Metformin and Cancer in Type 2 Diabetes

Corresponding author: Hyeong Kyu Park Department of Internal Medicine, Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, 59 Daesagwan-ro, Yongsan-gu, Seoul 140-743, Korea E-mail: [email protected] Many epidemiologic studies have demonstrated a link between type 2 diabetes and an increased risk of certain cancers, and cancer-related mortality [1,2]. A number of meta-analysis studies have shown an increase in the risk of breast, endometrial, colorectal, hepatocellular, pancreatic, bladder cancer, and non-Hodgkin’s lymphoma in diabetes patients, compared to nondiabetic subjects [1,3]. Some observational studies have shown that diabetes is positively associated with the mortality of endometrial, breast, and colorectal cancer patients [2,4-6]. Since the prevalence of type 2 diabetes is increasing globally, this association may impart a great burden to public health, and, therefore, has garnered much research attention. There are potential risk factors such as aging, obesity, and physical inactivity, which are shared by both diabetes and cancer. In addition, multiple biologic factors seem to play a role in the development of cancer in type 2 diabetes. These include hyperinsulinemia, hyperglycemia, sex hormones, oxidative stress, and inflammatory cytokines [7]. Insulin resistance and hyperinsulinemia are important characteristics of type 2 diabetes. Chronic hyperinsulinemia may increase the risk of cancer because insulin has a mitogenic and antiapoptotic effect. Insulin can bind and activate insulin receptor as well as insulin-like growth factor 1 receptor (IGF1R), which has a potent mitogenic and transforming activity. Insulin can also increase free IGF-1 levels by decreasing IGF1-binding proteins, which can enhance its mitogenic potential [1]. Several epidemiologic findings support this link, demonstrating that hyperinsulinemia is associated with an increased risk of developing endometrial and breast cancers in postmenopausal women without diabetes [8,9]. It is quite difficult to differentiate the specific effect of hyperglycemia on the cancer risk from that of hyperinsulinemia, because the two are usually present in most diabetes patients. A meta-analysis has recently shown that patients having lower hemoglobin A1c levels with intensive glucose control had no difference in cancer incidence, compared to those having higher A1c levels with standard control. However, cancer risk was not the primary outcome of the trials, suggesting that hyperglycemia may not be directly linked to increased cancer risk [10]. Hyperinsulinemia can reduce sex-hormone binding globulin (SHBG), leading to increased bioavailable estrogen, and may affect hormone-sensitive cancers in women with type 2 diabetes. A recent study has shown that higher estrogen, IGF-1, and C-peptide levels increased the risk of postmenopausal breast cancer, suggesting that the interaction between insulin, SHBG, and estrogen may influence the development of breast cancer [11]. Metabolic derangements in type 2 diabetes cause proinflammatory conditions and increased oxidative stress, increasing inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin 6. It is known that TNF-α can induce development and progression of some tumors [12]. Given the relationship between hyperinsulinemia and the increased risk of cancer in diabetic patients, medications such as insulin or secretagogues, which increase circulating insulin levels, may increase the cancer risk. It is reasonable to expect that insulin sensitizers such as metformin can reduce the cancer risk by decreasing hyperinsulinemia. Recently there have been a number of reports suggesting that diabetes medications are related to an increased risk of cancer. Although there are difficulties complicated by multiple medications and different Editorial Epidemiology