated groups and increased the insulin
receptors expression in the liver of groups III and IV compared to diabetic rats. Notably, these beneficial effects of E2
on diabetic rats were more prominent in group IV compared to those of group III. Conclusion: E2 has a beneficial ef-
fect on hyperglycemia, oxidative stress and ameliorates the liver dysfunction in diabetic rats and these effects may be
mediated through stimulating β-cell proliferation in pancreas and increased the insulin receptor expression in the
liver tissues.

Keywords: 17 β estradiol, diabetes, insulin, glucose tolerance, liver-male rat

Introduction temic glucose homeostasis [3, 4].

Diabetes mellitus is a chronic metabolic disor- Several studies have shown that treatment with
der that continues to present a major worldwide estrogen reduces diabetic complications [5],
health problem. It is characterized by absolute and normalizes the endothelial function in dia-
or relative deficiencies in insulin secretion and/ betes [6].
or insulin action associated with chronic hyper-
glycemia and disturbances of carbohydrate, Eestrogen receptors are present in islets of
lipid, and protein metabolism. As a conse- Langerhans [7] and the effects of 17 β -
quence of the metabolic derangements in dia- estradiol in some physiological aspects of the
betes, various complications including macro- islet of Langerhans have been known for a long
and micro-antioxidant dysfunctions develop [1]. time [8]. In spite of this, the mechanism of ac-
tion employed by 17β-estradiol is still largely
In diabetes, several features including an in- unknown [9].
crease in lipid peroxidation, alteration of the
glutathione redox state and a decrease in the Aim of the work
content of antioxidant enzymes appear [2]. The
antioxidant properties of steroid hormones have The first aim of the present work was to study
been shown in different cells and tissues. A the effect of E2 in a diabetic rat model, to gain a
number of studies have suggested that estro- better understanding of the potential protective
gens have a profound modulating effect on sys- effect of exogenous estrogens on hyperglyce-
 Estrogen and diabetes

mia, hepatic lipid peroxidation, enzymatic anti- Insulin ELISA Kit (Crystal Chem, Inc., Downers
oxidants, and histological changes of liver and Grove, IL).
pancreas in STZ-induced diabetes. And the sec-
ond aim is to discover their possible mechanism Test of oral glucose tolerance
(s) of actions.
A glucose solution (2 g/kg) was orally adminis-
Materials and methods tered to 4- hour-fasted rats, and blood samples
were taken at 0 (before glucose loading), 30,
Forty adult male white albino rats weighting 200 60, 90 and 120 minutes after glucose loading.
-220 gm provided by the Institutional Animal The serum glucose levels were measured be-
Care and Faculty of Medicine, University of As- fore loading and 30, 60, 90 and 120 minutes
siut were included in the experiment. The ex- after loading. The serum insulin levels were also
perimental protocol was approved the Ethical measured at 10 min after glucose loading to
Committee of by Faculty of Medicine, Assiut examine early insulin secretion.
University, Egypt. The experiment was per-
formed after a stabilization period in the labora- At the end of the experiment, all rats were
tory for several days. All rats were housed in a euthanized by decapitation. After decapitation
room with controlled temperature (22°C ± 2° of the rats, blood samples were collected from
C), humidity (50% ± 5%), and a 12-hour light/ retro-orbital vein in the heparin-containing tubes
dark cycle and were fed on chow and water ad and were immediately centrifuged. The plasma
libitum. was separated and stored at -20°C until ana-
lyzed for basal glucose and insulin levels of all
Grouping and diabetes induction studied groups [12].

