Type 2 Diabetes Mellitus and Cancer: The Role of Pharmacotherapy

Abstract

Purpose Type 2 diabetes mellitus (T2DM) is becoming increasingly prevalent worldwide. Epidemiologic data suggest that T2DM is associated with an increased incidence and mortality from many cancers. The purpose of this review is to discuss the links between diabetes and cancer, the effects of various antidiabetic medications on cancer incidence and mortality, and the effects of anticancer therapies on diabetes. Design This study is a review of preclinical and clinical data regarding the effects of antidiabetic medications on cancer incidence and mortality and the effects of anticancer therapies on glucose homeostasis. Results T2DM is associated with an increased risk and greater mortality from many cancer types. Metformin use has been associated with a decrease in cancer incidence and mortality, and there are many ongoing randomized trials investigating the effects of metformin on cancer-related outcomes. However, data regarding the association of other antidiabetes medications with cancer incidence and mortality are conflicting. Glucocorticoids, hormone-based therapies, inhibitors that target the phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin pathway, and insulin-like growth factor 1 receptor-targeted therapy have been associated with high rates of hyperglycemia. These agents mediate their deleterious metabolic effects by reducing insulin secretion and increasing insulin resistance in peripheral tissues. Conclusion Studies must be performed to optimize cancer screening strategies in individuals with T2DM. A greater understanding of the mechanisms that link diabetes and cancer are needed to identify targets for therapy in individuals with diabetes who develop cancer. Data from clinical studies are needed to further elucidate the effects of antidiabetic medications on cancer incidence and progression. As several anticancer therapies alter glucose homeostasis, physicians need to be aware of these potential effects. Careful patient screening and monitoring during treatment with these agents is necessary.

Fig 1.

Systemic effects of type 2 diabetes and insulin resistance that potentially promote tumor development and progression. Insulin resistance in metabolic tissues, such as fat, liver, and skeletal muscle, result in increased production of insulin from pancreatic β-cells, which leads to circulating hyperinsulinemia. Pancreatic β-cells eventually decompensate and hyperglycemia develops. Hyperglycemia also develops as a result of increased hepatic glucose production secondary to insulin resistance in the liver and decreased uptake into skeletal muscle and adipose tissue. Endogenous insulin acting on the liver increases insulin-like growth factor-1 (IGF-1) synthesis and leads to decreased concentrations of IGF-binding proteins (IGFBPs) 1 and 2, thus potentially increasing local concentration of bioavailable IGF-1. Adipose tissue inflammation occurs with insulin resistance with production of cytokines and changes in the circulating concentrations of adipokines, such as increased leptin and decreased adiponectin. Excess adiposity may lead to increased local aromatization of androgens to estrogens, which together with a decrease in the hepatic production of sex hormone–binding globulin (SHBG) caused by insulin resistance in the liver, may lead to an increase in levels of bioavailable estrogen. Insulin resistance is also associated with lipid abnormalities, including elevated triglycerides (TGs) and decreased HDL cholesterol. IL, interleukin; TNF, tumor necrosis factor.

Fig 2.

Effects of hyperinsulinemia on the tumor cell microenvironment and intracellular signaling that contribute to tumor growth and progression. The schematic depicts the potential direct and indirect effects of insulin on tumor growth. Insulin and insulin-like growth factors 1 and 2 (IGF-1 and IGF-2) bind to the two insulin receptor (IR) isoforms (IR-A, IR-B), IGF-1 receptor (IGF-1R), and IR/IGF-1R hybrid receptors (IR-A/IGF-1R, IR-B/IGF-1R) with different affinities. Solid arrows indicate strong affinity for the receptor, and dashed arrows represent weak affinity for the receptor. IGF-binding proteins (IGFBP) 1 and 2 are decreased by insulin and may result in increased bioavailable IGF-1 and IGF-2. Binding of insulin to IR primarily activates the phosphoinositide 3-kinase (PI3K)–Akt–mammalian target of rapamycin (mTOR) signaling pathway. Binding of IGF-1 and IGF-2 to IGF-1R stimulates the PI3K-Akt-mTOR and Ras-Raf-MAPK pathways. Increased local production of estrogen may occur as a result of increased expression of aromatase, activating estrogen receptor α in tumor cells. Inflammation in the tissue microenvironment may also be increased by hyperinsulinemia, which leads to local cytokine production and activation the Jak-Stat signaling pathway in the tumor. Erk, extracellular regulated kinase; IL, interleukin; IRS1/2, insulin receptor substrate; TNF, tumor necrosis factor.