Type 2 Diabetes and Cancer: The Nitric Oxide Connection

Type 2 diabetes (T2DM) is now considered an independent risk factor for the development of some types of cancers, including liver, pancreas, endometrium, colon, rectum, breast, and bladder cancers. Several underlying mechanisms have been proposed that connect T2DM and cancer: hyperglycemia, hyperinsulinemia, increased levels of free steroid and peptide hormones, oxidative stress, and proinflammatory cytokines. Because nitric oxide (NO), a multifunctional gaseous signaling molecule, plays a critical role in carcinogenesis and tumor growth progression, undesirable changes of the NO system in T2DM may be an important missing link between these two pathogenic conditions. Increased inducible NO synthase (iNOS) activity is seen in T2DM (due to inflammatory cytokines, mitochondrial dysfunction, hyperglycemia and hypoxia), where detrimental amounts of NO can result in the initial carcinogenic transformation of normal cells and progression to malignancy. The uncoupling of endothelial NO synthase (eNOS) and increased generation of free radicals in hyperglycemic conditions can also lead to the formation of highly reactive nitrogen species such as peroxynitrite, which can lead to DNA damage, carcinogenic mutations, and activation of critical pathways involved in cell proliferation and apoptosis. In this review, we focused on the hypothesis that the imbalanced NO metabolism in pathologic conditions such as T2DM may contribute to the development of cancer. Overall, current evidence strongly suggests that an imbalanced NO metabolism in T2DM may contribute to the development of cancer.