Exercise and Metformin to Impact Hyperinsulinemia in Colorectal Cancer Survivors

项目4：运动和代谢对结直肠癌幸存者高胰岛素血症的影响 总结 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，可能不仅与结直肠癌的发病风险有关，而且与结直肠癌患者的预后有关。这些因素对结直肠癌肿瘤发生和预后的影响的一个假设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 结肠癌风险和复发率在具有较高循环水平的胰岛素或C肽的个体中以及在具有较高水平的胰岛素样生长因子（IGF）-I或较低水平的IGF结合蛋白（IGFBP）-3的个体中升高。然而，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。有两项战略具有强大的科学依据， 胰岛素相关途径是运动干预和二甲双胍。观察性研究一致表明，锻炼可以降低结直肠癌的发病率，最近还可以降低癌症复发的风险和结直肠癌相关的死亡率。二甲双胍可降低高胰岛素血症并激活AMP活化蛋白激酶（AMPK），后者可抑制多种途径。在项目4中，我们提出了一项2 × 2随机试验，在完成治疗的2年内，在1 - 111期结直肠癌患者中，通过有效的行为支持技术指导的监督有氧运动与注意力控制和二甲双胍与安慰剂相比。主要目的是确定单独的监督运动训练和二甲双胍（单独或联合）是否可以降低基线至6个月的空腹胰岛素水平， 完成标准治疗的I-III期结直肠癌患者。次要目的包括（1）比较其他胰岛素相关生物标志物的变化，（2）探索6个月干预期间运动和二甲双胍在降低空腹胰岛素水平方面的叠加效应之外的相互作用效应，（3）比较身体组成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）确定计划行为理论的理论结构是否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.