In this study, we investigated the association between T2DM and the risk of developing cancer by means of analysis of population-based registry data in China. Our findings indicated that both men and women patients with T2DM had an increased risk of pancreatic cancer; men had an increased risk of liver and kidney cancer and women had an increased risk of breast cancer and leukemia. We have previously reported the increased risk of developing colorectal cancer in T2DM patients [21
]. In terms of anatomic sub-site, T2DM was significantly associated with an increased risk of colon cancer but not rectal cancer. Taken together, these findings indicated that Chinese patients with T2DM had an increased risk of developing several types of cancer.
The association between T2DM and the risk of developing common cancer has been extensively investigated. Wideroff et al. [6
] found that diabetic patients increased risk of developing cancer by only 10% (SIR
1.1), in an analysis involving all types of cancers in Denmark. However, no significant association was found between T2DM and an increased incidence of cancer (RR
0.99, 95% CI
0.90-1.09) in a UK study [23
]. In this study, we found an increased risk of cancer in T2DM in Chinese population. Asia populations including Chinese have relatively leaner and lower body mass index. The mean BMI of subjects in this study was 23.6. Inconsistency results among studies in difference countries indicate there may be ethnic difference on biologic effect of T2DM. In a population-based retrospective cohort study in Japan, Oba et al. found that diabetic patients had an increased risk of cancer mortality [19
]. Woodward et al. [20
] also found that the risk of cardiovascular disease and cancer from diabetes among the Asian population might be different from that among the western population. A meta-analysis of 23 studies involving preexisting diabetes mellitus, carried out by Barone et al. [24
] indicated that diabetes was associated with increased mortality with an HR of 1.41 (1.28-1.55) as compared with normoglycemic individuals across all cancer types.
The cancer risks in diabetes patients varies depending on the sub-sites of specific cancers. Our findings and results from previous studies indicate that the strongest association between T2DM and cancer risk is with pancreatic cancer [17
]. As compared with the general population, we found that male and female T2DM patients were 2.97 and 2.68 times more likely to develop pancreatic cancer, respectively. This finding was in agreement with previous studies [18
]. The pooled risk of developing pancreatic cancer in T2DM was 1.73 (1.59-1.88) [26
]. However, this association may be involved in a mix of patients with pre-existing diabetes and new-onset diabetes. New-onset diabetes is common in lean patients aged over 45
Our findings also indicated an association between T2DM and liver cancer in the Chinese men population. The results from a study by Oba et al. indicated that T2DM increased the risk of liver cancer with an adjusted relative risk (RR) of 2.93 (1.40-6.14) [27
]. Although the exact mechanisms underlying this association are still unclear, the following factors are attributable to an increased liver cancer risk in diabetic patients: the mitogenic action of insulin; liver inflammation; hepatocyte damage and repair; diabetes-related diseases of liver cancer, such as steatosis and cirrhosis; and nonalcoholic fatty liver disease [28
Nine cohort studies had examined the association between T2DM and kidney cancer, the pooled risk of kidney cancer was 1.42 (95% CI
]. About 3 times of kidney cancer risk was found in present study. Diabetes might increase the risk of kidney cancer by hyperinsulinemia and insulin resistance, higher IGF-1 in serum and hypertension. Chronic kidney diseases are common in diabetic patients.
T2DM was also found to be associated with an increased risk of colon, bladder, breast and endometrial cancers [10
]. However, in contrast to previous studies, we did not find a significant association between bladder and endometrial cancer. This finding might be attributable to population differences, inadequate sample size and short observational periods. Most previous studies reported a reduced risk of prostate cancer in diabetic patients [32
]. Consistent with nine previous case–control studies, no significant association was found with prostate cancer in the present study. There might be site-specific mechanisms involved in carcinogenesis in different organs.
Several mechanisms have been proposed to explain the relationship between T2DM and cancer risk. Diabetes is one of the most common endocrine disorders today, which is caused by both environmental and genetic factors. T2DM and common cancers share many risk factors, including age, obesity, higher intake of saturated fats and refined carbohydrates, sedentary lifestyle, tobacco smoking and some psychology factors [28
]. Shared risk factors could partly explain the clustering of T2DM and cancers. On the other hand, T2DM develops as a consequence of relative insulin insufficiency and is characterized by hyperinsulinemia and insulin resistance for compensation. Insulin is a well-recognized growth factor. Hyperinsulinemia promotes the proliferation of colon cancer cells in vitro and colonic tumors in experimental animals [36
]. Therefore, hyperinsulinemia might promote carcinogenesis directly [37
]. Through the interaction with insulin-like growth factor axis protein 1(IFG-1) and insulin-like growth factor binding proteins, hyperinsulinemia also might increase the level of IGF-1. IGF-1 is a potential mitogen and inhibitor of apoptosis [38
] and also can promote tumorigenesis in various cancer model systems. The plasma or serum level of IGF-1 was found to be associated with an increased risk of cancer [40
]. Recently, Jin et al. [42
] speculated that the compensation for glucagon-like peptide-1 by intestinal endocrine L cells activated the Wnt signaling pathway and cross-talk between Wnt and insulin signaling pathways. Therefore, shared environmental factors and insulin resistance support the association between T2DM and risk of developing cancer.
The present study had several strengths. It was a population-based cohort study with large sample size of 7950 T2DM patients, having a median follow-up length of more than 8
years. T2DM was diagnosed by clinicians, and patient data were recorded in the regional CDC, detected and verified in the CSRD and DSRD. The surveillance systems for both diabetes and cancer are components of the National Cancer and Diabetic Surveillance Systems in China. The representativeness of patients in our study was relatively high.
Nonetheless, our study had some limitations. Although the study provided large number of diabetes patients, number of some subtype cancer cases is relatively small. A small subtype cancer could lead to a low statistical power to detect significant association between T2DM and some subtype cancers such as cancers of the bladder, endometrium and lung. In addition, although age and gender were controlled in calculation of SIR, this study lacked the information of other confounding factors such as body mass index (BMI), obesity status or type of diabetes treatment. BMI was reported to be associated with increased the risk of both of T2DM and cancers [43
]. The antidiabetic drug metformin was found to be associated with reduced the risk of cancers [44
], so reduced association estimation might existed in this study. Diabetes is an under-diagnosed disease and some T2DM patients were not be diagnosed in this study and might be included as population controls. This would lead to diluted association.
In summary, the present study provides valuable evidence that T2DM increases the risk of developing cancer in Chinese population. This association was more evident for pancreas, liver, kidney and breast cancers and leukemia. Considering the high prevalence of T2DM in the population, even a small increase in cancer risk might have substantial consequences at the population level. Therefore, further examinations, such as frequent colonoscopy for colorectal cancer and other screening test for other cancers, should be employed in the management of T2DM patients.