Lifestyle, insulin, IGF-I and colorectal cancer

描述（由申请人提供）：西方生活方式的特征是低水平的体力活动，以及富含易消化（精制）碳水化合物和脂肪的能量密集饮食，与结肠癌风险增加有关。解释这种关联的病因学模型主要集中在饮食对结肠粘膜暴露于肠腔中致突变或促肿瘤化合物的影响。这些模型的局限性在于，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向关系。最近的一个理论指出，西方生活方式对结肠癌风险的影响可能至少部分是由胰岛素和胰岛素样生长因子（IGFs）代谢的改变介导的。胰岛素是调节能量代谢的关键激素。它通过增强IGF-I的合成和下调其几种结合蛋白（IGFBP-1和-2）来增加IGF-I的生物活性。胰岛素和IGF-I都刺激合成代谢（生长）过程，作为可用能量和基本底物（例如，氨基酸）。过量时，胰岛素或IGF-I的合成代谢信号可以通过抑制细胞凋亡和刺激细胞增殖来促进肿瘤的发展。暴饮暴食和肥胖倾向于增加血浆胰岛素和生物活性IGF-I，而血浆胰岛素和总的和生物可利用的IGF-I通过能量限制而降低，这在动物模型中保护免受多种形式的癌症。本研究的具体目的是：[1]检查是否增加了（诊断前）糖化血红蛋白血清水平（血浆葡萄糖的标志物）和C肽（胰岛素水平的标志物），IGFBP-1和IGFBP-2水平低，增加结肠癌的风险，可能还有直肠癌;[2]检查IGF-I浓度升高是否（绝对或相对于其主要血浆结合蛋白- IGFBP-3）增加结肠癌和直肠癌的风险;[3]检查高饮食血糖负荷是否增加结直肠癌风险;[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肽的关系。这项研究旨在增加对营养过度与结肠癌发展相关的病因机制的理解，这最终将允许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.