الفهرس 
Cover Page Title in EnglishOnly 14 pages are availabe for public view
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Abstract
Diabetes mellitus is a state in which the homeostasis of carbohydrate and lipid metabolism is improperly regulated by insulin, ultimetly leading to plasma glucose elevation. It is one of the largest endocrine disorders in the world, and is one of the major killers in recent times. Type I diabetes mellitus is caused by cellular-mediated auto-immune destruction of pancreatic islet ß-cells, leading to loss of insulin production. It usually starts during childhood, but can occur at all ages. Type II diabetes mellitus is increasing worldwide and it is the most common form of diabetes. Both type I and type II diabetes mellitus have complex pathophysiologies, including insulin resistance syndrome and hyperglycemia which are associated with abnormalities in ROS. The present study was carried in order to develop a suitable type II diabetic rat model that would closely mimic the natural history of the disease events from insulin resistance to ß-cell dysfunction, as well as metabolic features of human type II diabetes. After that, the study throw the light on the effect of NS oil as a monotherapy compared to GLI and MET on insulin receptor of such diabetic rat model and also, effect of NS oil combined with GLI or MET. Lastely, supplementation of I-OMe-AG538 was studied in current study. In this study NS oil was extracted by steam distillation process, GC analysis of the oil was done and GC-MS analysis was studied. Furthermore, acute toxicity study of NS oil extract was performed. After that total number of 240 male albino rats aging 8 to 10 weeks, weighing 110 to 150 gm acclimated on same conditions and put under good hygienic condition for a period of 14 days before starting the experiment to be adapted with the environment. Rats under study were divided fully randomly into two main groups, control and diabetic. Each group was subdivided into subgroups (each subgroup 10 rats): • Control group: Rats without any treatment and fed NPD. HFD-STZ induced diabetic rats: Rats fed HFD for 2 weeks then injected 35 mg/kg Bwt STZ. Non-diabetic NS oil-treated group: Rats were daily i/p administrated 2 ml/kg Bwt. Non-diabetic NS oil-administrated group: Rats were daily orally administrated 2 ml NS oil/kg Bwt. . Diabetic NS oil-treated group: Rats were daily administrated 2 ml NS oil/kg Bwt after induction of diabetes by intragastric tube. Non-diabetic DMSO-administrated group: Rats were orally administrated 2 ml DMSO/kg Bwt. Non-diabetic GLI-administrated group: Rats were orally administrated 0.8 mg GLI/kg Bwt. Diabetic GLI-treated group: Rats were orally administrated 0.8 mg GLI/kg Bwt after induction of diabetes . Non-diabetic MET-administrated group: Rats were orally administrated 100 mg MET/kg Bwt. Diabetic MET-treated group: Rats were orally administrated 100 mg MET/kg Bwt after induction of diabetes. Non-diabetic NS oil and GLI-administrated group: rats were daily injected 2 ml/kg Bwt NS oil i/p in combination with administration of 0.8 mg/kg Bwt GLI orally. However, another group of rats were administrated the combination of 2 ml/kg Bwt NS oil and 0.8 mg/kg Bwt GLI orally by using intragastric tube. Diabetic NS oil and GLI-treated group: Rats were daily orally administrated the combination of 2 ml NS oil /kg Bwt and 0.8 mg GLI/kg Bwt. Non-diabetic NS oil and MET-administrated group: rats were daily injected 2 ml/kg Bwt NS oil i/p in combination with administration of 100 mg/kg Bwt MET orally. But, another group of rats were administrated the combination of 2 ml/kg Bwt NS oil and 100 mg/kg Bwt MET by using intragastric tube. Diabetic NS oil and MET-treated group: Rats were daily orally administrated the combination of 2 ml/kg Bwt NS oil and 100 mg/kg Bwt MET. Non-diabetic IOMe-1 injected group: Rats were once injected 1/1000 IC50 I-OMe-AG538. Non-diabetic IOMe-1 and NS oil treated group: Rats were once injected 1/1000 