Prediabetes and cancer

Diabetic patients are at risk of additional diseases however this risk also exists prior to overt diabetes. Recent epidemiological studies suggests that during the prediabetic state patients are at an increased risk of cancer. Although these studies have methodological limitations, they suggest a positive association between prediabetes and specific cancers in men and women. Prediabetes is recognized by blood glucose concentrations above the normal level, but without exceeding the threshold to diagnose diabetes. Patients with prediabetes are at an increased risk of developing diabetes, diabetic complications and cardiovascular disease. However, newer evidence has associated prediabetes to an increased risk of cancer incidence and mortality.

Prediabetes and Cancer Risk

Some current literature suggests that prediabetic women, but not men, are at an increased risk of any cancer[1][2]. Alternate studies suggest prediabetes in both men and women is positively associated with pancreatic cancer, liver cancer, colon cancer and thyroid nodules[3][4][5][6][7]. In women, there is evidence linking prediabetes to an increased risk of breast cancer[8]. Conversely, other studies suggest there is no association[9]. Further studies suggests there may only be an increased risk in postmenopausal women while others suggest this may only be the case in women less than 49 years old[2][10]. In addition, prediabetic women are at an increased risk of endometrial cancer but not brain, thyroid, lung, liver, stomach, colon, rectum, cervical, ovarian, kidney or bladder cancer[1][2][11][12]. In men, there is an increased risk of stomach and colon cancer but not esophageal, nasopharynx, lung, liver, bladder, kidney, prostate or pancreatic cancer[1][2][12][13].

Prediabetes and Cancer Mortality

Few studies have investigated the association between prediabetes and cancer mortality and they report conflicting results. For example there is a positive association between prediabetes and all-cancer mortality in American and Japanese patients[14][15]. However other studies failed to find a similar association in those of European, Southeast Asian, African or Aboriginal descent[16][17][18][19]. Prediabetes in men may confer an increased risk of mortality from stomach, colorectal or liver cancer but not pancreatic, lung and bronchus, prostate, kidney or bladder cancer[20]. On the contrary, prediabetic women were not at an increased of mortality from stomach or colorectal, liver, pancreatic, bronchus and lung, breast or kidney or bladder cancer[20].

Prediabetes and Cancer – a meta-analysis

A meta-analysis of 16 studies and about 900,000 patients was recently reported to synthesize the available evidence for this association. It investigated a pooled estimate of cancer risk and mortality in men and women and found a positive association between prediabetes and stomach/colorectal, pancreatic, liver, breast and endometrial cancer, but not bronchus, lung, prostate, ovarian, kidney or bladder cancer[21]. Of these cancers, prediabetes was most strongly associated with an increased risk of liver, endometrial and stomach/colorectal cancer[21]. However, the all-cancer risk was attenuated when stratified by gender, race and age. In these cases, only men, Asians and those under 55 were at risk of any cancer[21]. Furthermore, Giugliano et al. suggests that these results be interpreted cautiously as the cancer specific associations are guided by few studies and blend cancer incidence and mortality[22].

Methodological Considerations

The results from the meta-analysis and past literature are generally similar. However, some bias is likely inherent in these studies, as many did not stratify the results by both gender and cancer site. Stratification would provide stronger evidence for the etiological role of prediabetes in the incidence of specific cancers. Similar to the epidemiologic research on the association between diabetes and cancer, the validity of the results with prediabetes would be further strengthened by recognizing the role of potential confounding variables, such as age, physical activity, diet, smoking status and alcohol consumption. Regardless of the limitations, there is a substantial body of evidence supporting a positive association between prediabetes and cancer.

Potential Biological Mechanism of Actions

When interpreting the epidemiologic literature on this, or any, association, we should also consider the biologic mechanisms and plausibility of the association. Contemporary literature posits that the association between diabetes and cancer may be mediated by either a state of hyperglycemia or hyperinsulinemia (See Hyperglycemia and cancerand Hyperinsulinemia and cancer). A hyperglycemic state may create a nutritional environment conducive to cellular proliferation. On the contrary, a hyperinsulinemic state may facilitate insulin-like growth factor mediated proliferation of neoplastic cells. It is known that in the years preceding diabetes, individuals may experience a period of elevated insulin levels with normal (or nearer normal) glycemia[23]. Thus, the elevated risk of cancer in people with prediabetes suggests hyperinsulinemia plays a more significant role in the pathogenesis of cancer in people with or at risk of developing diabetes.

