Epidemiologic studies suggest that type 2 diabetes (T2D) increases breast cancer risk and mortality, but there is limited experimental evidence supporting this association. Moreover, there has not been any definition of a pathophysiological pathway that diabetes may use to promote tumorigenesis. In the present study, we used the MKR mouse model of T2D to investigate molecular mechanisms that link T2D to breast cancer development and progression. MKR mice harbor a transgene encoding a dominant-negative, kinase-dead human insulin-like growth factor-I receptor (IGF-IR) that is expressed exclusively in skeletal muscle, where it acts to inactivate endogenous insulin receptor (IR) and IGF-IR. Although lean female MKR mice are insulin resistant and glucose intolerant, displaying accelerated mammary gland development and enhanced phosphorylation of IR/IGF-IR and Akt in mammary tissue, in the context of three different mouse models of breast cancer, these metabolic abnormalities were found to accelerate the development of hyperplastic precancerous lesions. Normal or malignant mammary tissue isolated from these mice exhibited increased phosphorylation of IR/ IGF-IR and Akt, whereas extracellular signal-regulated kinase 1/2 phosphorylation was largely unaffected. Tumor-promoting effects of T2D in the models were reversed by pharmacological blockade of IR/IGF-IR signaling by the small-molecule tyrosine kinase inhibitor BMS-536924. Our findings offer compelling experimental evidence that T2D accelerates mammary gland development and carcinogenesis,and that the IR and/or the IGF-IR are major mediators of these effects. Cancer Res; 70(2); 741-51. ©2010 AACR.

This review will summarize the metabolic effects of growth hormone (GH) on the adipose tissue, liver, and skeletal muscle with focus on lipid and carbohydrate metabolism. The metabolic effects of GH predominantly involve the stimulation of lipolysis in the adipose tissue resulting in an increased flux of free fatty acids (FFAs) into the circulation. In the muscle and liver, GH stimulates triglyceride (TG) uptake ,by enhancing lipoprotein lipase (LPL) expression, and its subsequent storage. The effects of GH on carbohydrate metabolism are more complicated and may be mediated indirectly via the antagonism of insulin action. Furthermore, GH has a net anabolic effect on protein metabolism although the molecular mechanisms of its actions are not completely understood. The major questions that still remain to be answered are (i) What are the molecular mechanisms by which GH regulates substrate metabolism? (ii) Does GH affect substrate metabolism directly or indirectly via IGF-1 or antagonism of insulin action?