Obesity, hyperinsulinemia and colon cancer

描述（由申请人提供）：有大量的流行病学证据表明超重或肥胖会增加结肠癌的风险。这一数据对男性的影响大于女性，对左结肠癌的影响大于右结肠癌，总体风险增加了一倍。两项使用扎克鼠的研究数据支持这一观点。糖尿病还与结肠癌的风险增加有关，这一点得到了一项动物研究的直接支持。已知胰岛素和胰岛素样生长因子在体外影响生物过程，如增殖和凋亡。由于肥胖和高胰岛素血症在动物模型和人类中经常共存，因此很难确定它们对疾病风险的单独贡献。在这个应用中，我们假设高胰岛素血症是超重和肥胖对结肠癌易感性增加的原因。我们将使用C57BL/6J小鼠来确定肥胖动物是否比它们的瘦同伴更容易受到致癌物诱导的结肠肿瘤发生。最初，这将通过比较野生型和Lepob突变体的反应来完成。在第二项研究中，将体重和胰岛素水平正常的瘦野生型小鼠的反应与肥胖和高胰岛素血症（喂食高椰子油引起的）或高胰岛素血症但不肥胖（喂食高果糖引起的）小鼠的反应进行比较。为了确定没有高胰岛素血症的肥胖对结肠肿瘤发生的贡献，使用二甲双胍降低Lepob突变体的血浆胰岛素水平。对结肠肿瘤发生的易感性将通过测量异常隐窝灶、隐窝细胞增殖、肿瘤发生率和多样性来评估。我们预计高胰岛素血症会刺激结肠肿瘤的发生，而没有高胰岛素血症的肥胖则不会。这些研究将提供新的知识，用于支持后续的R01应用。

DESCRIPTION (provided by applicant): There is substantial epidemiological evidence that being overweight or obese increases risk of colonic cancer. The data are stronger for men than for women and stronger for cancer of the left than right colon, with an overall doubling of risk. Data from two studies using Zucker rats support this notion. Diabetes is associated also with increased risk of colonic cancer, and this is directly supported by one animal study. Insulin and insulin-like growth factors are known to affect biological processes such as proliferation and apoptosis in vitro. Since obesity and hyperinsulinemia often co-exist in animal models and in humans, it has been difficult to determine their separate contributions to disease risk. In this application, we hypothesize that hyperinsulinemia is responsible for increased susceptibility of the overweight and obese to colonic cancer. We will use C57BL/6J mice to determine whether obese animals are more susceptible than their lean littermates to carcinogen-induced colon tumorigenesis. Initially, this will be done by comparing responses of wild-type versus Lepob mutants. In a second study, responses of lean, wild-type mice with normal weight and insulin levels will be compared to responses of mice that are both obese and hyperinsulinemic (induced by feeding a diet high in coconut oil) or hyperinsulinemic but not obese (induced by feeding a high-fructose diet). To determine the contribution that obesity in the absence of hyperinsulinemia makes to colonic tumorigenesis, plasma insulin levels will be reduced in Lepob mutants using metformin. Susceptibility to colonic tumorigenesis will be assessed by measuring aberrant crypt foci, crypt cell proliferation, and tumor incidence and multiplicity. We expect that hyperinsulinemia will stimulate colon tumorigenesis, whereas obesity in the absence of hyperinsulinemia will not. These studies will provide new knowledge that will be used to support a follow-up R01 application.