IC50 I-OMe-AG538 then administrated 2 ml NS oil/ kg Bwt i/p. Non-diabetic IOMe-2 injected group: Rats were injected 1/100 IC50 of I-OMe-AG538 day and day. Diabetic and IOMe-2 injected group: Rats were injected 1/100 IC50 of I-OMe-AG538 day and day after induction of diabetes. .Non-diabetic IOMe-2 and NS oil treated group: Rats were injected 1/100 IC50 of I-OMe-AG538 day and day and daily orally administrated 2 ml NS oil/kg Bwt. Diabetic, IOMe-2 and NS oil treated group: Rats were injected 1/100 IC50 of I-OMe-AG538 day and day after induction of diabetes, and then orally administrated with 2 ml NS oil/kg Bwt. Anthropometric measurement was monitored 4 times during the experimental period (at zero day, after 2 weeks from dietary manipulation, after 3 days from STZ injection and after 12 day from starting the treatment). Blood samples were collected from the eye canthus and blood glucose, TC and TG were assessed to follow up diabetes induction and treatment effect. After the end of the study blood samples and hepatic tissues were collected from the whole studied groups and submitted to the following biochemical, molecular and histopathological studies: .Colorimetric determination of plasma blood glucose. Colorimetric determination of lipid profiles (TC, TG and HDL-c) and calculation of LDL-c. Calculation of AI and AAI of serum. Determination of serum insulin by ELISA technique. Calculation of insulin/IR ratio.HOMA-IR and HOMA-ß assesement. Colorimetric determination of total protein in serum and liver homogenate. Colorimetric determination of liver enzymes activities (ALT and AST) in serum and liver homogenate. Colorimetric determination of pro-oxidants (TBARS and NO) in serum and liver homogenate. Determination of inflammatory marker (TNF-α) by ELISA technique in serum and liver homogenate. Molecular determination of ADAM17, IGF-1, PI3K and IR were elucidated by reverse transcriptase PCR. SDS-PAGE separation pattern of hepatic tissue. Western blot technique for IR ß-subunit.Histopathological studies of hepatic tissues. The current results showed that: . HFD-STZ diabetic rats revealed highly significant increase of blood glucose, TC, TG, LDL-c, AI, insulin. I/IR ratio, HOMA-IR, serum ALT and AST, TBARS, NO and TNF-α. Also ADAM17 expression was increased. However, HDL-c, AAI, HOMA-ß, total protein, hepatic ALT and AST concentrations were significantally decreased. In addition to, gene expression of IGF-1, PI3K and IR were diminished in comparison with control group. Biochemial and molecular results were confirmed by histopathological results. Treatment of diabetic rats with NS oil was corrected the diabetic condition approached to normal, but still higher than control rats due to the effect of DMSO which used as a vehicle for NS during its extraction. Both GLI and MET were caused reduction of blood glucose level, TC and TG only for 12 day and after 21 day the rats returned to diabetic condition. Consequently, the other biochemical and molecular parameters became similar to control diabetic rats. Combination therapy of NS oil and GLI or MET revealed better result than monotherapy with NS oil where blood glucose, insulin, HOMA-IR and I/IR were decreased. Also, there was improving in lipid profiles, insulin signaling pathway and oxidative stress markers. But, NS and MET was better than NS and GLI in reduction of inflammation resulted from complication of diabetes mellitus and this was confirmed by histopathological results on hepatic tissues. Injection of IOMe-1 once caused reversible hyperglycemia for one week only, after that, the rats become normoglycemic. IOMe-2 injection day and day revealed elevation of blood glucose, TC, TG and HOMA-IR which was resemble type I diabetes where IOMe-2 blocked IR. Severe inflammation and liver affection was also noticed in current study. These affections were nearly decreased after administration of NS oil. Using of NS oil by i/p method for treatment cause severe toxicity in rats and high mortality rates.