Insulin Resistance and Adenomas of the Colorectum

有相当多的证据表明，胰岛素和/或胰岛素样生长因子(IGF)可以增加结直肠肿瘤的风险。结直肠癌的流行病学危险因素类似于胰岛素抵抗综合征，前瞻性研究表明糖尿病和较高水平的IGF-1都与结直肠癌风险相关。以前的研究没有包括胰岛素抵抗的直接测量，也没有任何研究包括通过直接检查整个结肠直肠来完全确定大肠肿瘤的发生。这项研究将通过利用一个独特的机会来检查一个先前已进行胰岛素敏感性测量的多民族队列，来评估胰岛素抵抗和结直肠肿瘤之间的关系。胰岛素抵抗和动脉粥样硬化研究(IRAS)是一项由国家心肺和血液研究所支持的队列研究。IRAS在1991-1994年间对1628名平均年龄为55岁的人进行了动脉粥样硬化风险因素的检查。这一队列由四个临床中心(阿拉莫萨，Co.，洛杉矶，奥克兰和圣安东尼奥)组成，被确定为多种族(34%西班牙裔，28%非裔美国人，38%非西班牙裔白人)，双性别者，糖尿病风险不同。1998-1999年，超过85%的幸存群体接受了重新检查。这两项检查都包括自我报告的动脉粥样硬化危险因素(饮食、体力活动、吸烟、家族史)的测量，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的静脉葡萄糖耐量测试(FSIGT)。FSIGT是衡量胰岛素抵抗的敏感而特异的指标。所有幸存的队列成员(估计为1518人)将被邀请进行结肠镜筛查。可行性数据显示，将有1000人同意接受结肠镜检查，其中我们估计有240人(范围206-274)将有腺瘤。所有受试者的盲肠和直肠将进行粘膜活检，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。所有队列成员的血清样本将在结肠镜检查时以及在两次早期检查(1991-4和1998-9)时使用储存的血清样本进行胰岛素、IGF-1、IGFBP1和IGFBP3水平的检测。这项研究的优势在于可以获得葡萄糖耐量、胰岛素抵抗的前瞻性测量，大多数结直肠肿瘤风险因素的测量，以及来自多种族和双性别队列的储存血液样本的可获得性。对整个队列的完整大肠可视化将使与这些因素相关的大肠肿瘤风险的无偏估计成为可能。因此，这项研究提供了一种既省时又省钱的方法来检验与胰岛素抵抗相关的因素会显著增加结直肠肿瘤风险这一假设，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.