FOREARM ENDOTHELIAL FUNCTION IN NON-INSULIN DEPENDENT DIABETIC PATIENTS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。2型糖尿病与心血管事件的风险增加有关。传统的危险因素如高血压和高脂血症并不能完全解释这种风险的增加。胰岛素抵抗已成为心血管疾病的独立危险因素，并与许多其他心血管异常有关。特别是内皮功能似乎与胰岛素作用密切相关，内皮功能障碍不仅与2型糖尿病患者，而且与肥胖胰岛素抵抗者及其亲属的胰岛素抵抗有关。因此，胰岛素作用异常可能与内皮功能异常共同遗传。内皮炎症也被认为在2型糖尿病和肥胖患者中很常见，最近的证据表明胰岛素抵抗可能是胰岛素抵抗患者炎症标志物升高的一个相关因素。其他与糖尿病患者心血管疾病相关的非传统危险因素包括凝血和纤溶异常以及同型半胱氨酸升高。如果上述异常确实与胰岛素抵抗有关，那么用直接改善胰岛素敏感性的药物治疗胰岛素抵抗应该可以逆转这些异常。初步数据显示，曲格列酮可以改善内皮功能，降低胰岛素抵抗动物的血浆同型半胱氨酸，几项研究表明曲格列酮具有抗炎作用。曲格列酮因肝毒性问题被撤出市场。没有数据表明新的胰岛素增敏剂如罗格列酮没有这种肝毒性，并且已被证明对改善2型糖尿病患者的血糖控制有效。对这些非传统风险因素的有益影响尚未得到证实，尽管初步的动物和体外实验数据表明，这些益处很可能是一类效应。本研究旨在确定罗格列酮（RSG）联合阿托伐他汀是否能改善非胰岛素依赖型糖尿病患者磺脲类药物（SFU）治疗后的内皮功能（缺血后的肱动脉血管舒张反应，生化指标）。该研究还旨在确定在上述组合中加入二甲双胍（MET）是否比罗格列酮加阿托伐他汀更有效。

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.