The rats were divided into four groups consist- Biochemical measurements
ing of 10 rats each. Group I: normal control rats.
Group II: diabetic rats. Groups III: diabetic rats In plasma samples of all studied groups, the
were treated daily with 17β- estradiol activity of phosphatase alkaline (PAL), lactate
(Steraloids, Inc., Newport, RI) 500ug/kg/day by dehydrogenase (LDH), aspartate and lactate
oral gavage dissolved in 1% methylcellulose transaminases (AST and ALT) were measured
[10] for 15 days. Group IV: diabetic rats were using commercial kits from Sigma Munich
treated with E2 for 30 days. (Munich, Germany) and Boehringer-Mannheim
(Mannheim, Germany).
Diabetes was induced in overnight fasted rats
(16 h) by intraperitoneal injection (i.p.) of a sin- Livers from all groups were homogenized in a
gle dose of STZ "Sigma Chemical Co., St. Louis, phosphate buffer (1gm/2ml). In the liver ho-
MO" 65mg/kg dissolved in 10 mM citrate buffer mogenates of all studied groups, the lipid per-
(pH 4.5) .Then, after 4-5 days of STZ injection, oxidation was measured by the quantification of
rats were screened for blood glucose levels. thiobarbituric acid reactive substances (TBARS)
Rats with a serum postprandial glucose level of determined by the method of Buege and Aust
180-300 mg/dl were considered as mildly dia- [13]. The activity of superoxide dismutase in the
betic and were included in the experiment [11]. liver was assayed by the spectrophotometric
method of Marklund and Marklund [14]. The
Plasma glucose and insulin levels activities of glutathione peroxidase and catalase
were measured by the modified method of
During the experiments, the body weight, the Pagila and Valentine [15], and Aebi [16], re-
plasma glucose and insulin levels of each ani- spectively. The level of total protein was deter-
mal were measured everyday for all groups. mined by the method of Lowry et al [17].

The plasma glucose levels were determined Pathological examination

daily using the Autokit Glucose Test Kit (Wako
Diagnostics, Richmond, VA). The animals were Immediately after euthanasia, pancreas and
not fasted before they received blood glucose liver specimens were fixed immediately in 10%
measurements. Plasma insulin level was also buffered formalin, embedded in paraffin, pre-
determined, by using the Ultra Sensitive Rat pared as 5-μm-thick sections and stained with

157 Int J Physiol Pathophysiol Pharmacol 2012;4(3):156-166

 Estrogen and diabetes

Table 1. Plasma glucose, insulin levels and food intake in all studied groups
Group I Group II Group III Group IV
Glucose (mg/dl) 83.3±8.79 230.6±18.26*** 112.5±1.6** ## 93±8.88* +++

Insulin (ng/ml) 1.95±0.12 0.76±0.04*** 1.67±0.22** +++ # 1.8±0.11* +++

Food intake (gm/day) 23.6±1.17 35.1±1.29*** 26.2±1.93** +++ # 24.1±1.37 NS +++

The results are expressed as mean ± SD. ***p<0.001, **p<0.01, *p<0.05 as compared to group I. NS: non significant as com-
pared to group I, +++p<0.001 as compared to group II. ##p<0.01 and #p<0.05 as compared to group IV.

