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Obesity, hyperinsulinemia and colon cancer

肥胖、高胰岛素血症和结肠癌

基本信息

批准号：
6667270
负责人：
SHARON E FLEMING
金额：
$ 7.6万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-30 至 2004-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6667270
关键词：
apoptosis blood glucose body composition cell proliferation colon neoplasms comorbidity diabetes mellitus dietary carbohydrates dietary lipid genetically modified animals hyperinsulinism insulin insulinlike growth factor laboratory mouse metformin nutrition related neoplasm /cancer obesity plasma

项目摘要

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.

描述（由申请人提供）：有大量的流行病学证据表明，超重或肥胖会增加患结肠癌的风险。男性的数据比女性更强，左结肠癌比右结肠癌更强，总体风险增加一倍。两项使用Zucker大鼠的研究数据支持这一观点。糖尿病也与结肠癌风险增加有关，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影响生物学过程，如体外增殖和凋亡。由于肥胖和高胰岛素血症通常在动物模型和人类中共存，因此很难确定它们对疾病风险的单独贡献。在本申请中，我们假设高胰岛素血症是超重和肥胖者对结肠癌易感性增加的原因。我们将使用C57 BL/6 J小鼠来确定肥胖动物是否比其瘦的同窝出生的小鼠更容易受到致癌物诱导的结肠肿瘤发生的影响。最初，这将通过比较野生型与Lepob突变体的反应来完成。在第二项研究中，将具有正常体重和胰岛素水平的瘦的野生型小鼠的反应与肥胖和高胰岛素血症（通过喂食高椰子油饮食诱导）或高胰岛素血症但不肥胖（通过喂食高果糖饮食诱导）的小鼠的反应进行比较。为了确定在没有高胰岛素血症的情况下肥胖对结肠肿瘤发生的贡献，使用二甲双胍降低Lepob突变体中的血浆胰岛素水平。将通过测量异常隐窝病灶、隐窝细胞增殖以及肿瘤发生率和多样性来评估对结肠肿瘤发生的易感性。我们预计高胰岛素血症会刺激结肠肿瘤的发生，而不存在高胰岛素血症的肥胖则不会。这些研究将提供新知识，用于支持后续R 01申请。