1 Servizio di Epidemiologiae Biostatistica, Centro di Riferimento Oncologico, Pordenone, Italy; 2 Department of Nutritional Sciences, Faculty of Medicine, University of Toronto and the Clinical Nutrition and Risk Factor Modification Centre, St Michaels Hospital, Toronto, Ontario, Canada; 3 Istituto di Ricerche Farmacologiche Mario Negri, Milan; 4 Istituto di Statistica Medica e Biometria, Università degli Studi di Milano, Milan, Italy
Received 28 August 2003; accepted 22 December 2003
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ABSTRACT |
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Dietary carbohydrates have been directly associated with gastric cancer risk and have been considered general indicators of a poor diet. However, elevated levels of glucose and insulin elicited by consumption of high amounts of refined carbohydrates may stimulate mitogenic and cancer-promoting insulin-like growth factors (IGF). Glycemic index (GI) and glycemic load (GL), which represent indirect measures of dietary insulin demand, were analysed to understand further the association between carbohydrates and gastric cancer.
Patients and methods:
Data were derived from a hospital-based casecontrol study on gastric cancer, conducted in Italy between 1985 and 1997, including 769 cases with incident, histologically confirmed gastric cancer and 2081 controls admitted to the same hospital network as cases for acute, non-neoplastic diseases. All subjects were interviewed using a reproducible food frequency questionnaire.
Results:
The multivariate odds ratios (OR) for subsequent quartiles of dietary GL were 1.44 [95% confidence interval (CI) 1.111.87], 1.62 (95% CI 1.242.12) and 1.94 (95% CI 1.472.55). No consistent pattern of risk was seen with GI. The associations were consistent in different strata of age, education and body mass index, and were stronger in women.
Conclusions:
This study supports the hypothesis of a direct association between GL and gastric cancer risk, thus providing an innovative interpretation, linked to excess circulating insulin and related IGFs, for the association between carbohydrates and risk of gastric cancer.
Key words: carbohydrates, gastric cancer, glycemic index, glycemic load
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Introduction |
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Another possible interpretation of these findings, however, is in terms of glycemic index (GI) and glycemic load (GL) which are indicators of the rate of absorption of dietary carbohydrates and hence measures of insulin demand [12, 13], which in turn may be related to insulin-like growth factors (IGF) and their cancer-promoting and anti-apoptotic properties [14]. GI and GL have been associated with cancer of the colorectum, breast, ovary and endometrium [13, 1518], although the issue remains open to discussion [19].
We therefore analyzed the association of GI and GL with gastric cancer in a large casecontrol study conducted in northern Italy [2, 20].
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Materials and methods |
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A standard questionnaire was used by trained interviewers and included questions about sociodemographic and anthropometric factors, and information on smoking, alcohol and frequency of consumption of 29 food items.
GI values were assigned to these items [21] and the daily average GL was calculated by summing the products of the carbohydrate content per serving for each food or food group, times the average number of servings of that food per week, times its GI [22]. The daily average GI was computed as the GL divided by total carbohydrates.
Odds ratios (OR) and the corresponding 95% confidence intervals (CI) for quartiles of GI and GL were computed using unconditional multiple logistic regression models [23]. We considered two models: in the first one, the regression equations included terms for age, education, sex, area of residence, history of diabetes, body mass index (BMI), smoking, alcohol consumption, and intake of fruit and vegetables. The second model included also a measure of non-carbohydrate energy intake, to allow for any potential bias due to systematic over- or under-reporting [24].
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Results |
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Discussion |
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Dietary insulin demand is determined both by the type of carbohydrates consumed (i.e. GI) and the combination of type and amount (i.e. GL), the worse scenario being when high GI foods are consumed in high amounts (e.g. high amounts of refined grains). The lack of association between GI and risk of gastric cancer suggests that both amount and type of carbohydrates, rather than type alone, may be related to the process of gastric carcinogenesis.
The present findings provide an innovative interpretation for the association of carbohydrates and risk of gastric cancer. Carbohydrates may in fact be proxy of a poor diet, as well as indicators of a high endogenous insulin environment. Hyperinsulinemia is typically found in conditions of impaired glucose tolerance, which have been associated with increased cancer risk [30, 31]. Insulin has been shown to act as a cancer-promoting agent in both in vitro and animal studies [32, 33], possibly through an increased activity of IGF-1 [14]. IGF-1 inhibits apoptosis, increases production of vascular endothelial growth factors [14], and has been linked to increased mitogenesis in gastric cancer cell lines [34, 35]. Higher levels of IGF-1 have been found in patients with gastric cancer compared with healthy controls [36].
Potential limitations of the study include the reliability and validity of the GI and GL estimates, due to the relatively limited number of items. Recall and selection biases are also possible. However, awareness about any dietary hypotheses, and particularly those related to GI and GL, in gastric cancer was limited when the study was conducted. While it is conceivable that dietary habits of hospital controls differ from those of the general population, attention was paid to minimizing bias by excluding control subjects admitted for conditions that might have been associated with special dietary modifications. Interviewing all subjects in a hospital setting allowed greater comparability of dietary history between cases and controls, and the questionnaire was satisfactorily reproducible and reliable [37]. Furthermore, participation among eligible patients was practically complete, and the catchment areas for cases and controls were comparable. With reference to confounding, allowance for a large number of potential distorting factors, including a measure of non-carbohydrate calorie intake, was unable to explain the association between GL and gastric cancer risk.
In conclusion, the present study indicates that diets with high GL are directly related to gastric cancer risk, thus providing an additional interpretation to the observation that intakes of starchy foods and sugar [26, 27], but not whole grains [2, 28, 29], have been associated with increased gastric cancer risk.