hematoxylin and eosin (HE). Stained sections Results

were examined under light microscope
(Olympus CX31, Japan) and photographed using In this study, the effect of 17β estradiol (E2)
digital camera (Olympus, Camedia C-5060, Ja- administration on hyperglycemia and its detri-
pan). mental effects on pancreas and liver in a dia-
betic rat model that was induced by i.p. injection
Immunohistochemical analysis of 65mg/Kg of freshly prepared STZ were evalu-
ated.
The slides from spleen and liver of all experi-
mental groups were deparaffinized with three Effect of E2 on plasma glucose levels and other
changes of xylene and rehydrated through a diabetic manifestations in STZ treated rats
graded ethanol series to distilled water. Antigen
retrieval was performed by placing the slides in Table 1 showed that the mean plasma glucose
10 mM citrate buffer (pH3.0), heating them in a levels of group II was significantly higher than
microwave oven for 20 min, and allowing them those of three studied groups (p<0.001). When
to cool to room temperature for 20 min. Slides STZ-induced diabetic animals were treated with
were rinsed once with phosphate buffered sa- a dose of E2 for 15 days, the mean plasma glu-
line (PBS), and the endogenous peroxidase ac- cose levels was decreased but still significantly
tivity was blocked by incubating the samples for higher than those group I and IV (p<0.01 re-
30 min in the blocking solution (3% H2O2 in spectively). However, the mean plasma glucose
PBS), followed by rinsing three times with PBS. levels of group IV were decreased but still sig-
Non specific binding was blocked by incubating nificantly higher than those of group I (p<0.05).
the slides for 30min in PBS containing 2% nor-
mal goat serum (Vector Laboratories, Burlin- The insulin levels of group II were decreased
game, CA) and 1% Triton X-100, followed by significantly than those of the other studied
incubation with specific antibodies for insulin groups. The insulin levels of group III increased
receptors. but still significantly lower than those of control
group. Prolongation of treatment of group IV
Statistical analysis with E2 increases the insulin levels significantly
more than those of group III but still significantly
Data are expressed as mean ± SE for all pa- lower than those of control group (Table 1).
rameters. The data were analyzed using Graph
Pad Prism data analysis program (Graph Pad On the other hand, the daily food intake of ani-
Software, Inc., San Diego, CA, USA). For com- mals treated with STZ was markedly higher
parison of statistical significance between differ- compared to the other studied groups
ent groups Student Newman-Keuls t-test for (p<0.001).The food intake of group III was sig-
paired data were used. For multiple compari- nificantly higher than those of control animals
sons, one-way analysis of variance (ONE- WAY- and group IV (p<0.01 and p<0.05 respectively).
ANOVA) test followed by the least Significant Treatment of these diabetic animals with E2 for
Difference (LST). Correlations were assessed 30 days markedly suppressed their food intake
using Spearman’s non-parametric correlation (Table 1).
coefficient δ as described by Knapp and Miller
[18]. A value of P ≤ 0.05 was considered statis- In spite of increased food intake of group II,
tically significant. there was a lack of weight gain in this group,

158 Int J Physiol Pathophysiol Pharmacol 2012;4(3):156-166

 Estrogen and diabetes

which is a characteristic clinical feature of dia-

betes. Treatment of diabetic rats with E2 for
15and 30 days resulted in significant increase
in final body weights as compared to their initial
values (p<0.01 and p<0.001 respectively)
(Figure 1A).

Group III had a significantly reduced final body

weight compared to the control animals, and IV
group (p<0.01). The final body weight of group
IV was significantly lowered than those of group
I (p<0.05) (Figure 1B).

Effect of E2 treatment on oral glucose tolerance

test

To functionally assess the degree of β-cell func-

tion in different groups, the oral glucose toler-
ance test was performed to further assess glu-
cose and insulin response after glucose loading.
Figure 2A shows that the plasma glucose levels
in group II were dramatically increased after oral
glucose loading, which were significantly higher
Figure 1. A. Changes between initial (I) and final (F) than the levels in control rats, group III and IV
body weights of the studied groups. B: The final body
(p<0.001) and they remained at above 290
weights of the studied groups. Results are expressed
as the means ± SD (ten rats for each group). a: p mg/dl at 120 min after the glucose loading.
<0.001, b: p<0.01, NS: non significant as compared Treatment of group III with E2 attenuated the
to its corresponding data. ***p<0.001, **p<0.01 increase in plasma glucose levels compared to
and *p<0.05 as compared to group I. +++p<0.001 as the levels of group II (p<0.05) but the increase
compared to group III and #p<0.05 as compared to of plasma glucose of group IV was insignificantly
group IV. different from the levels of group I.

