الفهرس 
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Abstract
The aim of the present study was to assigned to study and
compare the therapeutic effects of the insulin sensitizer (metformin)
and insulin therapy and demonstrate its role in prevention of the high
fat diet experimentally -induced type II DM changes on both organs
kidney and brain in adult male albino rats, regarding the following
aspects , glycemic state, biochemical inflammatory and oxidative
parameters , kidney function tests , neurobehavioral tests and
histopathological changes in kidney &brain tissue.
To achieve this goal, fifty adult Wister male albino rats,
weighing 150–180 g (6–7 weeks old) were used in this study. Rats
were left for 2 weeks in their cages before the experimental study
(adaptation period ) . then, Rats were divided into the following
groups :
group 1: Control non-treated (C) group) (n=10 rats):
Rats of this group received a standard rat chow diet and water
ad libitum during study period. Rats were injected intraperitoneally
(I.P) by a single dose of citrate buffer these rats continued on their
respective diets until the end of the experimental study for 8 weeks.
group 2: Diabetic non-treated (D) group (n=10 rats):
Type 2 diabetes was induced by (High fat diet (HFD)- low dose
STZ) ,the rats were fed HFD for 2 weeks. After that ,rats were
injected with a single low dose of STZ (35mg/Kg. IP), when the
condition of diabetes was stable after 72 h, fasting blood glucose level
(FBG mg/dl) (12 hr.) was measured ,rats were considered diabetic if
they had fasting glucose of>150 mg/dL; and non-fasting glucose
levels of>200 mg .
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Summary
group 3: Diabetic metformin-treated (D+Met.) group (10 rats):
After being diabetic as in previous group, metformin was
administrated (250 mg/kg/per day). The does was calculated
according to the weight of each rat.
group 4: Diabetic insulin treated (D+Ins.) group (10 rats): After
being diabetic as in previous group, rats treated with NPH
insulin 40 u/kg/SC daily. Blood glucose concentrations were
monitored daily .
group 5: Diabetic combined insulin and metformin-treated
(D+Met.+Ins.) group (10 rats): After being diabetic as in
previous group, treatment was continued with both insulin &
metformin by same regimen as mentioned above in the latest 2
groups for 6 weeks.
At the end of the study period, neurobehavioral tests were done.
After that , rats of all groups were kept individually in metabolic cages
for 24 h to collect urinary samples to calculate the creatinine
clearance. Then, fasting retro-orbital blood sample from each rat was
collected to assess the different parameters as follows: glycemic
profile (fasting blood glucose, HbA1C, fasting insulin level, HOMAIR
index and QUIKI index) biochemical inflammatory and oxidative
parameters (il-18, NFKβ, SAA and TAC) kidney function tests (serum
creatinine, creatinine clearance, serum Blood Urea Nitrogen and
serum cystatin- C) Lastly, rats of all groups were sacrificed for
doppler flowmeter on renal artery to asses (MNV and RP )and the
kidneys were excised for histopathological examination, while the
forebrain was excised and homogenized and used for biochemical
measurement of MDA and histopathological examination.
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Summary
The results of the present study showed that feeding rats with (High fat diet - low dose STZ (35mg/Kg.IP) and water ad libitum for 6 weeks caused significant hyperglycemia indicating a successful establishment of type 2 DM. It was associated with impaired fasting blood glucose, increased glycated hemoglobin and increased insulin resistance as indicated by (HOMA and Quicki-IR indices) also, there were impairment in kidney and cognitive brain functions which was associated with increment in inflammoxidative biomarkers when compared with the corresponding values of C group. The H&E stained kidney and brain sections showed a microscopic picture of diabetic nephropathy and diabetic neurodegenerative changes.
Metformin treatment of diabetic rats with (250 mg/kg/per day). The does was calculated according to the weight of each rat. Thus revealed a statistically significant reduction of fasting serum glucose, HbA1c, HOMA-IR when compared to the corresponding values of diabetic –non treated group , These results were proven by histo-pathological study. Sections of the kidney and frontal lobe brain of the diabetic metformin-treated group illustrate mild degree of improvement in both tissue as well, it also accompanied by decreasement in inflammatory markers (SAA and Il -18) and elevated level of TAC. Moreover, the mean value of MNV in doppler U/S was significantly reduced but RRI was significantly increased when compared to the corresponding value of the diabetic -non treated group.
Insulin treatment of diabetic rats with (40 U/kg/per day) revealed a statistically significant reduction of fasting serum glucose, HbA1c, , HOMA-IR, SAA,IL18, T.MDA ,creatinine ,BUN ,cystatin -C, creatinine ,BUN ,cystatin -C accompanied with statistical
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Summary
significant elevation of serum insulin , TAC ,creatinine clearance when compared to the corresponding values of diabetic –non treated group . also these results were accompanied with improvement in all different parameters of the neurobehavioral tests that was done, These results were proven by histo-pathological study. Sections of the kidney and frontal lobe brain of the diabetic insulin -treated group illustrate moderate degree of improvement in both tissue as well, it also accompanied by increasement in MNV of renal blood flow in doppler U/S but RRI was significantly decreased when compared to the corresponding value of the diabetic -non treated group.
Combined metformin and insulin treatment of diabetic rats with the same previous doses revealed a statistically significant reduction of fasting serum glucose, HbA1c, HOMA-IR, SAA,NFΚΒ, IL-18, T.MDA, creatinine, BUN, cystatin -C, accompanied with statistical significant elevation of serum insulin, QUIKI index, TAC ,creatinine clearance when compared to the corresponding values of diabetic –non treated group . Also, these results were accompanied with marked improvement in all different parameters of the neurobehavioral tests that were done, these results were proven by histo-pathological study. Sections of the kidney and frontal lobe brain of the diabetic metformin and insulin -treated group illustrate marked degree of improvement nearly to control groups in both tissue as well, it also accompanied by significant increasement in MNV of renal blood flow in doppler U/S but RRI was significantly decreased when compared to the corresponding value of the diabetic-non treated, metformin, insulin treated groups.
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Summary
from the previous results, it can be concluded that combined diabetic treatment with metformin and insulin improved the glycemic state as it lowered fasting serum glucose, glycosylated hemoglobin, and insulin resistance in type II diabetic rats. However, the hypoglycemic effect of metformin was weaker than that of insulin. Also combined – treatment (dual therapy) resulted in significant improvement of kidney function and brain cognitive function rather than monotherapy in type II diabetic rats; this improvement was better than that of metformin alone. And this improvement was accompanied with marked DROP in inflammatory and oxidative stress markers .it was confirmed by histological staining of both tissues and compared with other groups. This may indicate that the added insulin therapy in type 2 DM had a superior effect on metformin treatment alone and this may be a promising and recommended therapy for type II diabetes mellitus from the start.