الفهرس 
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Abstract
The objective of this study was to assess the anti-hyperglycemic, anti-hyperlipidemic and antioxidant effects of navel orange peel hydroethanolic extract and its two constituting flavonoids naringin and naringenin in NA/STZ-induced diabetic rats and to indicate the probable physiological, biochemical and molecular mechanisms of action of these tested agents.
Diabetes was induced in 16 hours-fasted rats by a single intraperitoneal (i.p.) injection of 50 mg STZ/kg b.wt (dissolved in citrate buffer, pH 4.5), 15 minutes after the i.p. administration of 120 mg NA/kg b.wt.
The diabetic rats were divided into four groups; the first group was daily given the equivalent volume of vehicle (1% CMC) by oral gavage for 4 weeks and the other three groups were treated separately with hydroethanolic extract of navel orange peel, naringin or naringenin at dose levels of 100 mg/kg b. wt/day by oral gavage for 4 weeks. Another group of normal animals was kept under the same laboratory conditions and considered as normal control for diabetic groups. This group was also given the equivalent volume of vehicle (1% CMC) by oral gavage for daily 4 weeks.
After 4 weeks of treatment, oral glucose tolerance test was performed, and then rats were scarified and blood samples were collected and centrifuged. The obtained sera were used for quantitative determination of glucose, insulin, C-peptide, fructosamine levels, lipid profile (total cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol, vLDL-cholesterol and free fatty acids levels), as well as AST and ALT.
Livers were removed immediately after sacrifice and perfused with ice cold saline and then homogenized. The homogenate was centrifuged and the supernatant was used for biochemical analysis of glucose-6-phosphatase, glycogen phosphoylase, glutathione-S-transferase, glutathione peroxidase, glutathione, superoxide dismutase and lipid peroxidation. Half gram of liver of each rat was used for determination of liver glycogen. Moreover, pieces of visceral adipose tissue were kept at -30oc pending RNA extraction and RT-PCR analysis.
The acquired data of the pervious mentioned investigations revealed the following effects:
- The oral glucose tolerance was impaired in diabetic rats and it was significantly improved in the treated diabetic rats.
- The lowered serum insulin and C-peptide levels in diabetic rats were significantly increased as a result of treatments.
- The deteriorated HOMA-IR, HOMA-IS and HOMA-β cell function in diabetic rats were significantly improved as a result of treatments.
- Liver glycogen content was enormously depressed in the diabetic rats and was increased as a result of treatment with the tested agents.
- Glucose-6-phosphatase and glycogen phosphorylase activities were significantly decreased in the treated diabetic rats, which mean that the treatment with the tested materials improved the altered activities of these enzymes.
- The AST and ALT activities were significantly elevated in NA/STZ-induced diabetic rats as compared to normal ones and decreased as a result of treatments reflecting improvement in liver function.
- The kidney function parameters in serum that were deleteriously affected in diabetic rats were significantly ameliorated as a result of treatments.
- Lipid profile in serum of NA/STZ diabetic rats revealed significant elevation of total cholesterol, triglycerides, LDL-cholesterol, vLDL-cholesterol and free fatty acids concentrations while HDL-cholesterol was decreased. The treatment of diabetic rats with hydroethanolic extract of navel orange peel, naringin or naringenin led to ameliorative effects on the disrupted lipid profile.
- Visceral dipose tissue GLUT4, insulin receptor and adiponectin mRNA expressions have similar behavioral patterns as they were markedly declined in NA/STZ-induced diabetic rats. Treatment with navel orange peel hydroethanolic extract, naringin or naringenin were potentially upregulated the diminished GLUT4, insulin receptor and adiponectin mRNA expression.
- Liver lipid peroxidation elevated in diabetic rats was decreased as a result of treatments while the lowered liver antioxidants including glutathione, glutathione-S-transferase, glutathione peroxidase and superoxide dismutase were detectably increased as a result of treatments with navel orange peel hydroethanolic extract, naringin and naringenin.
In conclusion, the study revealed that hydroethanolic extract of navel orange peel, naringin and naringenin have both pancreatic (insulinotropic) and extrapancreatic (improved insulin action) effects. Treatment with hydroethanolic extract of navel orange peel, naringin and naringenin were found to beneficial on all aspects of disrupted metabolism of NA/STZ-induced diabetic rats. All treatment agents were effective in improving the impaired the glucose tolerance, increasing serum insulin and C-peptide levels, alleviating the disrupted lipid profile and ameliorating the antioxidant status in addition to increasing expression of adipose tissue GLUT-4, insulin receptor and adiponectin.