Potential utility of single and concurrent administration of a partial peroxisome proliferator activated receptor- γ agonist and a protein tyrosine phosphatase inhibitor in treating type II diabetic rats.
Thesis
It is estimated that diabetes mellitus (DM) accounts approximately for 6.8% of all deaths worldwide. Egypt is expected to be ranked among the world’s top 10 in terms of the highest number of people with DM in 2030. The risk of developing type II diabetes mellitus (T2DM) increases with age, obesity and lack of physical activity. In addition, the alarming increase in fructose consumption was found to be an important contributor to the epidemic of obesity and insulin resistant diabetes in both pediatric and adult populations. In most patients with T2DM, it was found that metformin alone is not enough to adequately control hyperglycemia. One member in the nuclear receptor superfamily, peroxisome-proliferator activated receptor gamma (PPARγ), has emerged as an important player in ameliorating insulin resistance (IR) and DM. At the same time, blockade of renin-angiotensin system (RAS) using angiotensin II-type1 (AT1) receptor blocker was shown to prevent DM and enhance insulin action. Moreover, enhanced expression and activity of the protein tyrosine phosphatase (PTP1B) is discussed as one possible mechanism for the development and existence of IR. Thus, this study was designed with the aim to investigate the effect of telmisartan, a partial agonist of PPARγ; sodium selenate, a PTP inhibitor; metformin, the well-known anti-diabetic agent, together with their combinations on a rat model that simulates the natural history and metabolic characteristics of human T2DM. This was achieved by feeding the rats with high-fat, high-fructose diet (HFFD) together with low dose of streptozotocin (STZ) rendering them diabetic and insulin resistant. The effectiveness of the drugs and their combinations was assessed by detecting the changes in serum glucose, insulin, adiponectin, HOMA-IR index as well as the lipid profile. In addition, the level of reduced glutathione (GSH) and the activity of PTP in the liver were determined. The results showed that the combination of telmisartan with sodium selenate or metformin corrected the altered serum total cholesterol, triglycerides (TG) and adiponectin. Also, telmisartan was able to restore serum glucose while sodium selenate was able to restore hepatic GSH back to normal levels, when each of them was used together with metformin. In conclusion, superior effect was emphasized when either telmisartan or sodium selenate was used as an adjunct to metformin.
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