Exercise and Metformin to Impact Hyperinsulinemia in Colorectal Cancer Survivors

项目4：运动和二甲双胍对结直肠癌幸存者高胰岛素血症的影响 摘要 观察证据表明，与能量平衡相关的因素，包括运动、体重和饮食，可能不仅与患结直肠癌的风险有关，而且与发展为结直肠癌的患者的预后有关。这些因素对结直肠癌发生和预后的影响的一个假说是与高胰岛素血症和胰岛素样生长因子有关。几项研究已经证明 循环中胰岛素或C肽水平较高的个体以及胰岛素样生长因子(IGF)-I水平较高或IGF结合蛋白(IGFBP)-3水平较低的个体患结肠癌的风险和复发率均较高。然而，目前还没有数据测试策略来降低结直肠癌幸存者的胰岛素或相关激素水平。两种具有强大科学依据的战略将对 与胰岛素相关的途径有运动干预和二甲双胍。在观察性研究中，运动一直被证明可以降低患结直肠癌的HSK，最近还降低了癌症复发和结直肠癌相关死亡率的风险。二甲双胍可降低高胰岛素血症，并激活AMP激活的蛋白激酶(AMPK)，从而抑制多种途径。在项目4中，我们提出了一项由有效的行为支持技术指导的2x2随机试验，用于L-L期结直肠癌患者在完成治疗2年内进行有氧运动与注意力控制、二甲双胍和安慰剂的比较。主要目标将是确定单独监督运动训练和二甲双胍单独或联合使用是否可以将空腹胰岛素水平从基线降低到6个月。 完成I-III期结直肠癌标准治疗的患者。次要目标包括：(1)比较其他与胰岛素有关的生物标志物的变化；(2)在6个月的干预过程中，除了运动和二甲双胍的相加作用外，还探索在降低空腹胰岛素水平方面的交互作用；(3)比较身体成分的变化以及饮食质量的自我导向变化；(4)比较 与胰岛素抵抗相关的促炎标志物，(5)决定计划行为理论的理论结构是否可以预测运动行为的变化。

Project 4: Exercise and Metformin to Impact Hyperinsulinemia in Colorectal Cancer Survivors Summary Observational evidence suggests that factors related to energy balance, including exercise, body weight and diet, may be related not only to the risk of developing colorectal cancer, but also to prognosis in patients who develop the disease. One hypothesis for the impact of these factors on colorectal cancer tumorigenesis and prognosis is related to hyperinsulinemia and insulin-like growth factors. Several studies have demonstrated that colon cancer risk and recurrence rates are elevated in individuals with higher circulating levels of insulin or C-peptide as well as in individuals with higher levels of insulin-like growth factor (IGF)-I or lower levels of IGF binding protein (IGFBP)-3. However, there are no data testing strategies to lower levels of insulin or related hormones in colorectal cancer survivors. Two strategies that have strong scientific rationale to impact on the insulin-related pathways are exercise intervention and metformin. Exercise has consistently been shown in observational studies to reduce the hsk of developing colorectal cancer and, more recently, risk of cancer recurrence and colorectal-cancer related mortality. Metformin reduces hyperinsulinemia and activates the AMP-activated protein kinase (AMPK) which suppresses a variety of pathways. In project 4, we propose a 2 x 2 randomized trial of supervised aerobic exercise guided by validated behavioral support techniques versus attention control and metformin versus placebo in stage l - l l l colorectal cancer patients within 2 years of completion of therapy. The primary objective will be to determine whether supervised exercise training alone and metformin, either alone or in combination, can decrease fasting insulin level from baseline to 6 months in patients who completed standard therapy for stage I - III colorectal cancer. Secondary objectives include (1) comparing changes in other insulin-related biomarkers, (2) explore for an interaction effect in addition to an additive effect of exercise and metformin in reducing fasting insulin level over the 6 month intervention, (3) compare changes in body composition as well as self-directed change in diet quality, (4) compare changes in pro-inflammatory markers related to insulin resistance, (5) determine whether the theoretical constructs of the theory of planned behavior predict change in exercise behavior.