Efficacy Of Metformin In The Methylnitrosourea-Induced Model Of ER

药物流行病学研究表明，与使用其他治疗方法的糖尿病患者相比，二甲双胍(一种目前被广泛用于治疗II型糖尿病的非专利药物，具有长期安全性)与糖尿病患者的癌症负担减轻有关。二甲双胍的活性可能的机制包括抑制复合体I的线粒体氧化磷酸化，这种抑制对癌症过程具有许多潜在的下游影响，包括细胞能量应激，激活ATP激活的蛋白激酶(AMPK)，以及抑制哺乳动物靶标雷帕霉素(MTOR)。二甲双胍还可以降低胰岛素样生长因子-1(IGF-1)的水平，IGF-1是一种在许多癌症中经常上调的生长因子。 这个任务顺序将检查二甲双胍对标准饮食、高脂肪饮食或高果糖饮食喂养的大鼠乳腺癌发病率和多发性的影响。高脂饮食和高果糖饮食都有望在动物中诱导糖尿病前期状态，其特征是代谢参数受损，包括胰岛素敏感性降低，糖耐量下降，三酰甘油和非酯化脂肪酸水平升高。预计这些糖尿病前期动物模型将更接近于食用高脂肪或高碳水化合物饮食以及更有可能使用二甲双胍的人类。

Pharmacoepidemiology studies indicated that metformin (a generic biguanide currently widely used in the treatment of type II diabetes with demonstrated long-term safety) is associated with decreased cancer burdens in diabetics, when compared to diabetics using other treatments. Plausible mechanisms for metformin's activities include inhibition of mitochondrial oxidative phosphorylation at complex I. This inhibition has many potential downstream implications for cancer processes, including cellular energetic stress, activation of ATP-activated protein kinase (AMPK), and inhibition of mammalian target ofrapamycin (mTOR). Metformin also decreases levels of insulin-like growth factor-1 (IGF-1), a growth factor that is often upregulated in many cancers. This task order will examine the effect of metformin on mammary cancer incidence and multiplicity in rats fed either a standard diet, a high fat diet, or a high fructose diet. Both the high fat diet and high fructose diets are expected to induce pre-diabetic states in the animals, which are characterized by impaired metabolic parameters including decreased insulin sensitivity, decreased glucose tolerance, and higher levels of triacylglycerols and nonesterified fatty acids. It is expected that these pre¿ diabetic animal models will more closely approximate humans who consume high fat or high carbohydrate diets and who are more likely to use metformin.