In addition, analysis of the plasma insulin level

during the first 60 min following oral glucose

Figure 2. Glucose tolerance curve in control, diabetic and treated groups with E2 for 15 and 30 days. Glucose toler-
ance test was performed to all groups. Glucose (2 g/kg B.W.) was administered orally after 4-hour fasting, and blood
samples were taken via the tail vein before and 30, 60, 90 and 120 min after glucose load. (A): Plasma glucose lev-
els (mg/dL) and (B) Plasma insulin levels (ng/mL) were measured at the indicated time points. The results are ex-
pressed as mean ± SD. Analysis of variance followed by the significance t- test was used to determine the statistical
significance. ***p<0.001, **p<0.01, *p<0.05 as compared to control group. NS: non significant as compared to
group I& III, +++p<0.001, ++p<0.01 as compared to group II. #p<0.05 as compared to group IV.

159 Int J Physiol Pathophysiol Pharmacol 2012;4(3):156-166

 Estrogen and diabetes

Figure 3. Effect of 17 β- estradiol (E2) on the hepatic GPx (A) activity and TBARS Levels (B). ***p<0.001, **p<0.01,
*p<0.05, NS: non significant as compared to group I. +++p<0.001, +p<0.05 as compared to group II. ##p<0.01,
#p<0.05 as compared to group IV.

loading was determined. Plasma insulin levels significantly increased the GPX activity levels
of each group during the oral glucose tolerance toward the normal levels of group I, as there
test were calculated as percent increase based were no significant differences between their
on the initial concentration levels of 1.95ng/ml levels.
for the control group, 0.76 ng/ml for group II,
and 1.67 ng/ml for the group III group and 1.8 The mean TBARS levels of group II were signifi-
ng/ml for the group IV (Figure 2B). The level of cantly higher than those of group I, III, IV
insulin was increased by 400% at 30 min in (p<0.001). The mean TBARS levels of group III
control animals, while there was no clear in- were significantly higher than those of group I
crease of insulin level in diabetic mice (group II). and IV (p<0.01). However these levels of group
In contrast, the level of insulin in E2-treated ani- IV were not significantly different from those of
mals (group III) was increased by 224.1% group I (Figure 3B).
(P<0.05).
Effect of E2 treatment on plasmatic LDH, GGT,
The glucose tolerance test reveals that while PAL, AST and ALT activities
the STZ-induced diabetic rats almost completely
lose the ability to secrete insulin in response to In addition, the effect of E2 treatment on plasma
glucose loading, treatment with E2 for 15 and levels of AST, ALT, LDH and PAL activities in all
30 days restores some of the ability to secrete studied groups were studied. The activities of
insulin. AST, ALT, LDH and ALP significantly increased in
diabetic rats compared to controls, group III and
Effect on hepatic TBARS and GPx levels IV (p<0.001 respectively). Although the activi-
ties of AST, ALT and LDH, of group III were sig-
Figure 3A showed the effect of E2 treatment on nificantly higher than those of group I and IV
the hepatic glutathione peroxidase (GPX) activ- (p<0.01). They were nearly normal in group IV
ity. The levels of GPx activities of group II were after E2 treatment for 30 days as there were no
significantly decreased compared to group I, III significant difference between the mean plasma
and IV (p<0.001, p<0.05 and p<0.001 respec- levels of these activities of group IV and group I
tively). E2 treatment for 15 days for group III (Figure 4A, B and C).
significantly increases the level of mean GPx
activity but it was still lower than those of group As shown in (Figure 4D), the mean plasma lev-
I and IV (p<0.05). els of PAL activities of group II were significantly
increased than those of group I, III and IV
However E2 treatment for 30 days for group IV (p<0.001). Although the mean levels of PAL

160 Int J Physiol Pathophysiol Pharmacol 2012;4(3):156-166

 Estrogen and diabetes

Figure 4. Effect of 17 β- estradiol (E2) treatment on plasma levels of AST (A), ALT(B), LDH(C) and PAL (D) activities in
all groups. The activities of AST, ALT, LDH and ALP significantly increased in diabetic rats compared to controls, group
III and IV (p<0.001 respectively). These activities decreased significantly after E2 treatment. Data represent mean ±
S.D. (n=10). ***p<0.001, **p<0.01, NS: non significant as compared to group I. +++p<0.001, +p<0.05 as compared
to group II. ##p<0.001, #p<0.05 as compared to group IV.

