الفهرس 
COVEROnly 14 pages are availabe for public view
 |  | from | 276 |  |  |
| | | from | 276 | | |
Abstract
Diabetes mellitus is a major clinical and public health problem in Egypt. The prevalence of type 2 diabetes is much higher than that of type 1 and accounts for about 90% of total existing diabetic cases in the world. Obesity and the longer life expectancy of the population are among its main contributors. Type 2 diabetes mellitus is characterized by some major metabolic abnormalities including: obesity, insulin resistance, and increased endogenous glucose output.
Glucose uptake into tissues is mediated by the facilitative carrier proteins Glut1 to 12. Glut 1 is primarily responsible for basal, noninsulin-mediated glucose transport that occurs in tissues such as the brain. Its expression has been shown to be regulated by a number of physiological stimuli and conditions such as hypoxia and changes in cytosolic calcium. On the other hand, Glut4 is considered the main insulin-responsive glucose transporter, located primarly in muscle cells and adipocytes, thus playing an important role in glucose homeostasis.
The use of alternative and traditional medical systems is increasing throughout the world, and as a consequence many traditional medicines are being investigated for both efficacy and safety. Many “phytonutrients”, or “phytochemicals” are becoming increasingly known for their therapeutic effects. In the present study, curcumin (the active ingredient of turmeric) and aqueous ginger extracts were used.
The aim of this study was to present a nongenetic type 2 diabetic model using the adult male Wistar rat. Also, to examine the gene expression of Glut 1&4 in the brain and muscle tissues from animals under the present experimental conditions, and to evaluate the therapeutic role of curcumin or aqueous ginger extract, in the treament of the symptoms of obesity and diabetes.
Conclusions from the present pilot study (n=42), showed that feeding male Wistar rats a high fat diet (HF-diet) for 2 weeks, followed by a single i.p. injection of STZ was the best model to represent type 2 diabetes, characterized by hyperglycemia (≥ 200 mg/dl), and insulin resistance.
In the main study, rats had access to food and water ad libitum and were equally divided into 7 groups (n=49).One group of rats (normal) was fed a N-diet throughout the experimental period (group 1).All the other rats (groups 2 to 7) were fed a HF-diet for 15 days, after which animals were divided into 2 main groups (designated groups 2 &5). Animals of the latter group (diabetic), each received a single intraperitoneal injection of STZ (35 mg/kg b.wt) dissolved in citrate buffer, while the former(nondiabetic) group(2) received the buffer only. These groups were then subdivided to study the therapeutic effect of curcumin (80 mg/kg b.wt) or ginger aqueous extract (500 mg/kg b.wt) treatment on diabetes, compared to controls. Treated rats were given the curcumin or aqueous ginger extract daily, by gastric intubation, for 8 weeks; starting 48 hours after STZ injection (diabetic groups 6&7), or after the buffer administration (nondiabetic groups 3&4). Rats were thus equally divided into the following 7 groups:
Group 1: Normal rats (N-diet).
Group 2: Nondiabetic HF-diet control rats.
Group 3: Nondiabetic curcumin-treated rats.
Group 4: Nondiabetic ginger -treated rats.
Group 5: Diabetic control rats.
Group 6: Diabetic curcumin-treated rats.
Group 7: Diabetic ginger-treated rats.
Body weights of all rats were followed weekly throughout the experimental period. After 10 weeks, rats were euthanized after withholding food for 16 h,, serum separated and stored at -4◦C, liver, muscle & pancreas excised, and frozen in liquid nitrogen until biochemical analyses were carried out. Brain and muscle for gene expression analysis(Glut1 &Glut 4), were stored in RNAlater till investigations. Biochemical estimations included serum glucose and insulin levels, (and the calculated HOMA-IR). Liver & muscle glycogen contents, serum total protein, triglycerides, total cholesterol, HDL-Ch, LDL-Ch, and liver & pancreas MDA concentrations, were also measured.
At the end of the experiment, the following results were achieved:
• Obesity was clearly observed in the HF-diet group compared to the normal control (P<0.001). It was accompanied by hyperglycemia, elevated insulin level (P<0.01) &HOMA-IR score (P<0.05), and a significant reduction in liver glycogen content (P<0.01). Obesity also caused hypertriglyceridemia, hypercholesterolemia, and high LDL-Ch, compared to the normall control (P<0.001).
• The body weight of the type 2 diabetic group was reduced significantly compared to the obese HF-diet control one (P<0.001). Also, hyperglycemia and insulin resistance were pronounced (P<0.001), as indicated by the high HOMA-IR scores compared to the control obese group (P<0.01). Reduction in liver and muscle glycogen contents (P<0.001), and in serum total protein content (P<0.001) were observed. Dyslipidemia was more pronounced in the diabetic than the obese control group, with elevated serum triglycerides, total cholesterol, LDL-Ch levels and a significant decrease in serum HDL-Ch level (P<0.001). Similarly, elevated levels of MDA in liver & pancreas were recorded compared to the corresponding control (P<0.001). Obesity and the diabetic status caused significant down-regulation of Glut1 &Glut4 gene expression, compared to those measured in their respective controls.
• Treatment with either curcumin or ginger extract, decreased the severity of the obesity induced by the HF-diet; and the diabetic rats regained some of their weights which were lost due to the induction of diabetes(P<0.001). Both curcumin and ginger extract treatment, caused glucose-lowering effects in the HF-diet and the diabetic groups. Also, they decreased insulin resistance, as shown by the reduced scores in the obese & diabetic groups HOMA-IR (P<0.05 to 0.001). At the same time, both aroma compounds increased the liver &muscle glycogen contents, and total serum protein in the diabetic groups compared to the nontreated control (P<0.05 to 0.001). Curcumin or ginger extract treatment decreased triglycerides, total cholesterol, and LDL-Ch, in the nondiabetic groups compared to its control group; and caused a pronounced reduction of dyslipidemia in the treated diabetic groups with significant increases in HDL-Ch compared to the diabetic control group (P<0.05 to 0.001). They also, significantly reduced the MDA levels in the liver and pancreas, compared to the nontreated diabetic control (P<0.001).
Curcumin had a significant modulatory effect on the up-regulation of Glut4 gene expression, compared to that in the type 2 diabetic status. Ginger extract exhibited pronounced up-regulation for both Glut1&Glut4 genes expression, compared to the diabetic control group.
In general, this study presents a diabetic animal model that conforms with the criteria of type 2 diabetes, i.e. hyperglycemia, insulin resistance, and dyslipidemia; and documents the down-regulation of glut1&4gene expression in the obese & diabetic rats. It also shows that all the previous features were substantially improved by the treatment with either curcumin or aqueous ginger extract following the induction of diabetes, thus recommending their daily use in the diet as a therapeutic as well as a prophylactic routine.