INSULIN RESISTANCE AND GLUCOCORTICOIDS

美洲印第安人不同地受到炎症性结缔组织病(CTD)的影响，如 类风湿性关节炎和系统性红斑狼疮。此外，肥胖、胰岛素抵抗和2型 糖尿病在美洲印第安人中比在欧洲血统的美国人中更常见。 CTD通常使用糖皮质激素治疗，但这些药物严重并发症的发生率很高。 这反映了上面列出的在美国印第安人中发现过多的疾病；即肥胖， 胰岛素抵抗、2型糖尿病和高血压。关于风险因素的数据很少， 使个人容易受到这些并发症的影响。我们假设一个主要的易感因素是胰岛素 抵抗，这在印度人中是非常常见的。因此，一个必然的假设是美洲印第安人会 糖皮质激素并发症的风险增加。同时，骨质疏松症也是常见的 糖皮质激素治疗的并发症；然而，骨密度改变的发病机制与 糖皮质激素可能不会引起胰岛素抵抗。因此，我们假设这种复杂性不会 在美洲印第安人中有所增加。这些假设将在前两个具体目标中得到检验。第一，预先存在 胰岛素抵抗将被评估为大腿肥胖症、高血压、 美国印第安人和高加索人风湿病患者中的糖耐量异常和2型糖尿病 接受糖皮质激素治疗。在第二个目标中，先前存在的胰岛素抵抗将被评估为风险。 美洲印第安人和高加索风湿病患者发生骨质疏松症的因素 接受球状皮质激素治疗。已知增加胰岛素敏感性的药物，如二甲双胍 减少胰岛素抵抗患者未来的糖尿病发病。我们假设二甲双胍会降低 使用糖皮质激素治疗的美洲印第安人中肥胖和糖尿病的发生率。这一假设 将通过一项随机、安慰剂对照的临床试验，对患有炎症性疾病的印度人进行试验 正在接受糖皮质激素治疗的结缔组织疾病。 美国印第安人通常有一种情况，身体对胰岛素反应不好，这 EADS导致2型糖尿病、高血压、肥胖症和血脂升高。我们认为这个问题 可能会给印度人带来更严重的糖皮质激素并发症，糖皮质激素用于治疗炎症性疾病。

American Indians are differentially affected by inflammatory connective tissue diseases (CTD) such as rheumatoid arthritis and systemic lupus erythematosus. In addition, obesity, insulin resistance, and type 2 diabetes mellitus are much more common in American Indians than in Americans of European ancestry. CTD are frequently treated with glucocorticoids, but these drugs have a high rate of serious complications that mirror the diseases listed above that are found in excess among American Indians; namely, obesity, insulin resistance, type 2 diabetes and hypertension. There are very little data concerning risk factors that predispose individuals to these complications. We hypothesize that a major predisposing factor is insulin resistance, which is extremely commonin Indians. Thus, a corollary hypothesis is that American Indians will be at increased risk of complications from glucocorticoids. Meanwhile, osteoporosis is also a common complication of glucocorticoid therapy; however, the pathogenesis of altered bone mineral density with glucocorticoids likely does not involve insulin resistance. Thus, we hypothesize that this complication will not be increased in American Indians. These hypotheses will be tested in the first two Specific Aim. First, preexisting insulin resistance will be assessed as a risk factor for development of trunchal obesity, hypertension, glucose intolerance and type 2 diabetes among American Indian and Caucasian rheumatic disease patients receiving glucocorticoid therapy. In the second aim, pre-existing insulin resistance will be assessed as a risk factor for development of osteoporosis among American Indians and Caucasian rheumatic disease patients receiving glococorticoid therapy. Agents that increase insulin sensitivity such as metformin are known to reduce future diabetes onset in persons with insulin resistance. We hypothesize that metformin will lower the incidence of obesity and diabetes among American Indians treated with glucocortioids. This hypotheses will be tested by a randomized placebo-controlled clinical trial of metformin in Indians with inflammatory connective tissue diseases who are being treated with glucocorticoids. American Indians very commonly have a condition in which the body does not respond well to insulin, this eads to type 2 diabetes, high blood pressure, obesity and elevated blood lipids. We think that this problem may give Indians worse complications from glucocorticoids, which are used to treat inflammatory illness.