This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Type 2 diabetes is associated with an increased risk for cardiovascular events. The traditional risk factors like hypertension and hyperlipidemia do not fully explain this increased risk. Insulin resistance has emerged as an independent risk factor for cardiovascular disease and is associated with a number of other cardiovascular abnormalities. In particular endothelial function appears to be closely related to insulin action and endothelial dysfunction is associated with insulin resistance not only in patients with Type 2 diabetes, but also in obese insulin resistant subjects and their relatives. Thus, it is possible that abnormalities of insulin action are co-inherited with abnormalities of endothelial function. Inflammation of the endothelium is also considered to be common in patients with Type 2 diabetes and obesity and recent evidence suggest that insulin resistance may be a factor that is associated with markers of inflammation being elevated in insulin resistant subjects. Other non-traditional risk factors associated with cardiovascular disease in diabetes include abnormal coagulation and fibrinolysis and elevated homocysteine. If the above abnormalities are indeed associated with insulin resistance then treating insulin resistance with drugs that directly improve insulin sensitivity should reverse these abnormalities. Preliminary data with troglitazone has suggested such possible benefit with improvement in endothelial function, lowering of plasma homocysteine in insulin resistant animals and several studies suggesting an anti-inflammatory effect. Troglitazone was withdrawn from the market due to problems with liver toxicity. There is no data to suggest that the newer insulin sensitizers like rosiglitazone do not have such liver toxicity and have been shown to be effective in improving blood glucose control in patients with Type 2 diabetes. The beneficial effect on these non-traditional risk factors have yet to be demonstrated although preliminary animal and in vitro data suggest that these benefits may well be a class effect. This study will aim to determine if Rosiglitazone (RSG), in combination with Atorvastatin, improves endothelial function (brachial artery vasodilatory response after ischemia, biochemical markers) in non-insulin dependent diabetic patients treated with Sulfonylureas (SFU). The study will also aim to determine if the addition of Metformin (MET) to the above combination is more effective than Rosiglitazone plus Atorvastatin.
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