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The present study was designed to investigate sex
differences in metabolic responses to immobilization stress
and to clarify the underlying mechanism(s). The possible
beneficial effects of vitamin D3 and lipoic acid
supplementation on the assumed stress- induced metabolic
alterations were, also, studied.
The study was performed on 80 adult albino rats of both
sexes, initially weighing 200-300 gm, half of the rats being
males and half being females. Rats were allocated into four
main groups, each of which were further subdivided into a
male group and a female group (10 rats in each group).
- group І: Control group.
- group ІІ: Stressed untreated group: Rats in this
group were subjected to immobilization stress by being
encaged 2 hours daily, 5 days/ week, for 4 weeks.
- group ІІІ: Vitamin D3- treated Stressed group: Rats
in this group were subjected to immobilization stress as in
group ІІ, and were treated at the same time by intraperitoneal
injection of vitamin D3 in a dose of 10 μg /Kg BW, every
other day.group ІV: Alpha-Lipoic acid- treated Stressed
group: Rats in this group were subjected to immobilization
stress, and were treated at the same time by α-lipoic acid in a
dose of 50mg/Kg BW, given daily by gavage.
All rats were subjected to determination of:
- Anthropometric parameters, including body weight,
body mass index (BMI), waist circumference (WC),
visceral fat weight (VFW), absolute and relative
pancreatic weights (APW, RPW; respectively) and
absolute and relative liver weight (ALW, RLW;
- Glycemic parameters, including fasting plasma
glucose, glucose uptake by diaphragm and glucose
output by kidneys.
- Lipid profile, including plasma levels of triglycerides
(Tg), total cholesterol (TC), high density lipoprotein
cholesterol (HDL-C), low density lipoprotein
cholesterol (LDL-C) and atherogenic index (AI).
- Oxidative stress markers, including plasma levels of
malondialdehyde (MDA), nitrite and total antioxidant
capacity (TAC).- Hormones, including plasma levels of insulin, leptin,
testosterone and estradiol.
- Homeostatic model assessment of beta cell function
(HOMA-B) and homeostatic assessment of insulin
resistance (HOMA- IR).
- Histological examination of pancreas and liver.
- Caspase 3 in pancreatic tissue by immunehistochemistry.
The results of the current study revealed that upon
exposure to stress both male and female rats showed
significantly decreased visceral fat weight, accompanied by
hyperglycemia and dyslipidemia, manifested by significantly
increased plasma level of glucose, TC, LDL-C and AI, as
well as significantly reduced plasma levels of TAC
indicating low antioxidant defenses together with
significantly low plasma insulin and HOMA-B denoting
pancreatic B- cell affection. In addition, plasma estrogen
level was significantly elevated in both male and female rats.
Moreover, in male rats, stress additionally resulted in
significantly decreased BMI%, plasma levels of testosterone,
HDL-C and glucose uptake by the diaphragm and significantly increased RLW, glucose output by the kidneys,
as well as plasma levels of Tg and MDA. Also, in female
rats, stress additionally resulted in significantly increased
plasma levels of nitrite and testosterone.
In comparison to the stressed male group, the stressed
female group displayed significantly higher BMI% and
plasma estrogen, whereas, the ALW, glucose output by the
kidneys, plasma Tg, TC, AI, TAC and plasma testosterone
were all significantly lower.
Regarding the histopathological examination of the
pancreas, both stressed male and female groups showed
degenerative and apoptotic changes in the pancreatic islet
cells, that were significantly worse in the male groups
compared to the female groups. Further, the liver
histopathological examination in both stressed male and
female groups revealed hepatocyte degeneration, apoptosis,
necrosis and fibrosis that were significantly greater in male
compared to female rats.
Upon vitamin D3 treatment, both stressed male and
female rats revealed significant increase in BMI %, accompanied by a significant decrease in plasma levels of
TC, fasting blood glucose and glucose output by kidneys.
Additionaly, vitamin D treated stressed male rats
exhibited significant increase in plasma testosterone, glucose
uptake by the diaphragm and HOMA-B, together with a
significant decrease in plasma levels of estrogen, Tg, LDL-C
and AI. On the other hand, plasma levels of TAC and insulin
were normalized to reach control values.
It was worth noting that only vitamin D- treated stressed
female rat group showed significantly increased waist
circunference and plasma levels of MDA and leptin and
significantly decreased plasma levels of testosterone and
estrogen to the control values, while HOMA-B was elevated
to approach the normal values.
In comparison to the vitamin D- treated stressed male rat
group, vitamin D- treated stressed female group showed
significantly lower glucose output by kidneys, plasma levels
of testosterone and insulin as well as HOMA-IR and
significantly higher plasma estrogen.
Further, vitamin D treated stressed female rats showed
greater improvement of pancreatic structure as compared to
vitamin D-treated stressed male group, although caspase 3
was significantly reduced in both treated groups compared to their respective untreated groups. Vitamin D3 administration
resulted in significant improvement of the liver architecture
of stressed male rats, whereas it resulted in less improvement
in the liver architecture of the stressed female group.
Upon alpha lipoic acid treatment, on the other hand,
both male and female stressed rats displayed significant
increase of BMI% and plasma testosterone, accompanied by
significant lowering of plasma glucose and estrogen levels.
In stressed male rats, alpha lipoic acid, also, significantly
increased plasma levels of TAC, insulin, glucose uptake by
the diaphragm and HOMA-B and significantly decreased
glucose output by the kidneys as well as the plasma levels of
Tg, TC, LDL-C and AI.
Compared with alpha lipoic acid- treated stressed male
rats, alpha lipoic acid- treated stressed female rats revealed
significantly higher plasma levels of estrogen and
testosterone and significantly lower plasma levels of insulin
Regarding the histological picture of the pancreatic islets
of Langerhans, alpha lipoic acid- treated male rats showed
evident improvement as compared to the untreated stressed
male rats, whereas the alpha lipoic acid-treated female rats showed little improvement as compared to the untreated
stressed female rats and the treated male rats.
In addition, alpha lipoic acid administration to stressed
male and female rats resulted in improvement of the
histological structure of the liver, as compared to their
corresponding untreated stressed groups, the improvement
being significantly greater in the treated female group
compared to treated male group.