Consumption of sugar and sugar-sweetened foods

Consumption of sugar and sugar-sweetened foods and the risk of pancreatic cancer in a prospective study1⫺3 Susanna C Larsson, Leif Bergkvist, and Alicja Wolk

KEY WORDS Cohort studies, diet, pancreatic cancer, soft drinks, sucrose, sugar

INTRODUCTION

Pancreatic cancer is among the most deadly cancers: the overall 5-y survival rate is only 앒5% (1). Because of this poor prognosis, identification of modifiable risk factors for pancreatic cancer is important. Evidence is mounting that abnormal glucose metabolism and hyperinsulinemia may be involved in the development of pancreatic cancer. Conditions such as diabetes mellitus, a high body mass index (BMI; in kg/m2), and physical inactivity, all hallmarks of insulin resistance, have been directly related to the risk of this malignancy (2–5). Moreover, prospective studies have reported approximately twice the risk of pancreatic cancer in persons in the highest category of postload

plasma glucose (6), fasting serum glucose (7, 8), or fasting insulin (7) concentrations compared with persons in the lowest category. Given the possible role of hyperglycemia and hyperinsulinemia in the development of pancreatic cancer, frequent consumption of sugar and high-sugar foods may increase the risk of pancreatic cancer by inducing frequent postprandial hyperglycemia, increasing insulin demand, and decreasing insulin sensitivity. A recent prospective study provided support for this hypothesis when it reported a significantly greater risk of pancreatic cancer in association with high consumption of sugar-sweetened soft drinks in women, although no greater risk was found in men (9). High consumption of sugar-sweetened beverages has also been associated with a greater weight gain and with higher risk of type 2 diabetes (10). Soft drinks are the leading source of added sugar in the US diet (11), and they could contribute to a high glycemic load of the diet. Dietary glycemic load, a quantitative measure of the glycemic effect of foods, has been positively (12) but not consistently (13, 14) associated with the risk of pancreatic cancer. In an international ecologic study (15), sugar consumption was the environmental factor most strongly and positively correlated with pancreatic cancer mortality in women. On the basis of this background, we sought to evaluate the hypothesis that high consumption of added sugar (ie, sugar added to coffee, tea, cereals, etc), soft drinks, and other high-sugar foods is associated with a greater risk of pancreatic cancer by analyzing prospective data from the Swedish Mammography Cohort (SMC) and the Cohort of Swedish Men (COSM). Our group previously found that persons in these cohorts who were obese or had a history of diabetes mellitus had a risk of pancreatic cancer 1.8 to 1.9 times that in persons with normal weight or without diabetes (5). 1

From the Division of Nutritional Epidemiology, National Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden (SCL and AW), and the Department of Surgery and the Centre for Clinical Research, Central Hospital, Va¨sterås, Sweden (LB). 2 Supported by research grants from the Swedish Research Council/Longitudinal Studies, the Swedish Cancer Foundation, Va¨stmanland County ¨ rebro County Council Research CommitResearch Fund against Cancer, O ¨ rebro Medical Center Research Foundation. tee, and O 3 Reprints not available. Address correspondence to SC Larsson, Division of Nutritional Epidemiology, The National Institute of Environmental Medicine, Karolinska Institute, PO Box 210, SE-171 77 Stockholm, Sweden. E-mail: [email protected]. Received April 27, 2006. Accepted for publication June 12, 2006.

Am J Clin Nutr 2006;84:1171– 6. Printed in USA. © 2006 American Society for Nutrition

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ABSTRACT Background: Emerging evidence indicates that hyperglycemia and hyperinsulinemia may be implicated in the development of pancreatic cancer. Frequent consumption of sugar and high-sugar foods may increase the risk of pancreatic cancer by inducing frequent postprandial hyperglycemia, increasing insulin demand, and decreasing insulin sensitivity. Objective: The objective of the study was to examine prospectively the association of the consumption of added sugar (ie, sugar added to coffee, tea, cereals, etc) and of high-sugar foods with the risk of pancreatic cancer in a population-based cohort study of Swedish women and men. Design: A food-frequency questionnaire was completed in 1997 by 77 797 women and men aged 45– 83 y who had no previous diagnosis of cancer or history of diabetes. The participants were followed through June 2005. Results: During a mean follow-up of 7.2 y, we identified 131 incident cases of pancreatic cancer. The consumption of added sugar, soft drinks, and sweetened fruit soups or stewed fruit was positively associated with the risk of pancreatic cancer. The multivariate hazard ratios for the highest compared with the lowest consumption categories were 1.69 (95% CI: 0.99, 2.89; P for trend ҃ 0.06) for sugar, 1.93 (1.18, 3.14; P for trend ҃ 0.02) for soft drinks, and 1.51 (0.97, 2.36; P for trend ҃ 0.05) for sweetened fruit soups or stewed fruit. Conclusion: High consumption of sugar and high-sugar foods may be associated with a greater risk of pancreatic cancer. Am J Clin Nutr 2006;84:1171– 6.