References

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  2. ^ Stattin, P. et al. Prospective study of hyperglycemia and cancer risk. Diabetes Care 30, 561–567 (2007).

  3. ^ Guo, H. et al. The prevalence of thyroid nodules and its relationship with metabolic parameters in a Chinese community-based population aged over 40 years. Endocrine 45, 230–235 (2014).

  4. ^ Anil, C., Akkurt, A., Ayturk, S., Kut, A. & Gursoy, A. Impaired glucose metabolism is a risk factor for increased thyroid volume and nodule prevalence in a mild-to-moderate iodine deficient area. Metabolism 62, 970–975 (2013).

  5. ^ Gwack, J. et al. Fasting Serum Glucose and Subsequent Liver Cancer Risk in a Korean Prospective Cohort. J. Prev. Med. Public Health 40, 23 (2007).

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  8. ^ Onitilo, A. A. et al. Type 2 diabetes mellitus, glycemic control, and cancer risk. Eur. J. Cancer Prev. 23, 134–140 (2014).

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  10. ^ Salinas-Martínez, A. M. et al. Prediabetes, diabetes, and risk of breast cancer: a case-control study. Arch. Med. Res. 45, 432–438 (2014).

  11. ^ Lambe, M. et al. Impaired glucose metabolism and diabetes and the risk of breast, endometrial, and ovarian cancer. Cancer Causes Control 22, 1163–1171 (2011).

  12. ^ Onitilo, A. A. et al. Increased risk of colon cancer in men in the pre-diabetes phase. PLoS One 8, e70426 (2013).

  13. ^ Yun, J. E. et al. Cigarette smoking, elevated fasting serum glucose, and risk of pancreatic cancer in Korean men. Int. J. Cancer 119, 208–212 (2006).

  14. ^ Saydah, S. H., Loria, C. M., Eberhardt, M. S. & Brancati, F. L. Abnormal glucose tolerance and the risk of cancer death in the United States. Am. J. Epidemiol. 157, 1092–1100 (2003).

  15. ^ Hirakawa, Y. et al. Association between glucose tolerance level and cancer death in a general Japanese population: the Hisayama Study. Am. J. Epidemiol. 176, 856–864 (2012).

  16. ^ Harding, J. L. et al. All-cause cancer mortality over 15 years in multi-ethnic Mauritius: the impact of diabetes and intermediate forms of glucose tolerance. Int. J. Cancer 131, 2385–2393 (2012).

  17. ^ Balkau, B., Forhan, A. & Eschwège, E. Two hour plasma glucose is not unequivocally predictive for early death in men with impaired fasting glucose: more results from the Paris Prospective Study. Diabetologia 45, 1224–1230 (2002).

  18. ^ Kowall, B. et al. Categories of glucose tolerance and continuous glycemic measures and mortality. Eur. J. Epidemiol. 26, 637–645 (2011).

  19. ^ Lu, W. et al. Effects of isolated post-challenge hyperglycemia on mortality in American Indians: the Strong Heart Study. Ann. Epidemiol. 13, 182–188 (2003).

  20. ^ Zhou, X. H. et al. Diabetes, prediabetes and cancer mortality. Diabetologia 53, 1867–1876 (2010).

  21. ^ Huang, Y. et al. Prediabetes and the risk of cancer: a meta-analysis. Diabetologia 57, 2261–2269 (2014).

  22. ^ Giugliano, D., Maiorino, M. I. & Esposito, K. Linking prediabetes and cancer: a complex issue. Diabetologia (2014). doi:10.1007/s00125-014-3426-2

  23. ^ Tabák, A. G. et al. Trajectories of glycaemia, insulin sensitivity, and insulin secretion before diagnosis of type 2 diabetes: an analysis from the Whitehall II study. Lancet 373, 2215–2221

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