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.