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SUBJECTS AND METHODS

Study population

Dietary assessment Dietary information was derived from a 96-item foodfrequency questionnaire. Participants were asked how often, on average, they had consumed each food over the previous year. Eight previously defined-response categories were provided, ranging from never to 욷3 times/d. The questionnaire also included open questions about some commonly consumed foods, such as added sugar (ie, sugar added to coffee, tea, cereals, etc) and soft drinks (including carbonated soft drinks and noncarbonated sweetened drinks; the type of soft drink—ie, sugarsweetened or artificially sweetened—was not specified). For these foods, a commonly used serving size [eg, 1 teaspoon or lump of sugar (ie, 앒5–7 g) and 1 glass (앒250 –300 g) of a soft drink] was indicated. In a validity study of 129 women randomly chosen from the SMC, the correlation coefficients between the average intake assessed by four 1-wk diet records (completed 3– 4 mo apart) and the food-frequency questionnaire were as follows: 0.7 for added sugar, 0.6 for soft drinks, 0.5 for sweetened fruit soups or stewed fruit, 0.5 for jam or marmalade, and 0.4 for sweets (A Wolk, unpublished observations, 1992). Identification of pancreatic cancer cases and follow-up Incident cases of pancreatic cancer [International Classification of Diseases, Ninth Revision (ICD-9) code 157] were identified through linkage to the national and regional Swedish cancer registries, both of which provide 앒100% case ascertainment

Statistical analysis For each study participant, person-years of follow-up (ie, the number of persons studied times the number of years of followup) were counted from 1 January 1998 to the date of diagnosis of pancreatic cancer, the date of death, the date of migration, or 30 June 2005, whichever came first. Categories of frequency of consumption of added sugar and sweetened foods were created, and the lowest category was used as the reference category. Cox proportional hazards models (18) were used to estimate hazard ratios with 95% CIs. Separate analyses for women and men showed similar patterns of associations, and tests for interaction with sex were not significant (P 쏜 0.4). We therefore present results for both sexes combined, after control for sex as a stratum variable in the Cox model to allow for different baseline hazard rates. Age adjustment was accomplished by stratifying on age (in mo) within each Cox model. In multivariate analyses, in addition to age and sex, we adjusted for education (less than high school, high school graduate, or more than high school), BMI (쏝25.0, 25.0 –29.9, or 욷 30), smoking status and pack-years of smoking (never smoker or past smoker and 쏝 20 pack-years, past smoker and 욷 20 pack-years, current smoker and 쏝 20 pack-years, current smoker and 20 –39 pack-years, or current smoker and 욷 40 pack-years), and intakes of total energy (continuous) and alcohol (quartiles). We also adjusted for other potential confounders, including physical activity, aspirin use, and intakes of dietary folate, fruit, vegetables, red meat, coffee, and tea; however, because these adjustments did not change the risk estimates, the variables were not included in the final models. In additional analyses, to remove early cases in which the association between the consumption of sugar and sweetened food and the risk of pancreatic cancer may have been biased because of changes in diet due to preclinical symptoms, we excluded cases of pancreatic cancer diagnosed during the first 2 or 4 y of follow-up. Tests for trends were conducted by assigning the median value to each intake category and modeling this value as a continuous variable. To examine whether the relations between sugar and soft drink consumption and the risk of pancreatic cancer were modified by BMI and physical inactivity, which can be important determinants of insulin resistance, we performed analyses stratified by BMI (쏝25 or 욷 25) and exercise (울1 or 욷2 h/wk). Statistical interaction was assessed by using the likelihood ratio test. All analyses were conducted by using SAS statistical software (version 9.1; SAS Institute Inc, Cary, NC). All P values are 2-sided. RESULTS

Baseline characteristics of the study population by consumption of added sugar and soft drinks are shown in Table 1. At baseline, 앒4% of the women and 앒14% of the men reported consumption of 욷5 servings added sugar/d; 7% of the women and 13% of the men reported consumption of 욷2 servings soft drinks/d. Women and men in the highest category of sugar and soft drink consumption were less likely to have postsecondary


