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Abstract The prevalence of diabetes increases exponentially worldwide. At the same time, both an increased consumption of unhealthy high calorie food and a sedentary behavior have been recorded in modern societies. This world’s largest endocrine disease is characterized by chronic hyperglycemia associated with abnormalities in carbohydrate, fat, and protein metabolism leading to a variety of microvascular, macrovascular, neurologic and infectious complications. Therefore, with the increasing prevalence of DM and obesity, effective treatment is critical for decreasing morbidity, mortality and complications as well as improving public health at large. The objective of the present study was to investigate the effect of telmisartan, a structurally unique AT1 receptor antagonist that can function as a partial PPARγ agonist ; sodium selenate, a PTP inhibitor; metformin, the well- known anti-diabetic agent, together with their combinations for 5 weeks, on a rat model that simulates the natural history and metabolic characteristics of human T2DM. This was achieved by feeding the rats with HFFD for 8 weeks followed by low dose of STZ rendering them diabetic and insulin resistant. The rat groups were divided as follows; group 1: Normal control rats that were fed NPD and received single dose of citrate buffer alone i.p. group 2: DIR rats that received 0.5% aqueous solution of carboxymethyl cellulose sodium as a vehicle of the treatment for 5 weeks. group 3: DIR rats that received telmisartan (5 mg/kg/day; p.o.) for 5 weeks . group 4: DIR rats that received sodium selenate (1.89 mg/kg/day; i.p.) for 5 weeks. group 5: DIR rats that received metformin (250 mg/kg/day; p.o.) for 5 weeks. Summary and Conclusions 131 group 6: DIR rats that received telmisartan (5 mg/kg/day; p.o.) plus sodium selenate (1.89 mg/kg/day; i.p.) for 5 weeks. group 7: DIR rats that received telmisartan (5 mg/kg/day; p.o.) plus metformin (250 mg/kg/day; p.o.) for 5 weeks. group 8: DIR rats that received sodium selenate (1.89 mg/kg/day; i.p.) plus metformin (250 mg/kg/day; p.o.) for 5 weeks. The results of the present study showed that telmisartan treatment reduced serum glucose and HOMA-IR index, decreased serum lipid profile and hepatic PTP, while serum insulin and liver GSH were increased. As for serum adiponectin level, it was successfully restored to normal levels. Sodium selenate treatment showed reduced serum glucose, TG, FFA, HOMA-IR index together with hepatic PTP. Only serum total cholesterol was restored to normal level while serum insulin and hepatic GSH levels were significantly increased. However, no significant change in serum adiponectin level was observed. Metformin treatment effectively reduced serum glucose level and HOMA-IR index together with a significant decline in serum lipid profile and hepatic PTP. On the other hand, serum insulin and hepatic GSH levels were increased. However, metformin didn’t produce any significant change in serum adiponectin level. Combination of telmisartan and sodium selenate effectively reduced serum glucose level, HOMA-IR index and FFA. Successfully, serum total cholesterol, TG and adiponectin levels were normalized. However, serum insulin and hepatic GSH content were significantly increased while hepatic PTP was significantly declined. Summary and Conclusions 132 Combined treatment of telmisartan and metformin restored serum glucose, total cholesterol, TG and adiponectin back to normal levels together with a signi ficant reduction in HOMA-IR, serum FFA and hepatic PTP. Serum insulin together with hepatic GSH content was significantly increased. Combined treatment of sodium selenate and metformin significantly reduced serum glucose, FFA, HOMA-IR index together with hepatic PTP content while serum total cholesterol, TG levels and hepatic GSH content were normalized. Serum insulin was significantly increased while adiponectin level was not changed. These data suggest that these drugs when administered alone might not efficiently restore hyperglycemia back to normal levels together with other manifestations like serum TG, adiponectin and hepatic GSH in diabetic rats. Also, these findings demonstrate the beneficial role of telmisartan as an adjunct to metformin in restoring serum glucose back to normal level. Therefore, this combinational therapy could be recommended to poorly controlled diabetic patients on metformin monotherapy. In addition, superior effect was shown in alleviating other metabolic disturbances when combination of telmisartan or sodium selenate was used with metformin. Future research should be directed to study the efficacy of other anti- diabetic combinations including telmisartan or sodium selenate. Also, it is recommended that further studies should be done to assess other cytokines which could serve as new indicators of anti-diabetic efficacy. This will finally determine if these results can be appropriately extrapolated to human diabetes, which may result in better and more efficient management of DM and its related complications. |