الفهرس 
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Abstract
The prevalence of diabetes increases exponentially worldwide. At the
same time, both an increased consumption of unhealthy high calorie food and a
sedentary behavior have been recorded in modern societies.
This world’s largest endocrine disease is characterized by chronic
hyperglycemia associated with abnormalities in carbohydrate, fat, and protein
metabolism leading to a variety of microvascular, macrovascular, neurologic
and infectious complications. Therefore, with the increasing prevalence of DM
and obesity, effective treatment is critical for decreasing morbidity, mortality
and complications as well as improving public health at large.
The objective of the present study was to investigate the effect of
telmisartan, a structurally unique AT1 receptor antagonist that can function as a
partial PPARγ agonist
; sodium selenate, a PTP inhibitor; metformin, the well-
known anti-diabetic agent, together with their combinations for 5 weeks, on a
rat model that simulates the natural history and metabolic characteristics of
human T2DM. This was achieved by feeding the rats with HFFD for 8 weeks
followed by low dose of STZ rendering them diabetic and insulin resistant.
The rat groups were divided as follows;
group 1:
Normal control rats that were fed NPD and received single dose of
citrate buffer alone i.p.
group 2:
DIR rats that received 0.5% aqueous solution of carboxymethyl
cellulose sodium as a vehicle of the treatment for 5 weeks.
group 3:
DIR rats that received telmisartan (5 mg/kg/day; p.o.) for 5
weeks
.
group 4:
DIR rats that received sodium selenate (1.89 mg/kg/day; i.p.) for 5
weeks.
group 5:
DIR rats that received metformin (250 mg/kg/day; p.o.) for 5
weeks.
Summary and Conclusions
131
group 6:
DIR rats that received telmisartan (5 mg/kg/day; p.o.) plus sodium
selenate (1.89 mg/kg/day; i.p.) for 5 weeks.
group 7:
DIR rats that received telmisartan (5 mg/kg/day; p.o.) plus
metformin (250 mg/kg/day; p.o.) for 5 weeks.
group 8:
DIR rats that received sodium selenate (1.89 mg/kg/day; i.p.) plus
metformin (250 mg/kg/day; p.o.) for 5 weeks.
The results of the present study showed that telmisartan treatment
reduced serum glucose and HOMA-IR index, decreased serum lipid profile and
hepatic PTP, while serum insulin and liver GSH were increased. As for serum
adiponectin level, it was successfully restored to normal levels.
Sodium selenate treatment showed reduced serum glucose, TG, FFA,
HOMA-IR index together with hepatic PTP. Only serum total cholesterol was
restored to normal level while serum insulin and hepatic GSH levels were
significantly increased. However, no significant change in serum adiponectin
level was observed.
Metformin treatment effectively reduced serum glucose level and
HOMA-IR index together with a significant decline in serum lipid profile and
hepatic PTP. On the other hand, serum insulin and hepatic GSH levels were
increased. However, metformin didn’t produce any significant change in serum
adiponectin level.
Combination of telmisartan and sodium selenate effectively reduced
serum glucose level, HOMA-IR index and FFA. Successfully, serum total
cholesterol, TG and adiponectin levels were normalized. However, serum
insulin and hepatic GSH content were significantly increased while hepatic PTP
was significantly declined.
Summary and Conclusions
132
Combined treatment of telmisartan and metformin restored serum
glucose, total cholesterol, TG and adiponectin back to normal levels together
with a signi
ficant reduction in
HOMA-IR, serum FFA and hepatic PTP. Serum
insulin together with hepatic GSH content was significantly increased.
Combined treatment of sodium selenate and metformin significantly
reduced serum glucose, FFA, HOMA-IR index together with hepatic PTP
content while serum total cholesterol, TG levels and hepatic GSH content were
normalized. Serum insulin was significantly increased while adiponectin level
was not changed.
These data suggest that these drugs when administered alone might not
efficiently restore hyperglycemia back to normal levels together with other
manifestations like serum TG, adiponectin and hepatic GSH in diabetic rats.
Also, these findings demonstrate the beneficial role of telmisartan as an adjunct
to metformin in restoring serum glucose back to normal level. Therefore, this
combinational therapy could be recommended to poorly controlled diabetic
patients on metformin monotherapy. In addition, superior effect was shown in
alleviating other metabolic disturbances when combination of telmisartan or
sodium selenate was used with metformin.
Future research should be directed to study the efficacy of other anti-
diabetic combinations including telmisartan or sodium selenate. Also, it is
recommended that further studies should be done to assess other cytokines
which could serve as new indicators of anti-diabetic efficacy. This will finally
determine if these results can be appropriately extrapolated to human diabetes,
which may result in better and more efficient management of DM and its related
complications.