This investigation is based on data from 2 population-based prospective cohorts, the SMC and the COSM. Detailed information on the SMC was published previously (16). In brief, the cohort was established between 1987 and 1990, when all women who were born between 1914 and 1948 and who lived in the counties of Va¨stmanland and Uppsala in central Sweden received a mailed questionnaire concerning diet, weight, height, and education. In the fall of 1997, a more comprehensive questionnaire (앒350 items) was mailed to all 56 030 SMC participants who were still alive and residing in the study area. This questionnaire collected information on diet and on other lifestyle factors (including smoking history) and medical history; 39 227 women (70%) returned a completed questionnaire. The COSM was initiated in the fall of 1997, when all men who were born between 1918 and 1952 and who resided in the counties of ¨ rebro in central Sweden received a questionVa¨stmanland and O naire that was identical (except for some sex-specific questions) to the 1997 SMC questionnaire. Of the 100 303 eligible men, 48 850 (49%) completed the questionnaire. For the current analyses, we used information from respondents to the 1997 questionnaire. We excluded participants with implausible values for energy intake [ie, 3 SDs from the logetransformed mean energy intake in women (n ҃ 531) and men (n ҃ 600)], those with an erroneous or missing National Registration Number (243 women and 260 men), and those who had a history of cancer (1837 women and 2684 men) or diabetes (1343 women and 2782 men). These exclusions left 77 797 participants (35 273 women and 42 524 men) aged 45– 83 y for the analyses. The subjects’ completion of the self-administered questionnaire was considered to convey informed consent. The study was approved by the Regional Ethics Review Board in Stockholm.

in Sweden (17). Because their causes may be different from those of the exocrine tumors, islet cell carcinomas (ICD-9 code 157.4; n ҃ 3 cases) were not included as cases in this study. We obtained information on dates of deaths and dates of migration (ie, moving from the study area) through linkage to the Swedish death and population registries at Statistics Sweden.

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SUGAR, SWEETENED FOODS, AND PANCREATIC CANCER TABLE 1 Age-standardized baseline characteristics of the study population by consumption of added sugar and soft drinks1 Added sugar consumption (servings/d)2 Characteristic Women (n ҃ 35 273) n Age (y) Postsecondary education (%) Current smoker (%) Pack-years4 BMI (kg/m2) Alcohol intake (g/d) Men (n ҃ 42 524) n Age (y) Postsecondary education (%) Current smoker (%) Pack-years4 BMI (kg/m2) Alcohol intake (g/d)

Soft drink consumption (servings/d)

