Efficacy Of Metformin In The Methylnitrosourea-Induced Model Of ER

二甲双胍在甲基亚硝基脲诱导的 ER 模型中的功效

• 批准号: 8739513
• 负责人: TERISA DAVIS
• 金额: $ 43.59万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-18 至 2015-09-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8739513
• 关键词: Animal Model; Animals; Biguanides; Cancer Burden; Carbohydrates; Complex; Diet; Fatty acid glycerol esters; Fructose; Generic Drugs; Growth Factor; Human; Incidence; Insulin-Like Growth Factor I; Malignant Neoplasms; Mammary Neoplasms; Metabolic; Metformin; Methylnitrosourea; Mitochondria; Modeling; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Oxidative Phosphorylation; Pharmacoepidemiology; Preventive; Process; Protein Kinase; Rattus; Safety; Stress; Triglycerides; diabetic; diabetic rat; feeding; glucose tolerance; insulin sensitivity; metabolomics

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.

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（目前广泛用于治疗II型糖尿病的一种通用双胍类药物，已证明具有长期安全性）与糖尿病患者癌症负担降低相关。二甲双胍活性的合理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具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）的活化和哺乳动物靶ofrapamycin（mTOR）的抑制。二甲双胍还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。 本任务单将在喂食标准饲料、高脂肪饲料或高果糖饲料的大鼠中检查二甲双胍对乳腺癌发病率和多重性的影响。预期高脂肪饮食和高果糖饮食均会诱导动物出现糖尿病前期状态，其特征在于代谢参数受损，包括胰岛素敏感性降低、葡萄糖耐量降低以及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食用高脂肪或高碳水化合物饮食以及更可能使用二甲双胍的人。