Insulin Resistance and Adenomas of the Colorectum

胰岛素抵抗和结直肠腺瘤

• 批准号: 6331928
• 负责人: Ralph B. DAgostino
• 金额: $ 32.97万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6331928
• 关键词: adenoma; apoptosis; binding proteins; biomarker; body physical activity; cancer risk; cell proliferation; clinical research; colorectal neoplasms; dietary lipid; endoscopy; gastrointestinal imaging /visualization; gene mutation; glucose tolerance; hormone regulation /control mechanism; human subject; hypertriglyceridemia; insulin; insulin sensitivity /resistance; insulinlike growth factor; intestinal mucosa; neoplasm /cancer epidemiology; neoplasm /cancer genetics; obesity; oncogenes

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.

有大量证据表明，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，前瞻性研究表明，糖尿病和 高水平的IGF-1与结直肠癌风险相关。没有 以前的研究包括直接测量胰岛素抵抗，也没有 任何包括通过直接检查完全确定结直肠肿瘤 检查整个结肠直肠。本研究将评估 胰岛素抵抗和结直肠肿瘤之间的联系， 独特的机会来检查一个多民族的队列， 胰岛素的敏感性。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中心支持的队列研究。 院IRAS在1991-1994年对1628名平均年龄为55岁的人进行了调查， 动脉粥样硬化危险因素在四个临床中心聚集的队列 （Alamosa，Co.，洛杉矶、奥克兰和圣安东尼奥）成立， 多民族（34%的西班牙裔，28%的非洲裔美国人和38%的 非西班牙裔白色）、两性，以及糖尿病风险的变化。1998- 1999年， 85%的幸存者接受了重新检查。两次考试 已经包括了动脉粥样硬化的自我报告的危险因素的测量（饮食， 身体活动、烟草使用、家族史）以及人体测量， 最重要的是，口服葡萄糖耐量试验和频繁采样 静脉葡萄糖耐量试验（FSIGT）。FSIGT是一种敏感的， 胰岛素抵抗的特定测量。所有存活队列成员（估计 1518）将被邀请进行筛查结肠镜检查。可行性数据 表明1000人同意进行结肠镜检查，其中我们 估计240例（范围206-274）将患有腺瘤。将进行粘膜活检 从所有受试者的盲肠和直肠中取出，所有腺瘤将被切除， 检查组织学特征、Ki-ras突变、增殖和 凋亡将测定血清样本的胰岛素、IGF-1、IGFBPI和IGFBP 3 所有队列成员在结肠镜检查时以及 使用储存血清进行的两次早期检查（1991 -4和1998-9）的时间 样品这项研究提供了前瞻性的可用性， 葡萄糖耐量、胰岛素抵抗的测量， 结直肠肿瘤危险因素和储存血液样本的可用性 来自多种族和双性别群体。完整的结肠直肠可视化， 这一整个队列将能够无偏地估计结直肠肿瘤风险 与这些因素有关。因此，这项研究提供了一个时间效率和 一种经济有效的方法来检验结肠直肠肿瘤风险是 与胰岛素抵抗相关的因素大幅增加， 研究这种风险增加的生物学机制。