activities in group III were higher than those of eration of the beta cells were noticed (Figure
group I and IV (p<0.01),while the levels of group 5G).
IV were not significantly different from those of
group I. Examination of the liver of STZ-induced diabetic
rats revealed vaculation of the hepatocytes
Histopathological results (Figure 6B), focal and diffuse Kupffer cell prolif-
eration (Figure 6C), coagulative necrosis of the
The histopathological examination of HE-stained liver cells with monouclear infiltration (Figure
sections of the pancreas of STZ-induced dia- 6D), when compared with control liver (Figure
betic rats showed vascular and parenchymal 6A). After 15 days, the liver showed vaculation
changes. The vascular changes were in the form of the hepatocytes and proliferation of the
of congestion, edema and thrombosis (Figure Kupffer cells (Figure 6E). After 30 days of treat-
5B and C). Fibrosis in the interstitiam with infil- ment, the liver underwent regeneration and
tration of mononuclear cells such as lympho- Kupffer cell proliferation were also seen (Figure
cytes was seen (Figure 5D). The parenchymal 6F).
changes were observed in the pancreatic islets
in STZ-induced diabetic rats where cells were Immunohistochemistry
destroyed and underwent shrinkage (Figure 4E),
when compared with islets of control animals Immunohistochemical results of insulin receptor
(Figure 5A). After 15 days of treatment the islets in the liver revealed positive insulin reaction in
retuned to its normal appearance except some the control rats and moderate expression of
lymphocytic infiltration were seen (Figure 5F). insulin receptors after 15 days of treatment.
After 30 days, the whole examined tissue in the After 30 days, the insulin receptor expression
pancreas resembles the control one. Also, prolif- resembles the control pancreas. STZ-induced

161 Int J Physiol Pathophysiol Pharmacol 2012;4(3):156-166

 Estrogen and diabetes

as well as the mechanism of

its actions.

In this study, the blood glu-

cose levels of animals with
mild diabetes (blood glucose
ranging from 180 to 300 mg/
dl) were significantly reduced
after estrogen treatment in
group III and IV compared to
untreated group, yet, their
improvement was not to such
an extent that their values
were back to normal. The
hypoglycemic effect of E2 in
this study was attributable to
an improved glucose toler-
ance of group III and IV, and
this may result from an im-
proved ability of the pancreas
to release insulin following
oral glucose loading as the
amount of insulin of group III
and IV were significantly in-
creased than those of group
II. This finding is consistent
with results obtained from
Yambe et al [19] who re-
ported that treatment of dia-
betic rats with E for 15 days
decreased the blood glucose
levels but not back to normal.

Mechanistically, it was sug-

gested in earlier studies that
E2 has a direct insulinotropic
Figure 5. Representative micrograph of the pancreas from control, STZ -
effect by blocking the ATP-
induced diabetic and treated rats. A) Control pancreas. B) Congestion of the sensitive potassium channels
blood vessel (arrow). C) Thrombosis (arrow and edema (asterisk). D) Fibrosis present in the cytoplasmic
and lymphocytic infiltration. E) pancreatic islets degenerated and destroyed. F) membrane of pancreatic β-
Few lymphocytic infiltrations after 15 days of treatment. G) pancreatic islets cells [20].
showing proliferation of beta cells (arrow) after 30 days of treatment. HE stain.
Bar= 50μm. The mean plasma levels of
insulin of diabetic rats were
significantly decreased than
those of groups III and IV. It is
diabetic rats showed negative insulin receptor suggested that the elevated levels of sex steroid
(Figure 7). hormones (particularly estrogens) during preg-
nancy may stimulate the proliferation of islet β-
Discussion cell growth, which then results in increased in-
sulin synthesis and release [21].
In the present study, the effect of 17 β-estradiol
(E2) treatment in a diabetic rat model is studied, Our results are in consistence with Liu and Mau-
to gain a better understanding of the potential vais-Jarvis [22] who reported that all positive
protective actions of an endogenous estrogen changes towards better glycemic control could

162 Int J Physiol Pathophysiol Pharmacol 2012;4(3):156-166

 Estrogen and diabetes

liferation of the existing β-

cells which played a critical
role in the renewal of the β-
cell pool.

