الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Diabetes mellitus (DM)) or simply diabetes is a group of metabolic disorder of multiple etiology characterized by chronic hyperglycemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. The effects of diabetes mellitus include long-term damage, dysfunction and failure of various organs. The more prevalent form of diabetes is type 2 diabetes which accounts for more than 90% of cases. The pathogenesis of type 2 diabetes is complex and involving progressive development of insulin resistance and a relative deficiency in insulin secretion. The burden of this disorder is enormous, owing to its rapidly increasing global prevalence, the devastating damage it can do to many organs of the body, and the direct and indirect costs. The estimated worldwide prevalence of diabetes among adults was 285 million (6.4%) in 2010, and this value is predicted to rise to around 439 million (7.7%) by 2030. The pandemic of type 2 diabetes, along with its high human and economic costs, is showing no signs of abatement and, therefore, new approaches are urgently needed to prevent, slow the progression, and limit the consequences of this disease.
The treatments of diabetes include diet, exercise, use of oral hypoglycemic agents and insulin is the primary forms of treatment for diabetes. Currently available synthetic anti-diabetic agents besides being expensive produce serious side effects. Apart from currently available therapeutic options, traditional medicines or complementary and alternative medicines are a fruitful source of future drugs to counteract insulin resistance. A major advantage of traditional medicine is that they have been used to treat human diseases for many years and so there is considerable knowledge concerning in vivo efficacy and safety, two of the confounding problems facing other new chemical entities. However, in most cases there is little rigorous scientific evidence proving their efficacy and the mode of action is generally not known. It has been estimated that up to one-third of patients with diabetes mellitus use some form of complementary and alternative medicine.
Bitter melon (Momordica charantia) is a popular fruit used for the treatment of diabetes and related conditions amongst the indigenous populations of Asia, South America, India and East Africa. Abundant pre-clinical studies have documented the anti-diabetic and hypoglycemic effects of Bitter melon however the precise mode of action is still unclear. This thesis aimed to evaluate the hypoglycemic activity and the probable underlying mechanisms of action of Bitter melon extract in diabetic rats by studying the changes in insulin signaling pathway in different peripheral tissues.
To achieve this aim we use rat model of type 2 diabetes mellitus which generated by injecting Wistar rats on the 5th day of their birth (n5=birth) intra-peritoneally with 100 mg/kg of STZ. All rats were followed up for 8-12 weeks to establish diabetes which was confirmed by fasting blood glucose level more than 200 mg/dl. The male diabetic rats will be divided into four groups: Group 1: the diabetic control group which received no treatment. Group 2: Bitter melon treated group. This group was divided into 4 subgroups (10 arts each) each group was treated daily with different oral doses of Bitter melon ethanolic extract (100 mg/kg,200 mg/kg,400 mg/kg and 600 mg/kg) for 30 days. Group 3: Glibenclamide treated group that was treated with glibenclamide 0.1 mg/kg (n=10) for 30 days. Also the study included a 10 healthy control rats (Group 4).
The results indicated that, the n-STZ diabetic rat model showed the typical manifestations of type 2 diabetes mellitus (T2DM) including increased weight gain, hyperglycemia, decreased insulin level and elevated HOMA-insulin resistance index compared to control rats. Also in the diabetic rats, the impaired glucose homeostasis is associated with disturbed lipid metabolism as indicated by elevated triglycerides, total cholesterol and LDL-cholesterol and decline in HDL-cholesterol.
The treatment of the diabetic rats with serial doses of ethanolic extract of bitter melon showed a dose dependent decrease in body weight and increase in fasting insulin level while the fasting blood sugar and HOMA-insulin resistance index showed dose-dependent decline with the doses from 100 to 400 mg/kg with the best results obtained with 400 mg/kg dose, the highest dose (600 mg/kg) showed significant elevated values compared to untreated diabetic rats. When comparing the efficacy of bitter melon with conventional drugs like sulfonylurea (glibenclamide) we found that bitter melon extract at dose of 400 mg/kg showed comparable improvements in glucose homeostasis parameters with glibenclamide.
The insulin resistance in diabetic rats was associated with impaired insulin signaling in liver and muscles as indicated by lowered phosphor-insulin receptor (Phospho-IR), IRS-1, PKC and Glut4. The treatment of diabetic rats with bitter melon showed a dose-dependent increase of several components of insulin signaling in liver (P-IR and IRS-1) and muscle (P-IR, IRS-1, PKC and Glut4) with the doses from 100 to 400 mg/kg while the highest dose (600mg/kg) showed less efficient effect than the lower doses. This induction effect on the expression of these components of insulin signaling at the protein level may indicate that the constituents of bitter melon may act as a positive regulators at the transcriptional, post-transcriptional and/or translational level of gene expression, however the specific constituents responsible for these induction effect need further studies.
The treatment with bitter melon show triglycerides lowering effect at low doses (100 and 200 mg/kg) while the higher doses have no significant effect. Total cholesterol showed very mild correction with bitter melon treatment. While HDL-cholesterol showed dose-dependent increase, the LDL-cholesterol showed a dose-dependent decline with bitter melon extract at doses from 100 to 400 mg/kg while highest dose showed lesser effect. Also, glibenclamide showed partial correction of lipid profile.
from the results of the present study and other related studies we can conclude that:
1- Bitter melon extract is a powerful glucose -lowering factor that play important role as anti-diabetic treatment.
2- Bitter melon produces its effect through multiple pathways:
a- Acting as insulin secretagogue, which induce insulin secretion from β-cell
b- Mimicking insulin action, through its constituents like p-insulin (polypeptide P) which induce insulin like action in peripheral tissue
c-Induce peripheral tissues expression of the insulin signaling components and act as insulin sensitizer.
3- The bitter melon extract at low doses produce anti-diabetic effects equivalent to classical sulfonylurea (glibenclamide) however, high dose is less efficient and may worsen the diabetic situation.
4- Bitter melon extract have a lipid-lowering effect which partially correct dyslipidemia observed in the diabetic rats
5-Bitter melon is recommended as food supplement or pharmacological extract to treat type 2 diabetes mellitus.