الفهرس 
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Abstract
Hepatic steatosis (storing excess amount of fats in the liver ) is the
primary stage in a variety of liver diseases called NAFLD. These diseases
vary from simple steatosis to NASH, fibrosis, and cirrhosis. Most patients
with NAFLD experience long-term diabetes or glucose-impaired tolerance .
Type 2 diabetes mellitus is the most common type of diabetes. It has
been that the highest percentage of NAFLD is present among obese patients
with T2DM; approximately 75% of type 2 diabetic patients were diagnosed
with NAFLD, especially NASH, and regularly exhibited more severe
prognosis.
A clear association between DM and NASH has been confirmed. DM
has a vital role in enhancing liver injury progression, which consequently
exaggerates abnormal glucose and lipid metabolism. As a result, the possible
risks of cardiac-cerebral, vascular, and peripheral vascular events in DM
patients are increased .Thus, avoiding liver injury is a vital issue during the
management of DM. Studies also revealed the potential role of SGLT2
inhibitors, a kind of novel oral hypoglycemic agents, in improving
dyslipidemia, liver steatosis and NASH .
Therefore, the current study was conducted to investigate the efficacy
of dapagliflozin to inhibit steatohepatitis in diabetic rats and examine the
underlying mechanisms for this effect by assessment of the possible
antioxidant and anti-inflammatory role of dapagliflozin along with its impact
on TGFβ and alpha-SMA.
Summary and conclusion
78
Methods and results :
1. Fifty rats weighing 120-150 gm were randomly distributed into five
groups, ten rats each, and the rats were treated as follows. group 1:
normal group and was fed by normal chow diet for 15 weeks. Starting
from week 9, rats received saline. group 2: served as control diabetic
and received saline. group 3, 4, and 5: received daily graded doses of
dapagliflozin (0.75, 1.5, 3 mg/kg, p.o.), respectively. All rats’ groups
except group 1 were fed High Fat Diet (HFD) (10% lard, 2%
cholesterol, 0.3% bile) for 8 weeks, followed by a single dose of STZ
(30 mg/kg I.P) for diabetes mellitus induction. For additional 6 weeks,
HFD was given along with the following treatment regimen.
2. Serum samples were collected and used for subsequent biochemical
determination of liver enzymes, total cholesterol, triglycerides, serum
insulin, and insulin resistance index. Rats were then sacrificed by
cervical dislocation, and the liver tissues were dissected. Specimens of
livers from different groups were intended for histopathological
assessment. The rest of the liver tissues were frozen immediately at -
80ºC for homogenization and assessment of various biochemical
parameters.
3. Assessment of NF-κB using western blot technique accompanied with
SDS PAGE electrophoresis. ELISA was used to assess IL-1β, TGF- β
beside determination of lipid peroxidation in the liver, such as
Malondialdehyde (MDA), as well as oxidative stress indicators by
measuring reduced glutathione (GSH) levels, catalase, and superoxide
dismutase (SOD) activities.
4. The histological examination was performed using the histological
scoring system for NAFLD by an experienced pathologist without prior
Summary and conclusion
79
knowledge of the treatments. Evaluation of steatosis, steatohepatitis,
and fibrosis based on Kleiner and Matsuzawa scoring system.
5. The hepatic steatosis induction was confirmed by an increase in total
cholesterol and triglyceride levels compared to normal values along
with the presence of marked hepatic steatosis by histological
examination in addition to a significant increase in liver weight and
liver index in diabetic control compared to the normal group (P<0.05).
6. Dapagliflozin treatment led to a significant (P<0.05) decrease in the
liver index and significantly (P<0.05) depressed the level of total
cholesterol and triglycerides compared to the control diabetic group.
7. The study results revealed high transaminase liver enzymes level in
control diabetic group compared to the normal. Also, dapagliflozin has
a noticeable hepatoprotective effect regarding controlling AST and
ALT levels. This effect is due to the improvement of the metabolic
balance mediated by SGLT2 inhibitors.
8. The results showed significant elevation of MDA level along with a
reduction in GSH, SOD, and catalase levels in the control diabetic
group, it also revealed the hepatoprotective effects of dapagliflozin by
displaying a dose-dependent increase in the antioxidant enzymes SOD,
Catalase activities, and GSH accompanied by decrease in MDA level.
9. The current study showed a clear inflammatory state in steatohepatitis,
as evidenced by significant elevation in hepatic NF-κB and IL-1β levels
in the control diabetic group. The potent hepatoprotective effect of
dapagliflozin showed improving hyperglycemia-induced tissue
inflammation mediated by diminishing NF-κB expression and IL-1β
level.