In the present study, it is

noted that STZ-induced dia-
betic rats had a reduced body
weight gain as there were no
significant differences be-
tween their initial and final
weight, but a significantly
increased food intake com-
pared to control animals, sug-
gesting the presence of
growth retardation due to the
lack of insulin and, subse-
quently, the reduction of nu-
trient uptake by various cells
in the body. In comparison,
the body weight gain of ani-
mals treated with STZ+E2 was
significantly increased com-
pared to diabetic animals.

E2 treatment decreased food

intake of group III to a level
which was still significantly
higher than those of control.
Figure 6. Representative micrograph of the liver from control, STZ-induced But when E2 treatment lasted
diabetic and E2 treated rats. A) Control liver. B) Vacuolated hepatocytes to a longer period in group IV,
(arrows). C) Focal Kupffer cell proliferation (asterisks). D) Coagulative necrosis the food intake decreased to
of the hepatocytes with mononuclear infiltration. E) After 15 days, hepatocyte
a level close to that of normal
vacuolation and Kupffer cells proliferation. F) 30 days after treatment, Regen-
eration of the hepatocytes. HE stain. Bar= 50μm. animals. This observation
agrees with several earlier
studies in mice, rats, and
other mammals showing that
be attributed to the roles played by estradiol E2 has a suppressive effect on food intake [25].
both at β-cells of the pancreas as well as periph- Mechanistically, it has been demonstrated that
eral insulin-sensitive tissues. the estrogen's effect on feeding and body
weight changes is mediated via activation of the
The beneficial effects of E2 on pancreas func- ERα signaling pathways [26, 27]. This was also
tion were supported by our histological findings supported by findings of Yamabe et al [19] who
which demonstrated that E2 treatment of group reported that the ability of E2 to decrease food
III was accompanied by restoring the structure intake may partially contribute to its hypoglyce-
of the pancreas besides some lymphocytic infil- mic effect. However, it should also be noted that
teration, but group IV had a histological struc- the plasma glucose levels in animals treated
ture resembles that of control group and the with STZ +E2 (group III and IV) are lower than
results showed that E2 treatment stimulates the levels seen in animals treated with STZ
proliferation of islet β-cells in group IV. The pro- alone. Taken together, it appears that the hypo-
gressive improvement in the structure of the glycemic effect of E2 appears to be largely inde-
pancreas is seen with prolongation of period of pendent of its suppression of food intake.
treatment of estrogen. These results were in-
consistent with those of Meier et al [23, 24]. Hyperglycemia degrades antioxidant enzyme
Yambe et al [19] suggested that E2 causes pro- defenses by allowing reactive oxygen species to

163 Int J Physiol Pathophysiol Pharmacol 2012;4(3):156-166

 Estrogen and diabetes

These findings were sup-

ported by the histological
results in this study, as E2
treatment results in regen-
eration and proliferation of
Kupffer cells and restored
the structure of the liver in
group IV nearly to normal
structure.

