In this large prospective cohort of Chinese men and women in Singapore, those who reported regular soft drink consumption were at increased risk of pancreatic cancer when compared with those who largely abstained. There was no association between consumption of juice and risk of pancreatic cancer.
To date, four prospective studies have investigated soft drink consumption and pancreatic cancer (26
), one of which included fruit juice (ref. 28
; ). Our findings are largely consistent with three of the four studies. In a prospective analysis of U.S. nurses and other health professionals, women (205 cases/20 years follow-up) who consumed >3 sugar-sweetened drinks/wk had a 57% greater risk of pancreatic cancer than did women who consumed ≤1 sugar-sweetened soft drinks/mo; however, there was no association in men (174 cases/20 years follow-up; ref. 24
). A prospective analysis of Swedish adults (131 cases/7.2 years follow-up) reported that those who consumed ≥2 soft drinks/d had a 93% significantly greater risk of pancreatic cancer than did those who consumed no soft drinks (25
). A large prospective study (434 cases/8 years follow-up) of the Multiethnic Cohort reported a positive but statistically nonsignificant association between the two highest categories of soda intake and pancreatic cancer risk (26
). This same cohort also reported a null effect of juice intake on pancreatic cancer risk, again consistent with our findings. In contrast to these studies, a prospective study, including 1,258 pancreatic cancer cases (7.2 years follow-up), reported no association between soft drink intake and pancreatic cancer (27
Prospective studies of sugar-sweetened beverages and pancreatic cancer
Our results are also in agreement with most case-control studies (5
); however, a recent case-control study found no association between soft drink consumption and pancreatic cancer (31
Soft drink consumption coincides with many other unhealthy lifestyle characteristics, making it difficult to separate smoking, caloric intake, body weight, and type 2 diabetes mellitus from soft drink consumption. In agreement with a previous Asian cohort study (4
), current smokers in our study had an increased risk for pancreatic cancer. Unlike our study, the other study observed a significant association between pack-years and pancreatic cancer risk. Also consistent with their study, overweight and obesity (BMI ≥ 25 versus 18 to <25) in our study were not significantly associated with pancreatic cancer risk. However, in their study, waist circumference was associated with a significantly greater risk of pancreatic cancer; suggesting that central obesity is an independent risk factor for the disease. Our study did not ascertain waist circumference. Contrary to our findings, the other Asian study found that individuals with diabetes mellitus had a 75% significantly greater risk of pancreatic cancer compared with individuals without diabetes mellitus. Finally, in our analyses, the influence of soft drink intake on the risk of pancreatic cancer remained virtually unchanged after adjustment for smoking status, energy intake, BMI, and type 2 diabetes mellitus.
The hypothesized mechanism linking type 2 diabetes mellitus or abnormal glucose metabolism to pancreatic cancer involves insulin. Chronically elevated glucose concentrations are directly associated with a reduction in insulin sensitivity (10
). Hyperinsulinemia, a result of insulin insensitivity, has been shown to increase local circulation and cell division within the pancreas (32
). Because their blood supply first passes through the insulin-producing islets of Langerhans, pancreatic exocrine cells are estimated to be exposed to insulin concentrations that are 20-fold higher than the systemic circulation, which some have hypothesized may have implications for pancreatic cancer promotion (34
High insulin concentrations may increase free insulin-like growth factor (IGF) levels by reducing levels of IGF-binding proteins (35
). Exposure to IGF has been shown to cause proliferation in pancreatic cancer cell lines (36
). Elevated insulin concentrations have also been shown to activate IGF receptors, which may lead to cancer cell proliferation (37
). Overexpression of IGF-I, IGF-I receptor, and IGF-II receptor has been found in human pancreatic cancer cells in comparison with normal pancreatic cancer cells, further suggesting that the signaling pathways of IGF and IGF receptors may be involved in pancreatic carcinogenesis (36
). A recent nested case-control study, within four large prospective studies, observed no evidence that the risk of pancreatic cancer was influenced by prediagnostic plasma levels of IGF-I, IGF-II, or IGF-binding protein-3 (39
). However, in the same cohort, the researchers observed a significant inverse association between IGF-binding protein-1 and the risk of pancreatic cancer (40
Elevated post-load and fasting plasma glucose (10
), nonfasting plasma C-peptide (13
), and fasting serum insulin (14
) have been associated with an increased risk of pancreatic cancer in prospective studies, suggesting that dietary items that lead to hyperglycemia can similarly influence pancreatic carcinogenesis. In a recent large epidemiologic study, researchers observed a statistically significant positive trend between C-peptide levels and pancreatic cancer risk among those participants who provided nonfasting blood specimens (13
). No association was observed between fasting plasma insulin levels and pancreatic cancer risk. This suggests that postprandial insulin may be a better measure for the association with cancer risk than fasting insulin levels and is consistent with the independent role of soft drink consumption in the development of pancreatic cancer observed in our study.
The mechanism presented here supports the notion that sugar-sweetened beverages with a high glycemic load may increase risk for pancreatic cancer. Most studies have shown no association between glycemic load and pancreatic cancer, except in subgroup analyses (41
). The contradictory findings from these studies may be due to the measurement errors inherent in food frequency questionnaire for the calculation of a summary score for the overall exposure to glycemic load (47
). Given that glycemic loads for food items in our study questionnaire were unavailable, we were unable to examine the total glycemic load in relation to risk of pancreatic cancer risk in this study population.
The lack of association between juice intake and pancreatic cancer risk may result from difference in the composition of juices and soft drinks. This notion is supported by our findings that showed an elevated risk of pancreatic cancer among soft drink consumers after excluding juice consumers. Finally, another explanation is that juice consumption is related with healthier lifestyle and dietary patterns than soft drink consumption, as seen in .
Our study has several strengths. To our knowledge, this is the first prospective cohort of an Asian population to examine the association between sugar-sweetened beverages and pancreatic cancer. The prospective design of our study precluded recall bias and the need for next-of-kin respondents. Also in this study, differential follow-up is unlikely because identification of deaths and cases is highly accurate in this cohort. Other strengths include the high response rate, a detailed face-to-face interview at baseline, and a virtually complete ascertainment of cancer cases and deaths (3
There are limitations to consider as well. Pancreatic cancer is rare; therefore, the number of cases in this study is relatively small. The combination of lower relative soft drink consumption compared with other populations and the lower case rates limits the ability to examine a wider distribution of drink consumption. Due to the rarity of pancreatic cancer, we had a slim distribution of cases, limiting the power and giving potential to a chance association. Also, because we were unable to collect repeated dietary measurements in this study, we were unable to account for changes in consumption of soft drinks and juices, especially when the diagnosis of diabetes occurred after the baseline interview. Finally, we could not rule out the possibility of residual confounding by factors associated with the habit of drinking soft drinks or other unascertained factors such as waist circumference.
In conclusion, the present study adds to the evidence that soft drink consumption may play a role in the development of pancreatic cancer. Our findings underscore the need for further large prospective epidemiologic studies in Asian populations. As well, clinical studies examining biomarkers for glycemia and insulinemia and taking a mechanistic approach to the question of soft drink consumption and pancreatic cancer are warranted as there is still much to understand on the link between sugar-sweetened beverages and pancreatic cancer.