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（一种通用的双胍类药物，目前广泛用于II型糖尿病的治疗，具有长期安全性）与糖尿病患者癌症负担的减轻有关。二甲双胍活性的可能机制包括抑制复合物i的线粒体氧化磷酸化，这种抑制对癌症过程有许多潜在的下游影响，包括细胞能量应激、atp活化蛋白激酶（AMPK）的激活和哺乳动物雷帕霉素靶点（mTOR）的抑制。二甲双胍还能降低胰岛素样生长因子-1 （IGF-1）的水平，这是一种在许多癌症中经常上调的生长因子。

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.