Report of the Japan Diabetes Society/Japanese Cancer Association Joint Committee on Diabetes and Cancer

Abstract

In recent years, diabetes has been shown to be associated with cancer risk, and this has led to a joint committee being formed, enlisting experts from the Japan Diabetes Society and the Japanese Cancer Association to address this issue. Epidemiological data in Japan provides evidence to demonstrate that diabetes is associated with increased risk for cancers, especially colorectal, liver, and pancreatic cancers. The mechanisms through which diabetes is assumed to promote oncogenesis include insulin resistance and associated hyperinsulinemia, hyperglycemia, and inflammation. Common risk factors for type 2 diabetes and cancer include aging, male sex, obesity, physical inactivity, inappropriate diet (excessive red/processed meat intake, inadequate vegetable/fruit/dietary fiber intake), excessive alcohol drinking, and smoking. Given that inappropriate diet/exercise, smoking and excessive alcohol drinking are common risk factors for diabetes and cancer, diet/exercise therapy, smoking cessation and alcohol moderation may be associated with decreased risk for cancer in diabetic patients. There is as yet limited evidence as to whether any particular antidiabetic agents may influence cancer risk.

Figure 1

Hypothetical mechanism of oncogenesis associated with insulin resistance and hyperinsulinemia. The onset of obesity leads to production of free fatty acids and tumor necrosis factor‐α (TNF‐α) in adipose tissue as well as to decreased adiponectin secretion, thus promoting insulin resistance. Compensatory hyperinsulinemia occurs to decrease insulin‐like growth factor binding proteins‐1 and ‐2 (IGFBP‐1/2) production, which, as a consequence, leads to an elevation of insulin‐like growth factor (IGF) activity. Against this background, mediated by their respective receptors, insulin and IGF‐1 signaling induces cell proliferation and inhibits cell apoptosis, thus leading to the onset or progression of cancer. Adapted by permission from Macmillan Publishers Ltd: Nat Rev Cancer,35 copyright (2004).

Figure 2

Hypothetical mechanism of oncogenesis as mediated by active estrogen in hyperinsulinemia. With diabetes, conversion of ρ4 androstenedione(ρ4A) to biologically active estrogen (E2) is promoted in adipocytes by aromatase and 17β‐hydroxysteroid dehydrogenase (17β‐HSD) via testosterone (T) or estrone (E1). At the same time, hyperinsulinemia leads to decreased synthesis of sex hormone binding globulin (SHBG). Thus, it is thought likely that these combine to lead to an increase in the level of biologically active estrogen. While the effects of active estrogen vary depending on the target organ, active estrogen is assumed to inhibit apoptosis and increase cell proliferation in such tissues as mammary epithelium and endometrium, thus promoting oncogenesis. Adapted by permission from Macmillan Publishers Ltd: Nat Rev Cancer,35 copyright (2004).

Figure 3

Pathophysiological mechanisms of inflammation induced by hyperglycemia and their role in oncogenesis. Hyperglycemia/hyperlipidemia and associated oxidative stress induce secretion of various biologically active substances including adipokines. Tumor necrosis factor‐α (TNF‐α) promotes IκB phosphorylation (P) and degradation via the IκB kinase (IKK) pathway, thereby inducing nuclear factor‐κB (NF‐κB) activation. The other cytokines induce signal transducer and activator of transcription‐3 (STAT3) activation via the Jak1/2 pathway. The NF‐κB and STAT3 activation in the nucleus leads to inflammatory cytokine production, thereby aggravating diabetes‐associated inflammation, while at the same time contributing to oncogenesis through their contribution to signaling for cell proliferation and survival.52, 53

Figure 4

Proportion of individuals in Japan strongly suspected of having diabetes, 2002 versus 2010. Source: Ministry of Health, Labour and Welfare of Japan. National Health/Nutrition Survey 2012.60

Figure 5

Cancer incidence in Japan by age class over time, 1985 versus 2005. Source: Center for Cancer Control and Information Services, National Cancer Center, Japan (http://ganjoho.jp/pro/statistics/en/gdball.html). 61

Figure 6

Hypothetical mechanism through which metformin is assumed to inhibit carcinogenesis. Of the mechanisms of action of metformin which still remain less well elucidated, one possible mechanism through which metformin is assumed to inhibit carcinogenesis is that metformin induces AMP kinase (AMPK) phosphorylation (P) and activation via LKB1, which leads to inhibition of gluconeogenesis in the liver, thus improving insulin sensitivity. As a consequence, this leads to decreases in insulin and active insulin‐like growth factor‐1 (IGF‐1). Additionally, metformin‐activated AMPK is shown to contribute to inhibition of mTOR, which regulates cell proliferation and survival, downstream of PI3 kinase (PI3K) and AKT. By inhibiting insulin and IGF‐1 signaling at the ligand level as well as at the intracellular signaling level, metformin is assumed to exert tumor‐inhibitory effects.126, 127