Diabetes and risk of cancer

Abstract

Recent epidemiological studies have revealed the association of elevated cancer risk and diabetes mellitus [1–13]. Because the prevalence of diabetes mellitus and cancer is increasing worldwide, understanding the higher risk of specific types of cancer is important in management of diabetic patients. The American Diabetes Association (ADA) and the American Cancer Society (ACS) produced a consensus report on the increased risk of liver, pancreas, endometrial, colorectal, breast, and bladder cancer among diabetic patients [14]. In 2013, the joint committee of the Japan Diabetes Society (JDS) and the Japanese Cancer Association (JCA) reported the association of diabetes and cancer, including colorectal, liver, and pancreatic cancer, among Japanese diabetic patients [15]. Although the mechanisms underlying this association are not fully understood, several potential mechanisms which promote oncogenesis in diabetes have been discussed. Chronic inflammation, insulin resistance associated with hyperinsulinemia, and hyperglycemia have been suggested as potential mechanisms. These factors may lead to increased risk of cancer in diabetes and promote oncogenesis in different ways. Numerous studies have suggested the effect of insulin and chronic inflammation on cancer progression in diabetes. The experimental and epidemiological evidence is most consistent with the hyperinsulinemia and chronic inflammation hypothesis. In particular, progression of hepatocellular carcinoma seems to be closely associated with chronic inflammation and insulin resistance related to hyperinsulinemia. In a large scale cohort study in Japan, diabetes led to a high risk of hepatocellular carcinoma [16]. A meta-analysis also showed that diabetes increases the risk of hepatocellular carcinoma [12] and diabetes is risk factor for hepatocellular carcinoma among patients with nonalcoholic fatty liver disease (NAFLD) [17]. A recent clinical review suggested that NAFLD and nonalcoholic steatohepatitis (NASH) patients, especially those with diabetes, should be monitored for the onset of hepatocellular carcinoma [18]. However, the involvement of hyperglycemia in cancer development is less clear and few studies have shown the contribution of hyperglycemia to cancer progression and metastasis. Cancer cells maintain an abnormally high rate of glycolysis, even in the presence of oxygen, a phenomenon called the Warburg effect [19]. Enhanced glucose uptake in cancer is revealed by positron emission tomography (PET) scans, a widely used method of cancer detection, and clinical use of PET scans is well established. Despite many years of investigation, the specific regulatory mechanisms responsible for the Warburg effect are not fully understood. Increased expression of glucose transporter 1 has been observed, and this enables cancer cells to absorb extracellular glucose [20]. Increased type 2 hexokinase activity in cancer has also been demonstrated [21–23]. Although hexokinase is involved in the first irreversible stage of glycolysis, it is not the late limiting enzyme of the process. Fructose 2,6-bisphosphate (F2,6BP) is a powerful allosteric activator of 6-phosphofructo-1-kinase (PFK-1), which is the rate-limiting enzyme of glycolysis [24]. F2,6BP increases the affinity of PFK-1 for fructose 6-phosphate and reduces the inhibitory effect of ATP. Previous work has revealed markedly elevated levels of F2,6BP in several cancer cell lines [25–27]. The intracellular concentration of F2,6BP depends on the activity of the bifunctional enzyme 6-phosphofructo-2-kinase/fructose2,6-bisphosphatase (PFK-2/FBPase) [28]. At least four & Toshiya Atsumi tatsumi@nissei-hp.com