0

0.1–1.9

2.0 – 4.9

욷5.0

0

0.1– 0.4

0.5–1.9

욷2.0

21 676 61.1 앐 9.03 19.5 23.6 14.9 앐 11.2 25.1 앐 3.9 4.2 앐 5.3

7035 61.9 앐 9.2 19.8 18.9 13.2 앐 10.7 24.8 앐 3.7 4.3 앐 5.1

5001 63.5 앐 9.7 18.2 24.2 15.2 앐 11.6 24.7 앐 3.9 3.8 앐 5.0

1561 61.8 앐 9.6 16.5 37.6 18.3 앐 12.0 24.5 앐 3.7 3.4 앐 5.0

20 417 61.8 앐 9.2 20.8 24.8 14.7 앐 11.2 24.8 앐 3.8 4.4 앐 5.3

7270 59.6 앐 8.4 19.1 19.5 13.9 앐 10.7 25.1 앐 3.9 4.0 앐 5.1

5098 62.7 앐 9.5 15.3 22.0 15.9 앐 11.6 25.2 앐 4.0 3.7 앐 5.1

2488 64.2 앐 9.5 14.6 26.3 17.0 앐 12.1 25.3 앐 4.2 3.5 앐 4.9

20 634 59.3 앐 9.5 17.1 24.0 20.4 앐 14.5 26.0 앐 3.3 10.8 앐 9.0

6925 60.5 앐 9.7 17.8 19.3 17.5 앐 13.8 25.6 앐 3.1 10.3 앐 8.5

8825 61.4 앐 9.9 16.8 24.8 20.4 앐 15.0 25.4 앐 3.1 10.3 앐 9.0

6140 60.0 앐 9.7 13.3 35.0 24.0 앐 16.1 25.4 앐 3.2 9.9 앐 9.0

20 806 60.8 앐 9.7 18.3 21.6 20.8 앐 15.3 25.5 앐 3.2 11.4 앐 9.3

7263 57.8 앐 9.2 19.0 24.9 18.9 앐 13.5 25.6 앐 3.2 10.1 앐 8.2

8848 59.7 앐 9.7 14.7 23.4 20.7 앐 14.6 25.9 앐 3.3 9.6 앐 8.5

5607 60.5 앐 9.8 10.2 27.2 21.7 앐 15.4 26.2 앐 3.5 8.8 앐 9.0

education and were more likely to smoke than were those who never consumed sugar and soft drinks. In addition, women and men who consumed more sugar and soft drinks generally drank less alcohol than did those who consumed less sugar and soft drinks. BMI decreased slightly across categories of sugar consumption but increased across categories of soft drink consumption. Intakes of each of the sweetened foods and sugar were weakly correlated with one other; Spearman’s correlation coefficients ranged from 0.06 for sugar and sweets to 0.26 for sweetened fruit soups or stewed fruit and jam or marmalade. Among the 77 797 women and men followed for 563 430 person-years (mean: 7.2 y), 131 incident cases of pancreatic cancer (61 women and 70 men) were diagnosed. After adjustment for age, sex, education, smoking, BMI, and energy and alcohol intakes, we found that participants with high consumption of added sugar, soft drinks, and sweetened fruit soups or sweetened fruit had a risk of pancreatic cancer 1.5 to 1.9 times that in participants with low consumption of those items (Table 2). The associations of sugar and soft drink consumption with pancreatic cancer risk became slightly stronger when we excluded cases diagnosed during the first 2 y of follow-up (n ҃ 24); the multivariate hazard ratios for the highest compared with the lowest category of consumption were 1.95 (95% CI: 1.10, 3.46) for sugar and 2.30 (1.35, 3.92) for soft drinks. When cases diagnosed during the first 4 y of follow-up were removed (n ҃ 54), the corresponding hazard ratios were 1.92 (0.98, 3.75) for sugar and 2.62 (1.39, 4.92) for soft drinks. No association was observed between the consumption of jam or marmalade or sweets and the risk of pancreatic cancer (Table 2). The positive association between soft drink consumption and pancreatic cancer risk may be stronger in persons who are overweight or sedentary, as suggested by a previous study (9). In the current study, the associations of added sugar and soft drink consumption with pancreatic cancer risk did not vary across

strata of BMI or physical activity (P for interaction 쏜 0.45 for all). DISCUSSION

In this prospective analysis, we observed a significantly greater risk of pancreatic cancer associated with high consumption of added sugar, soft drinks, and sweetened fruit soups or stewed fruit than low consumption of those items. No associations were found between the consumption of jam or marmalade or sweets and pancreatic cancer risk. The lack of association with these foods may be due to the fact that these foods are consumed less frequently (weekly) and in smaller servings (앒30 g/serving) than are added sugar and soft drinks (daily) and soft drinks and fruit soups or stewed fruit (앒250 g/serving). We are aware of only one previous study that investigated the association between soft drink consumption and the risk of pancreatic cancer. In that prospective analysis of US nurses and other health professionals (9), women who consumed 쏜3 sugarsweetened soft drinks/wk had a significantly greater (57%) risk of pancreatic cancer than did women who consumed 쏝1 sugarsweetened soft drink/mo; no increase in risk was observed in men. Results of this US prospective study may not be directly comparable with the results in the current study, however, because sucrose is the sugar added as a caloric sweetener to soft drinks in Sweden, whereas high-fructose corn syrup is the major source of caloric sweeteners in soft drinks in the United States. High-fructose corn syrup and sucrose do, however, have similar effects on blood glucose (19). In the current study, the risk of pancreatic cancer was greater only among those who consumed 욷2 soft drinks/d. Thus, the weaker association in women and the lack of association in men between soft drink consumption and pancreatic cancer in the US study (9) may be related to the lower consumption (highest category, 쏜3 times/wk) in that more


1 P values for trend across categories of added sugar and soft drink consumption were statistically significant (P 쏝 0.01) except pack-years across categories of soft drink consumption in men (P ҃ 0.09). The interactions with sex were not significant. 2 Sugar added to coffee, tea, cereals, etc. 3 x៮ 앐 SD (all such values). 4 Calculated for current and past smokers.

