الفهرس 
Introduction and aim of the workOnly 14 pages are availabe for public view
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Abstract
Over the last years, experimental data have illuminated the role of inflammation in atherogenesis and insulin resistance. Increased serum levels of inflammatory biomarkers of arteriosclerosis, like CRP, TNF-α or IL-6, as well as novel markers like MCP-1, soluble CD40 ligand (sCD40L), and matrix metalloproteinases (MMP) have been shown to predict cardiovascular risk and seem to reflect the overall burden of vascular disease in patients. Interestingly, some of these markers are elevated in patients with type 2 DM and insulin resistance, indicating a pivotal role of inflammation in this metabolic disorder.
Recently, PPAR-γ agonists, oral insulin sensitizers, are used extensively in the treatment of insulin resistance and type 2 DM; therefore, the impact of PPAR-γ agonists on atherosclerosis is important. Recent experimental and clinical data support a beneficial role of TZDs (PPAR-γ agonists) in the prevention and treatment of vascular inflammation, which can lead to atherosclerosis.
It has been proposed that some ARBs, such as telmisartan, act as partial activators of PPAR-γ at concentrations that are achieved with the recommended oral doses for antihypertensive treatment.
In in vivo part of our study we used telmisartan in hypertensive type 2 diabetic patients, we found that treatment of the patients with telmisartan leads to a significant decrease of both systolic and diastolic blood pressure with no effect on BMI or in the parameters of glucose metabolism. On lipid metabolism we observed significant reduction only on FFA concentration. Moreover, we found that telmisartan significantly affect the parameters of insulin resistance (evauated by HOMA-IR and IRI) in patients not receiving insulin, sulphonylurea, or nateglinide. We found that telmisartan treatment has no effect on total and high molecular weight adiponectin. However, telmisartan significantly decrease the leptin level in all groups of patients.
In in vitro part of our study we showed that TNF-α signicantly increase the production and mRNA expression of both IL-6 and MCP-1 from the 3T3-L1 adipocytes and with the pretreatment of the cells with either telmisartan or pioglitazone we found significant decrease in production and mRNA expression of both cytokines. Investigating the possible mechanisms of these effects, we found that TNF-α significantly increased the phosphorylation of MAP kinases as well as IκB-α and with the use of telmisartan and pioglitazone the phosphorylation of these kinases was significantly decreased. These results suggest that these mechanisms share in the action of both telmisartan and pioglitazone in the reduction of these cytokines. To confirm these results, we used MAP kinases inhibitors before stimulation of the cells by TNF-α and we found that there was significant decrease in mRNA expression of both cytokines with the use of MAP kinase inhibitors. Moreover, we found that with the use of TPCK (NF-κB inhibitors) there was significant decrease in the mRNA expression of both cytokines indicating the role of NF-κB in the production of these cytokines.
Conclusion
We conclude that pioglitazone (a well known PPAR-γ agonist) and telmisartan (a partial PPAR-γ agonist) are capable to reduce the effect of TNF-α on the production of inflammatory cytokines. We suggest that telmisartan and pioglitazone may improve insulin resistance by inhibition of IL-6 and MCP-1 production from adipocytes through inhibition of MAP Kinase pathway.
Identification of an antihypertensive agent such as telmisartan that has combined AT1-R antagonism and PPAR-γ activation would constitute an important agent that improves the metabolic and inflammatory derangements associated with MS. It may provide a unique therapeutic approach of the chronic metabolic and inflammatory processes in various organs.
We recommend the following:
1- Assessing other cytokines such as MCP-1 and IL-6 in diabetic patients and examining the effect of telmisartan and pioglitazone on these cytokines.
2- Testing the effect of both telmisartan and pioglitazone in diabetic patients to detect any synergistic effect between the two agents.
3- Exploring the role of telmisartan in MS.
4- Performing a similar study in upper Egypt to test the effect of these drug on patients with different ethnicity.