Insulin Resistance and Adenomas of the Colorectum

有相当多的证据表明胰岛素和/或类胰岛素 生长因子(IGF)会增加大肠肿瘤的风险。流行病学 结直肠肿瘤的危险因素与胰岛素相似。 抵抗综合征和前瞻性研究表明，糖尿病和 IGF-1水平升高与结直肠癌风险相关。不是 以前的研究已经包括了胰岛素抵抗的直接测量，也没有 任何包括完全确定大肠肿瘤的直接 对整个结肠直肠的检查。这项研究将评估这一关系 胰岛素抵抗与结直肠肿瘤之间的关系 独一无二的机会来检查多种族队列，他们之前的衡量标准是 人们已经对胰岛素敏感了。胰岛素抵抗与动脉粥样硬化 研究(IRAS)是一项由国家心肺和血液研究所资助的队列研究 研究所。IRAS在1991-1994年间检查了1628名平均年龄为55岁的人 动脉粥样硬化的危险因素。这一队列由四个临床中心组成 (阿拉莫萨公司、洛杉矶、奥克兰和圣安东尼奥)成立于 多种族(34%西班牙裔，28%非裔美国人，38% 非西班牙裔白人)，双性别者，糖尿病风险各不相同。在1998-1999年间 对幸存的队列中85%的人进行了重新检查。两次考试都是 包括了自我报告的动脉粥样硬化危险因素的测量(饮食， 体力活动、烟草使用、家族史)以及人体测量， 最重要的是，口服葡萄糖耐量测试和频繁采样 静脉葡萄糖耐量试验(FSIGT)。FSIGT是一种敏感的 胰岛素抵抗的具体衡量标准。所有幸存的队列成员(估计 1518)将被邀请进行结肠镜筛查。可行性数据 表示将有1000人同意进行结肠镜检查，其中我们 估计有240例(范围206-274)会有腺瘤。将进行粘膜活检 从所有受试者的盲肠和直肠，所有腺瘤将被切除并 检查组织学特征、Ki-ras突变、增殖和 细胞凋亡。将检测血清样本中的胰岛素、IGF-1、IGFBPI和IGFBP3 所有队列成员在结肠镜检查时以及在 使用保存的血清进行两次早期检查(199.1-4和1998-9)的时间 样本。这项研究提供了预期的可用性的优势 糖耐量、胰岛素抵抗、大多数 大肠肿瘤危险因素和储存血液样本的可获得性 来自一个多种族和双性别者群体。完整的结直肠可视化 这整个队列将使对结直肠肿瘤风险的无偏见估计成为可能。 与这些因素有关。因此，这项研究提供了一种省时和 经济高效的方法来检验结直肠肿瘤风险是 与胰岛素抵抗相关的因素显著增加，并 研究这种风险增加的生物机制。

There is considerable evidence that insulin and/or insulin-like growth factors (IGFs) can increase risk of colorectal neoplasia. Epidemiologic risk factors for colorectal neoplasia are similar to those for insulin resistance syndromes, and prospective studies have shown both diabetes and higher levels of IGF-1 to be associated with colorectal cancer risk. No previous studies have included direct measures of insulin resistance, nor have any included complete ascertainment of colorectal neoplasia by direct examination of the entire colorectum. This study will assess the relationship between insulin resistance and colorectal neoplasia by taking advantage of a unique opportunity to examine a multi-ethnic cohort on whom prior measures of insulin sensitivity have been made. The Insulin Resistance and Atherosclerosis Study (IRAS) is a cohort study supported by the National Heart Lung and Blood Institute. IRAS examined 1628 people of average age 55 in 1991-1994 for atherosclerosis risk factors. The cohort, assembled in four clinical centers (Alamosa, Co., Los Angeles, Oakland, and San Antonio) was established to be multi-ethnic (34 percent Hispanic, 28 percent African American, and 38 percent non-Hispanic white), bi-gender, and varied in diabetes risk. In 1998-1 999 over 85 percent of the surviving cohort was re-examined. Both of the examinations have included measures of self-reported risk factors for atherosclerosis (diet, physical activity, tobacco use, family history) as well as anthropometry and, most importantly, oral glucose tolerance testing and frequently-sampled intravenous glucose tolerance tests (FSIGT). The FSIGT is a sensitive and specific measure of insulin resistance. All surviving cohort members (estimated 1518) will be invited to have a screening colonoscopy. Feasibility data indicate that 1000 will agree to have a colonoscopic exam, among whom we estimate 240 (range 206-274) will have adenomas. Mucosal biopsies will be taken from the cecum and rectum of all subjects, and all adenomas will be removed and examined for histologic features, Ki-ras mutations, proliferation, and apoptosis. Serum samples will be assayed for insulin, IGF-1, IGFBPI, and IGFBP3 levels for all cohort members at both the time of colonoscopy, as well as at the time of two earlier examinations (199 1-4 and 1998-9) using stored serum samples. This study offers the advantage of the availability of prospective measures of glucose tolerance, insulin resistance, measurements of most colorectal neoplasia risk factors, and the availability of stored blood samples from a multi-ethnic and bi-gender cohort. Complete colorectal visualization of this entire cohort will enable unbiased estimates of colorectal neoplasia risk related to these factors. This study therefore offers a time-efficient and a cost-efficient method to test the hypothesis that colorectal neoplasia risk is increased substantially by factors related to insulin resistance, and to examine the biologic mechanisms whereby that risk is increased.