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TABLE 2 Hazard ratios (HRs) and 95% CIs for pancreatic cancer according to consumption of added sugar and sweetened foods1 Food items (servings)2

Cases

Person-years

Age- and sex-adjusted HR (95% CI)

Multivariate HR (95% CI)3

Multivariate HR (95% CI)3,4

n 66 18 26 21

307 399 101 653 99 229 55 149

1.00 (reference) 0.78 (0.46, 1.32) 1.03 (0.65, 1.64) 1.92 (1.15, 3.20) 0.02

1.00 (reference) 0.82 (0.49, 1.40) 1.01 (0.63, 1.62) 1.69 (0.99, 2.89) 0.06

1.00 (reference) 0.84 (0.47–1.50) 0.98 (0.57, 1.66) 1.95 (1.10, 3.46) 0.03

66 19 20 26

298 098 106 658 100 976 57 698

1.00 (reference) 0.98 (0.59, 1.64) 0.91 (0.55, 1.51) 2.00 (1.26, 3.17) 0.01

1.00 (reference) 1.06 (0.63, 1.78) 0.93 (0.56, 1.56) 1.93 (1.18, 3.14) 0.02

1.00 (reference) 1.15 (0.65, 2.04) 1.04 (0.59, 1.82) 2.30 (1.35, 3.92) 0.006

41 39 51

216 718 210 134 136 578

1.00 (reference) 0.96 (0.62, 1.50) 1.37 (0.90, 2.10) 0.10

1.00 (reference) 1.04 (0.66, 1.63) 1.51 (0.97, 2.36) 0.05

1.00 (reference) 1.08 (0.66, 1.76) 1.46 (0.89, 2.40) 0.11

21 30 80

90 270 161 975 311 185

1.00 (reference) 1.01 (0.57, 1.78) 1.06 (0.65, 1.73) 0.75

1.00 (reference) 1.04 (0.59, 1.85) 1.15 (0.70, 1.89) 0.54

1.00 (reference) 1.08 (0.58, 1.98) 0.98 (0.57, 1.70) 0.79

58 43 30

192 523 221 466 149 441

1.00 (reference) 0.89 (0.59, 1.33) 0.94 (0.60, 1.48) 0.82

1.00 (reference) 0.90 (0.60, 1.36) 0.90 (0.57, 1.43) 0.67

1.00 (reference) 0.91 (0.58, 1.44) 0.96 (0.58, 1.59) 0.89

1

Cox proportional hazards models were used to calculate hazard ratios. Range of intake; median in parentheses (all such values). 3 Adjusted for age (in mo), sex, education (less than high school, high school graduate, or more than high school), smoking status and pack-years (never smoked, past smoker 쏝20 pack-years, past smoker 욷20 pack-years, current smoker 쏝20 pack-years, current smoker 20 –39 pack-years, or current smoker 욷40 pack-years), BMI [(in kg/m2) 쏝25.0, 25.0 –29.9, or 욷30], and intakes of total energy (continuous) and alcohol (quartiles). 4 Analysis excluded cases diagnosed during the first 2 y of follow-up. From lowest to highest category, n ҃ 53, 15, 20, and 19 for added sugar; 51, 16, 17, and 23 for soft drinks; 33, 33, and 41 for sweetened fruit soups or stewed fruit; 18, 27, and 62 for jam or marmalade; and 46, 35, and 26 for sweets. 5 Added to coffee, tea, cereals, etc. 2

health-conscious population than in our population-based cohort study. Few studies have examined the intakes of added sugar (20), simple (monosaccharide and disaccharide) sugars (21–23), refined sugars (24), or sucrose (12, 13, 23, 25) in relation to the risk of pancreatic cancer, and only 3 of those studies (12, 13, 23) had a prospective study design. In a case-control study (20), women with high intakes of added sugar had 3.7 times the risk of pancreatic cancer as did women with low intakes, but the association with high intakes was not significant in men (1.3 times the risk than was seen in men with low intakes). The risk reported for high intakes of simple (21) or refined (24) sugars in 2 case-control studies was approximately twice that for low intakes, but no significant association with simple sugar was reported in another case-control study (22). In contrast, a prospective cohort of male smokers observed a reduction in risk of pancreatic cancer associated with high intakes of simple sugars (monosaccharides and disaccharides combined) and sucrose (23). Sucrose intake was not significantly associated with pancreatic cancer risk in 2 other prospective studies (12, 13) and in 1 case-control study (25).

