Lifestyle, insulin, IGF-I and colorectal cancer

描述(申请人提供)：西方人的生活方式，特点是体力活动水平低，高能量饮食富含易消化(精制)的碳水化合物和脂肪，与患结肠癌的风险增加有关。解释这种联系的病因学模型主要集中在饮食对结肠核仁暴露于肠腔内诱变或促癌化合物的影响。这些模型的一个局限性是，它们不能解释风险与体力活动的反向关系或风险与肥胖的正关系。最近的一项理论指出，西方生活方式对结肠癌风险的影响可能至少部分是通过胰岛素和胰岛素样生长因子(IGF)代谢的变化来调节的。胰岛素是调节能量代谢的关键激素。它通过促进IGF-I的合成和下调其几个结合蛋白(IGFBP-1和-2)来提高其生物活性。胰岛素和IGF-I都刺激合成代谢(生长)过程，这是可用能量和基本底物(如氨基酸)的函数。此外，由胰岛素或IGF-I产生的合成代谢信号可通过抑制细胞凋亡和刺激细胞增殖来促进肿瘤的发展。过量饮食和肥胖倾向于增加血浆胰岛素和生物活性的IGF-I，而血浆胰岛素和总的和生物可利用的IGF-I因能量限制而降低，从而在动物模型中预防多种形式的癌症。本研究的具体目的是：[1]检查(诊断前)血清糖化血红蛋白(血糖的标志物)和C-肽(胰岛素水平的标志物)水平升高以及IGFBP-1和IGFBP-2水平降低是否会增加患结肠癌和直肠癌的风险；[2]检查IGF-I浓度升高(绝对的或相对于其主要血浆结合蛋白-IGFBP-3)是否会增加患结肠癌和直肠癌的风险；[3]检查高血糖负荷是否会增加结直肠癌的风险；和[4]描述饮食(特别是血糖负荷)、人体测量指数和其他生活方式变量与每种血清多肽的关系。这项研究旨在增加对过度营养与结肠癌发生相关的病因机制的理解，这最终将有助于制定更精确的营养指南，以有效预防结肠癌。

DESCRIPTION (provided by applicant): A Western lifestyle, characterized by a low level of physical activity, and an energy-dense diet rich in easily digestible (refined) carbohydrates and fats, is associated with an increased risk of developing colon cancer. Etiologic models to explain this association have focused mostly on effects of diet on exposures of the colonic rnucosa to mutagenic or tumor-promoting compounds in the gut lumen. A limitation of these models is that they do not explain the inverse relation of risk with physical activity or the positive relation of risk with obesity. A more recent theory states that effects of a Western lifestyle on colon cancer risk may at least in part be mediated by alterations in the metabolism of insulin and insulin-like growth factors (IGFs). Insulin is a key hormone in the regulation of energy metabolism. It increases the bio-activity of IGF-I by enhancing its synthesis, and by down regulating several of its binding proteins (IGFBP-1 and -2). Insulin and IGF-I both stimulate anabolic (growth) processes, as a function of available energy and elementary substrates (e.g., amino acids). In excess, the anabolic signals by insulin or IGF-I can promote tumor development by inhibiting apoptosis, and by stimulating cell proliferation. Overeating and obesity tend to increase plasma insulin and bio-active IGF-I, whereas plasma insulin and total and bioavailable IGF-I are decreased by energy restriction, which protects against many forms of cancer in animal models. The specific aims of the present study are: [1] to examine whether increased (prediagnostic) serum levels of glycated hemoglobin (a marker for plasma glucose) and C-peptide (a marker for insulin levels), and low levels of IGFBP-1 and IGFBP-2, increase risk of colon cancer, and possibly rectal cancer; [2] to examine whether elevated IGF-I concentrations (absolute, or relative to its major plasmatic binding protein -- IGFBP-3) are increase risk of colon and rectal cancers; [3] to examine whether high dietary glycemic load increases colorectal cancer risk ; and [4] to describe relationships of diet (particularly glycemic load), anthropometric indices, and other lifestyle variables with each of the serum peptides. This study seeks to increase understanding of etiologic mechanisms relating over nutrition to colon cancer development, which will eventually allow the in formulation of more precise nutritional guidelines for efficient prevention.