الفهرس 
IntroductionOnly 14 pages are availabe for public view
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Abstract
Diabetes mellitus is a chronic disease that is characterized by characterized by hyperglycemia.. It is the most prevalent disease in the world in which the number of diabetic patients will jump from 382 million patients in year 2013 to 592 million in year 2035. It causes number of complications like retinopathy, neuropathy, and peripheral vascular insufficiencies. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels. T2DM is characterized by the presence of insulin resistance with insufficient secretion of insulin. Extract of ellagic acid from different fruits (strawberry, rasberries, pomegranate and welnuts) has shown a wide range of pharmacological activities. Ellagic acid has anti-diabetic, anti-cancer, anti-oxidant, and anti- inflammatory effects. Animals This study was carried out on 50 adult male albino rats, weighing (220±30 g). Rats were divided into 5 equal groups each group contains 10 rats as follow: group 1 (G1): animals were left without any treatment any this group acted as control group. group 2 (G2): animals were treated by ellagic acid only at dose of 50 mg/kg for 30 days. group 3 (G3): animals were treated by STZ only at dose of 55μg/kg for single one dose and this group acted as diabetic group (positive control group). group 4 (G4): animals were treated by ellagic acid (50 mg/kg) for 15 days, then injected by STZ for single dose (55μg/kg), then treated by ellagic acid (50 mg/kg) for another 15 days. This group considered as co-treated group. group 5 (G5): rats were injected by STZ for single dose ((55μg/kg), then treated by ellagic acid (50 mg/kg) for 30 days. 601 At the end of experimental period, animals were fasten 8-10 hours before they were euthanized. Blood samples were put in EDTA tubes for HBA1C analysis and dry sterile centrifuge tubes. Serum were prepared by centrifugation for 10 minutes at 5000 rpm for estimating pancreatic enzymes, liver function, and lipid profile. Pancreatic and hepatic tissues were divide into two parts. The first part of tissue was put in formalin for histological and immunohistochemical investigations. The second part of tissue was put in - 80° C for gene expression determination. The results Fasting blood glucose: There was a significant difference in fasting blood glucose between diabetic group and postttreated group. FBG was very high in diabetic group ≥250. But in cotreated and posttreated groups, there was a significant decrease in FBG. Ellagic acid is considered to be a therapeutic agent for diabetes type 2. Pancreatic enzymes: Alpha-amylase was significantly (p<0.00001) increased in diabetic rats as compared with control. On the other hand, serum lipase was significantly decreased in diabetic rats as compared to control. A significant decrease in alphaamylase and a significant increased in lipase were observed in co- and post treated groups as compared with diabetic group, with best results for post treated group. Liver enzymes: In this study, liver enzymes (AST, ALT and ALP) increase in diabetic group, relative to the control. In groups treated with ellagic acid (IV&V), liver enzymes decrease, compared to diabetic group. English Lipid profile: In the present study, lipid profile (TG, TC, LDL-C, and VLDL-C) elevated in diabetic group, relative to normal control, but HDL-C reduced in diabetic group compared to the control. On the other hand, in groups treated with EA (co-treated & posttreated), TG, TC, LDL-C, and VLDL-C decreased relative to diabetic group, but HDL-C increased in treated groups compared to diabetic group. Histological investigations: Pancreas: In control and EA groups histological investigastions revealed normal structure of the pancreas. Langerhan’s islets show a normal shape with numberous β- cells which have a regular round shape with distinct sphere-shaped nuclei. In diabetic rats, pancreatic tissues revealed decreased β-cells number and decreased islets size. In co-treated and posttreated groups, numerous islets revealed a nearly normal shape and regenerated cells. Liver: In the control and ellagic acid groups, histological investigastions showed normal structure of hepatocytes. But, in diabetic group liver sections showed hepatotoxicity manifested by marked inflammatory cells, many of apoptotic cells, degeneration in hepatic cords, and congested blood sinusoids. Liver sections in co-treated group showed mild to moderate inflammatory cells and congested blood sinusoids. In post-treated group, liver sections displayed a good improvement the hepatocytes with mild degeneration, and mild inflammatory cells. Immunohistochemical investigations: 1. Proliferating cell nuclear antigen (PCNA) immunoreactivity This study revealed that the changes in anti-PCNA immunoreactivity in pancreatic and hepatic sections in different groups were strong positive reaction for anti-PCNA immunoreactivity in pancreatic and hepatic sections were observed English in control and ellagic acid groups, mild to moderate in diabetic group, moderate in co-treated and strong in post-treated groups. 2. Insulin immunoreactivity The current study revealed that the changes in insulin immunoreactivity in β- cells on pancreas sections in different groups. β- cells in pancreas sections in control and ellagic acid groups revealed strong positive reaction for insulin immunoreactivity. In contrast; mild to moderate insulin positive reactions were observed in β- cells in pancreas sections in diabetic group. On the other hand; β- cells in pancreas in co-treated and post-treated groups revealed moderate to strong insulin positive reactions 3. Tumor necrosis factor (TNF-α) Current study revealed the changes in and anti-TNF-α immunoreactivity in pancreatic sections in different groups. Mild positive reaction for anti-TNF-α immunoreactivity in pancreatiic sections was observed in control and ellagic acid groups, strong in diabetic group, moderate in co-treated and moderate to mild in post-treated groups. 4. Interleukin -6 (IL-6) Current study revealed the changes in anti-IL-6 immunoreactivity in pancreatic and hepatic sections in different groups. Mild positive reaction for anti- IL-6 immunoreactivity in pancreatic and hepatic sections were observed in control and ellagic acid groups, strong in diabetic group, moderate in co-treated and moderate to mild in post-treated groups. Gene expressions of IGF-1 and klotho : The RT-PCR data indicated that, in experimental diabetes by STZ the expression of IGF-1 and klotho genes was significantly (P< 0.00001) downregulated compare to the control rats. Over expression of klotho and IGF-1 genes was induced when diabetic rats treated with ellagic acid (G4&G5) compare to diabetic untreated rats.