The observed positive relations between the consumption of sugar and soft drinks and the risk of pancreatic cancer may be explained within the context of hyperglycemia, insulin resistance, and resulting hyperinsulinemia. Consumption of sugarsweetened soft drinks, which contain large amounts of rapidly absorbable sugars, induces a rapid and dramatic increase in both blood glucose and insulin concentrations (26). A state of relative postprandial hyperglycemia and primary hyperinsulinemia may cause insulin resistance, which in turn usually leads to compensatory hyperinsulinemia (27). Hyperinsulinemia has been shown to increase local blood flow and cell division within the pancreas (28, 29). During hyperinsulinemia, the exocrine cells of the pancreas are exposed to extremely high insulin concentrations because their blood supply passes through the insulin-producing pancreatic islet (30). Elevated insulin concentrations could activate the insulin-like growth factor 1 receptor, which may lead to growth-promoting effects (31). Moreover, by down-regulating insulin-like growth factor 1, excess insulin may result in greater exposure to free insulin-like growth factor 1 (32), which has been shown to stimulate growth in pancreatic cell lines (33–35).


Added sugar5 0 0.1–1.9/d (1.0/d) 2.0–4.9/d (2.9/d) 욷5.0/d (7.0/d) P for trend Soft drinks 0 0.1–0.4/d (0.3/d) 0.5–1.9/d (1.0/d) 욷2.0/d (2.1/d) P for trend Fruit soups or stewed fruit 0 1–3/mo (0.5/wk) 욷1.0/wk (1.5/wk) P for trend Jam or marmalade 0 1–3/mo (0.5/wk) 욷1.0/wk (3.5/wk) P for trend Sweets 0 1–3/mo (0.5/wk) 욷1.0/wk (1.5/wk) P for trend

SUGAR, SWEETENED FOODS, AND PANCREATIC CANCER

SCL and AW were responsible for the study concept and design; AW was responsible for data collection; SCL was responsible for statistical analyses; SCL, LB, and AW were responsible for interpretation of results; SCL was responsible for writing the draft of the manuscript; SCL, LB, and AW provided critical review of the manuscript; and all authors reviewed and approved the final manuscript. None of the authors had a financial or personal conflict of interest.

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Besides the mechanisms described above, the consumption of high-sugar foods may increase the risk of pancreatic cancer by the direct effects of elevated glucose concentrations. A chronic excess of glucose has toxic effects on the pancreatic islet and results in beta cell dysfunction and eventually cell death, a phenomenon that has been called glucose toxicity (36). One potential central mechanism for glucose toxicity is the increased formation of reactive oxygen species that in prolonged excess cause chronic oxidative stress (36). The pancreatic islet is especially sensitive to reactive oxygen species because of the islet’s low concentration of antioxidant enzymes (37). Thus, high-sugar diets may increase pancreatic cancer risk, at least in part, by hyperglycemia-induced oxidative stress and free radical damage to pancreatic cells. The strengths of this study include its prospective and population-based design, high rates of follow-up, and the detailed information on diet and on potential risk factors for pancreatic cancer. The prospective design precluded recall and selection bias, and the completeness of follow-up reduces the possibility that our findings have been affected by differential follow-up. Because our results persisted after the exclusion of cases diagnosed during the first 2 and 4 y of follow-up, it is unlikely that the associations we observed arose because of dietary changes related to preclinical disease. One limitation of the current study is that we could not distinguish between sugarsweetened and diet (ie, artificially sweetened) soft drinks. Other limitations are the relatively short follow-up and the small number of cases. Moreover, because diet was assessed with the use of a self-administered food-frequency questionnaire, some misclassification of sugar and sweetened food consumption is inevitable. However, because dietary information was colleted before the diagnosis of pancreatic cancer, any misclassification would most likely have attenuated rather than exaggerated a true association. In summary, results from this prospective study suggest that high consumption of sugar and sweetened foods may increase the risk of pancreatic cancer. Given the practical implications of these findings and the poor prognosis of pancreatic cancer, further research on sugar and high-sugar foods in relation to pancreatic cancer risk is warranted.

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35. Bergmann U, Funatomi H, Yokoyama M, Beger HG, Korc M. Insulin-like growth factor I overexpression in human pancreatic cancer: evidence for autocrine and paracrine roles. Cancer Res 1995;55: 2007–11. 36. Robertson RP. Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta cells in diabetes. J Biol Chem 2004;279:42351– 4. 37. Grankvist K, Marklund SL, Taljedal IB. CuZn-superoxide dismutase, Mn-superoxide dismutase, catalase and glutathione peroxidase in pancreatic islets and other tissues in the mouse. Biochem J 1981;199:393– 8.
