الفهرس 
AbstractOnly 14 pages are availabe for public view
 |  | from | 303 |  |  |
| | | from | 303 | | |
Abstract
The objective of this study was to assess the anti-hyperglycemic, anti-hyperlipidemic and antioxidant effects of C. reticulata peel hydroehanolic extract and its two constistuing flavonoids hesperidin and quercetin in NA/STZ-induced diabetic rats and to state the probable physiological, biochemical and molecular mechanisms of action of these tested agents.
Diabetes mellitus was induced in 16 hours-fasted rats by a single interperitoneal (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 seperetely with hydroethanolic extract of Citrus reticulata (C. reticulata) peel, hesperidin and quercetin at dose levels of 100mg /kg b.wt/day by oral gavage for 4 weeks. Another group of normal animals was kept under the same laboratory conditions and was 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 quantitave determination of glucose, insulin, C-peptide and 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 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 phosphorylase, 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 previous mentioned investigations revealed the following effects:
1- GC-MS and HPLC-MS analyses of the extract were performed and indicated the presence of multiple flavonoids including hesperidn, quercetin, naringin and polymethoxylated flavones (nobeletin and tangeretin).
2- The oral glucose tolerance was impaired in diabetic rats and it was significantly improved in the treated diabetic rats; C. reticulata fruit peel hydroethanolic extract was the most potent in improving the oral glucose tolerance.
3- The lowered serum insulin and C-peptide levels in diabetic rats were significantly increased as a result of treatments.
4- The deteriorated HOMA-IR, HOMA-IS and HOMA-β cell function in diabetic rats were significantly improved as a result of treatments.
5- Liver glycogen content was enormously depressed in the diabetic rats and was increased as a result of treatment with the tested agents.
6- Glucose-6-phosohatase 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.
7- The AST and ALT acivities 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.
8- The kidney function parameters in serum that were deleteriously affected in diabetic rats were significantly ameliorated as a result of treatments.
9- 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 C. reticulata peel, hesperidin and quercetin led to ameliorative effects on the disrupted lipid profile.
The treatments of diabetic rats with C. reticulata fruit peel extract; hesperidin and quercetin induced remarkable improvement in the islets’ histological architecture.
Visceral adipose tissue GLUT-4, insulin receptor β-subunite and adiponectin mRNA expressions have similar behavioral patterns as they were markedly declined in NA/STZ-induced diabetic rats. Treatment with C. reticulata fruit peel hydroethanolic extract, hesperidin and quercetin upregulated the diminished GLUT-4, insulin receptor β-subunite 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-S-transferase, glutathione peroxidase, glutathione, superoxide dismutase were detectably increased as a result of treatments with C. reticulata fruit peel hydroethanolic extract, hesperidin and quercetin.
In conclusion, the present study revealed that the treatment with C. reticulata fruit peel hydroethanolic extract, hesperidin and quercetin exerted antihyperglycemic and antihyperlipidemic effects which seemed to be mediated via enhancement of insulin release, insulin action and antioxidant defense system in NA/STZ-induced diabetic rats. The improved insulin release was demonstrated via the increased serum insulin and C-peptide levels in addition to the elevated calculated HOMA β-cell function while the improvement in insulin action was manifested by the increase in HOMA-IS and decrease in HOMA-IR in association with the elevation in mRNA expression levels of insulin receptor β-subunit, GLUT-4 and adiponectin in adipose tissues. The C. reticulata fruit peel hydroethanolic extract has more potent anti-hyperglycemic and anti-hypercholesterolemic effects than hesperidin and quercetin. In addition to, antihyperglycemic and antihyperlipidemic effects, C. reticulata fruit peel hydroethanolic extract, hesperidin and quercetin have potent ameliorative effect on liver and kidney functions which may secondary to the improvements in the glycemic state, lipid profile and antioxidant defense system. In spite of these alleviative effects in NA/STZ-induced diabetic rats, further clinical studies are required to assess the efficacy and safety of C. reticulata fruit peel hydroethanolic extract, hesperidin and quercetin in type 2 diabetic human beings.