Both diabetes and cancer are prevalent diseases whose incidence is increasing globally. Worldwide, the prevalence of cancer has been difficult to establish because many areas do not have cancer registries, but in 2008 there were an estimated 12.4 million new cancer cases diagnosed. The most commonly diagnosed cancers are lung/bronchus, breast, and colorectal, whereas the most common causes of cancer deaths are lung, stomach, and liver cancer (1
). In the U.S., the most commonly diagnosed cancers are prostate, lung/bronchus, and colon/rectum in men and breast, lung/bronchus, and colon/rectum in women. Of the world population between the ages of 20 and 79 years, an estimated 285 million people, or 6.6%, have diabetes (2
). In 2007, diabetes prevalence in the U.S. was 10.7% of persons aged 20 years and older (23.6 million individuals), with an estimated 1.6 million new cases per year. Type 2 diabetes is the most common form, accounting for ~95% of prevalent cases (3
). Worldwide, cancer is the 2nd and diabetes is the 12th leading cause of death (4
). In the U.S., cancer is the 2nd and diabetes is the 7th leading cause of death; the latter is likely an underestimate, since diabetes is underreported on death certificates as both a cause and comorbid condition (3
Cancer and diabetes are diagnosed within the same individual more frequently than would be expected by chance, even after adjusting for age. Both diseases are complex with multiple subtypes. Diabetes is typically divided into two major subtypes, type 1 and type 2 diabetes, along with less common types, while cancer is typically classified by its anatomic origin (of which there are over 50, e.g., lymphoma, leukemia, lung, and breast cancer) and within which there may be multiple subtypes (e.g., leukemia). Further, the pathophysiologies underlying both cancer and diabetes are (with rare exceptions) incompletely understood.
For more than 50 years, clinicians have reported the occurrence of patients with concurrent diabetes and cancer. However, as early as 1959, Joslin et al. (5
) stated, “Studies of the association of diabetes and cancer have been conducted over a period of years, but evidence of a positive association remains inconclusive.” Subsequently, an association between the two diseases was identified in the 1960s in population-based studies. More recently, the results of several studies have been combined for meta-analytic study (6
), indicating that some cancers develop more commonly in patients with diabetes (predominantly type 2), while prostate cancer occurs less often in men with diabetes. The relative risks imparted by diabetes are greatest (about twofold or higher) for cancers of the liver, pancreas, and endometrium, and lesser (about 1.2–1.5 fold) for cancers of the colon and rectum, breast, and bladder. Other cancers (e.g., lung) do not appear to be associated with an increased risk in diabetes, and the evidence for others (e.g., kidney, non-Hodgkin lymphoma) is inconclusive. Few studies have explored links with type 1 diabetes.
Since insulin is produced by pancreatic β-cells and then transported via the portal vein to the liver, both the liver and the pancreas are exposed to high concentrations of endogenously produced insulin. Diabetes-related factors including steatosis, nonalcoholic fatty liver disease, and cirrhosis may also enhance susceptibility to liver cancer. With regard to pancreatic cancer, interpretation of the causal nature of the association is complicated by the fact that abnormal glucose metabolism may be a consequence of pancreatic cancer (so-called “reverse causality”). However, a positive association between diabetes and pancreatic cancer risk has been found when restricted to diabetes that precedes the diagnosis of pancreatic cancer by at least 5 years, so reverse causation does not likely account for the entirety of the association.
Only for prostate cancer is diabetes associated with a lower risk. This association has been observed both before and after the advent of screening with prostate-specific antigen (PSA), so detection bias due to differential PSA utilization does not account for this finding. Some metabolic factors associated with diabetes, such as reduced testosterone levels, may be involved (although circulating testosterone levels have not been consistently associated with prostate cancer incidence). While obesity has not been associated, and in some studies is even inversely associated, with prostate cancer incidence, obese men with prostate cancer have higher cancer mortality rates than those of normal weight (7
). In addition to metabolic factors such as hyperinsulinemia, obesity may be associated with clinical factors (such as delayed diagnosis, poorer treatment) that may underlie the worsened prostate cancer prognosis.
Results of some, but not all, epidemiological studies suggest that diabetes may significantly increase mortality in patients with cancer (8
). For example, in one study, 5-year mortality rates were significantly higher (hazard ratio 1.39) in patients diagnosed with both breast cancer and diabetes than in comparable breast cancer patients without diabetes (9
). Since diabetes is associated with excess age-adjusted mortality, whether the apparent excess mortality associated with diabetes in cancer patients is any greater than the excess mortality observed among diabetic patients without cancer is unclear. Of note, higher pre-diagnosis C-peptide levels (an indirect marker of insulin resistance) have been associated with a poorer disease-specific survival for prostate cancer (7
) and colorectal cancer (10