الفهرس 
IntroductionOnly 14 pages are availabe for public view
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Abstract
Type 2 Diabetes mellitus (T2DM) is a heterogeneous metabolic disorder characterized by impaired cellular responses to insulin known as insulin resistance and followed by progressive partial pancreatic β-cell dysfunction. Due to insulin resistance, pancreatic β- cells secrete abnormally high levels of insulin in order to control blood glucose levels, however overtime, hyperglycemia, hyperinsulinemia, pancreatic β-cell dysfunction and subsequent progressive pancreatic β-cell destruction occur In the present study, a rat model of T2DM was established by application of the HFD/fructose/STZ method. After 30 days of feeding with HFD and 25% fructose in drinking water, rats were injected with single STZ (35 mg/kg, i.p.). Canagliflozin (10 mg/kg/day), adipoRon (25 mg/kg/day), diacerein (100 mg/kg/day) and indapamide (10 mg/kg/day) were given orally from the 5th to the end 8th week of the experiment. The drugs evaluated significantly attenuated HFD/fructose/STZ-induced T2DM through interference with different pathophysiological axises. Adiponectin´s modulatory impact : Daily oral administration of canagliflozin, adipoRon, diacerein and indapamide for 1 month significantly enhanced serum adiponectin levels. The medications appear to have modulated adipocytes function, preserved their integrity, and improved their hormonal secretory functions. as evidenced by their morphological advancements.Thus, it can be inferred that direct stimulation of adiponectin receptors confers better antidiabetic impact compared to modulation of endogenous adiponectin levels using therapeutic agents. But, it is worthy to mention that modulation of endogenous adiponectin levels conferred a significant antidiabetic impact as well. Metabolically : Canagliflozin, adipoRon, diacerein and indapamide for 1 month significantly reduced blood glucose, reduced HbA1c% and increased serum insulin. It appears that the drugs managed to modulate pancreatic β-cells functions, preserve their integrity and enhance their hormonal secretory functions. as proven by their morphological improvements. Restoration of ROS/anti-oxidant balance : Canagliflozin, adipoRon, diacerein and indapamide revealed antioxidant properties in epididymal adipocytes and ER oxidative stress which was revealed by enhancement of serum TAC with significant reduction in epididymal adipocytes MDA content. The antioxidant properties appear to participate in reduction of HFD/fructose/STZ-induced DNA fragmentation and preservation of β-cells and epididymal adipocytes morphological and secretory functions. Anti-inflammatory and immunomodulatory effects : Canagliflozin, adipoRon, diacerein and indapamide treatments reduced serum levels of TNF-α, epididymal adipose tissue´s expression of NLRP3 and NFκB. Moreover, they attenuated macrophages infiltration into epididymal adipocytes and reduced CD68 expression. Furthermore, they significantly enhanced the serum levels of the anti-inflammatory IL-10. Histopathologically : Canagliflozin, adipoRon, diacerein and indapamide markedly improved epididymal adipocytes and β-cells diameter and morphological properties. Further extensive clinical studies are recommended for evaluation of the effectiveness of these drugs in treatment and reversal of T2DM and to distinguish the effective therapeutic doses.