Insulin Resistance and Adenomas of the Colorectum

大量证据表明，胰岛素和/或胰岛素样生长因子（IGFs）可增加结直肠癌的风险。结直肠癌的流行病学危险因素与胰岛素抵抗综合征相似，前瞻性研究表明糖尿病和较高水平的IGF-1与结直肠癌的风险相关。以前的研究没有包括胰岛素抵抗的直接测量，也没有包括通过直接检查整个结直肠来完全确定结直肠肿瘤。本研究将评估胰岛素抵抗和结直肠肿瘤之间的关系，利用一个独特的机会来检查一个多种族的队列，这些队列先前已经对胰岛素敏感性进行了测量。胰岛素抵抗和动脉粥样硬化研究（IRAS）是由国家心肺和血液研究所支持的一项队列研究。IRAS在1991-1994年间对1628名平均年龄55岁的人进行了动脉粥样硬化危险因素的调查。该队列由四个临床中心（Alamosa, Co., Los Angeles, Oakland, and San Antonio）组成，被确定为多种族（34%的西班牙裔，28%的非裔美国人和38%的非西班牙裔白人），双性别，糖尿病风险不同。在1998-1999年间，超过85%的幸存者被重新检查。这两项检查都包括动脉粥样硬化的自我报告危险因素（饮食、体育活动、吸烟、家族史），以及人体测量，最重要的是，口服葡萄糖耐量试验和频繁采样的静脉葡萄糖耐量试验（FSIGT）。FSIGT是胰岛素抵抗的一种敏感而特异的测量方法。所有幸存的队列成员（估计1518人）将被邀请进行筛查结肠镜检查。可行性数据表明，1000人将同意进行结肠镜检查，其中我们估计240人（范围为206- 274）将患有腺瘤。将对所有受试者的盲肠和直肠进行粘膜活检，并切除所有腺瘤，检查其组织学特征、Ki-ras突变、增殖和凋亡。将在结肠镜检查时，以及使用储存的血清样本进行两次早期检查（1991-4和1998-9）时，对所有队列成员的血清样本进行胰岛素、IGF-1、IGFBP1和IGFBP3水平的检测。这项研究提供了葡萄糖耐量、胰岛素抵抗、大多数结直肠肿瘤危险因素的前瞻性测量的优势，以及来自多种族和双性别队列的存储血液样本的可用性。整个队列的完整结肠直肠可视化将使与这些因素相关的结直肠肿瘤风险的无偏估计成为可能。因此，本研究提供了一种既省时又经济的方法来检验与胰岛素抵抗相关的因素显著增加结直肠瘤变风险的假设，并检验这种风险增加的生物学机制。

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 1998-1999 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, IGFBP1, and IGFBP3 levels for all cohort members at both the time of colonoscopy, as well as at the time of two earlier examinations (1991-4 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.