At the peripheral insulin-

sensitive tissues, estradiol is
known to modulate insulin
sensitivity and, conse-
quently, glucose homeosta-
sis. This was inconsistent
with our immunohistological
results which showed that
the group III and IV had in-
creased expressions of insu-
Figure 7. Representative micrograph of the liver from control, STZ-induced lin receptors compared to
diabetic and E2 treated rats. A) Control liver showing positive insulin receptor. that of STZ induced diabetic
B) STZ induced a decrease insulin receptor. C) Moderate expression of insulin
rats. The insulin receptors
receptor after 15 days of treatment. D) After 30 days, the insulin receptors
well expressed as control liver. Bar= 50μm. expression in group IV was
higher than those of group
III. These results were sup-
ported by the previous re-
damage cells and tissues [28]. This study port that the low concentrations of 17–β–
showed that hyperglycemia in group II is accom- estradiol (similar to early pregnancy) could be
panied with the increase of lipid peroxidation as responsible for the increase in insulin sensitivity
evidenced by the significant increase in hepatic by increasing the amount of insulin receptors in
lipid peroxidation (TBARs), the decrease of he- peripheral tissues [31].
patic GPx enzyme activities and the increase in
plasma AST, ALT, LDH and PAL activities. These This was explained by the fact that estradiol can
results were supported by those of Hamdena et counteract the effects of hyperglycemia-induced
al [28] who reported that hyperglycemia pro- downstream singling of the insulin receptors, as
duced by STZ leads to the over-production of well as modulating insulin receptors tyrosine
free radicals, the inactivation of the antioxidant phosphorylation and that 17β-estradiol is re-
enzymes by the non-enzymatic glycation of pro- sponsible for the increase in insulin secretion
teins and exerts deleterious effects on the func- and the modulation of the insulin receptors,
tion of pancreatic β cells. In this study, treat- thus normalizing glycaemia and defending glu-
ment of diabetic rats with E2 for 15 days im- cose-induced liver toxicity [32].
proved the levels of hepatic GPx and plasma
antioxidants and decreased the hepatic TBRAs. Conclusions
The improvement increased in group IV as the
period of treatment lasted to 30 days. These In conclusion, this experimental study revealed
findings are in agreement with EL naser et al that 17 β-estradiol had beneficial effects on STZ
[29] who reported that estradiol treatment induced diabetic rats. It has hypoglycemic effect
showed more effective role in reducing oxidative and restore the function and structure of pan-
stress than do insulin treatment although none creas and liver. The effect of 17 β-estradiol on
of them succeeded in getting it back to normal diabetes may be due to its antioxidant action as
control values. In addition, estrogens have been estrogens decrease the oxidative stress induced
implicated in antioxidant response element by STZ in liver cells by the increase of hepatic
(ARE)-mediated gene transcription and the antioxidant defense system and scavenge of
upregulation of SOD and GPX in hepatic cells plasma free radical. In addition, the mechanism
[30]. of action of E2 could be through the upregula-

164 Int J Physiol Pathophysiol Pharmacol 2012;4(3):156-166

 Estrogen and diabetes

tion of insulin receptors, by increasing the insu- [11] Vahabi B, Lawson K, McKay NG, Sellers DJ.
lin receptors expression in the liver tissues. Phasic activity of urinary bladder smooth mus-
These intriguing observations raise the possibil- cle in the streptozotocin- induced diabetic rat:
ity that administration of oral E2 may be benefi- Effect of potassium channel modulators. Euro-
pean Journal of Pharmacology 2011; 660: 431-
cial in type II diabetic patients with accelerated 437.
loss of pancreatic islet β-cells. [12] Whittington KB, Solomon SS, Lu ZN. Islet al-
lograft in the cryptochid testes of spontane-
Address correspondence to: Dr. Marwa A Ahmed, ously diabetic BB/Wor dp rats: response to
Associate Professor of Physiology, Faculty of Medi- glucose, glipizide and arginine. Endocrinology
cine, Assiut University, Assiut 71526, Egypt. Tel: 1991; 128: 2671-2677.
+20882286584; E-mail: [email protected] [13] Buege JA, Aust SD. Microsomal lipid peroxida-
tion. Methods Enzymol 1984; 105: 302-310.
References [14] Marklund S, Marklund G. Involvement of the
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