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Acknowledgements |
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FOOTNOTES |
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REFERENCES |
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2. La Vecchia C, Negri E, Decarli A et al. A case-control study of diet and gastric cancer in northern Italy. Int J Cancer 1987; 40: 484489.[ISI][Medline]
3. Buiatti E, Palli D, Decarli A et al. A case-control study of gastric cancer and diet in Italy. Int J Cancer 1989; 44: 611616.[ISI][Medline]
4. Graham S, Lilienfeld AM, Tidings JE. Dietary and purgation factors in the epidemiology of gastric cancer. Cancer 1967; 20: 22242234.[ISI][Medline]
5. Bielke E. Epidemiologic studies of cancer of the stomach, colon, and rectum; with special emphasis on the role of diet. Scand J Gastroenterol Suppl 1974; 31: 1235.[Medline]
6. Modan B, Lubin F, Barell V et al. The role of starches in etiology of gastric cancer. Cancer 1974; 34: 20872092.[ISI][Medline]
7. Risch HA, Jain M, Choi NW et al. Dietary factors and the incidence of cancer of the stomach. Am J Epidemiol 1985; 122: 947959.[Abstract]
8. Trichopoulos D, Ouranos G, Day NE et al. Diet and cancer of the stomach: a case-control study in Greece. Int J Cancer 1985; 36: 291297.[ISI][Medline]
9. Tuyns AJ, Kaaks R, Haelterman M, Riboli E. Diet and gastric cancer. A case-control study in Belgium. Int J Cancer 1992; 51: 16.[ISI][Medline]
10. Howson CP, Hiyama T, Wynder EL. The decline in gastric cancer: epidemiology of an unplanned triumph. Epidemiol Rev 1986; 8: 127.[ISI][Medline]
11. Nomura A. Stomach cancer. In Schottenfeld D, Fraumeni JF (eds): Cancer Epidemiology and Prevention. Oxford: Oxford University Press, 1996.
12. Jenkins DJ, Wolever TM, Taylor RH et al. Glycemic index of foods: a physiological basis for carbohydrate exchange. Am J Clin Nutr 1981; 34: 362366.[Abstract]
13. Franceschi S, Dal Maso L, Augustin L et al. Dietary glycemic load and colorectal cancer risk. Ann Oncol 2001; 12: 173178.[Abstract]
14. Giovannucci E. Insulin, insulin-like growth factors and colon cancer: a review of the evidence. J Nutr 2001; 131 (11 Suppl): 3109S3120S.
15. Slattery ML, Benson J, Berry TD et al. Dietary sugar and colon cancer. Cancer Epidemiol Biomarkers Prev 1997; 6: 677685.[Abstract]
16. Augustin LS, Franceschi S, Jenkins DJ et al. Glycemic index in chronic disease: a review. Eur J Clin Nutr 2002; 56: 10491071.[CrossRef][ISI][Medline]
17. Augustin LS, Polesel J, Bosetti C et al. Dietary glycemic index, glycemic load and ovarian cancer risk: a case-control study in Italy. Ann Oncol 2003; 14: 7884.
18. Augustin LS, Gallus S, Bosetti C et al. Glycemic index and glycemic load in endometrial cancer. Int J Cancer 2003; 105: 404407.[CrossRef][ISI][Medline]
19. Terry PD, Jain M, Miller AB et al. Glycemic load, carbohydrate intake, and risk of colorectal cancer in women: a prospective cohort study. J Natl Cancer Inst 2003; 95: 914916.
20. La Vecchia C, Ferraroni M, DAvanzo B et al. Selected micronutrient intake and the risk of gastric cancer. Cancer Epidemiol Biomarkers Prev 1994; 3: 393398.[Abstract]
21. Foster-Powell K, Holt SH, Brand-Miller JC. International table of glycemic index and glycemic load values: 2002. Am J Clin Nutr 2002; 76: 556.
22. Wolever TM, Nguyen PM, Chiasson JL et al. Determinants of diet glycemic index calculated retrospectively from diet records of 342 individuals with non-insulin-dependent diabetes mellitus. Am J Clin Nutr 1994; 59: 12651269.[Abstract]
23. Breslow NE, Day NE. Statistical Methods in Cancer Research. Vol. I. The Analysis of Case-control Studies. IARC Scientific Publications No. 32. Lyon: International Agency for Research on Cancer, 1980.
24. Willett W, Stampfer MJ. Total energy intake: implications for epidemiologic analyses. Am J Epidemiol 1986; 124: 1727.[Abstract]
25. De Stefani E, Boffetta P, Deneo-Pellegrini H et al. Carbohydrates and risk of stomach cancer in Uruguay. Int J Cancer 1999; 82: 618621.[CrossRef][ISI][Medline]
26. La Vecchia C, Bosetti C, Negri E, Franceschi S. Refined sugar intake and the risk of gastric cancer. Int J Cancer 1998; 78: 130131.[CrossRef][ISI][Medline]
27. Buiatti E, Palli D, Decarli A et al. A case-control study of gastric cancer and diet in Italy: II. Association with nutrients. Int J Cancer 1990; 45: 896901.[ISI][Medline]
28. Chatenoud L, La Vecchia C, Franceschi S et al. Refined-cereal intake and risk of selected cancers in Italy. Am J Clin Nutr 1999; 70: 11071110.
29. La Vecchia C, Chatenoud L, Negri E, Franceschi S. Session: whole cereal grains, fibre and human cancer. Wholegrain cereals and cancer in Italy. Proc Nutr Soc 2003; 62: 4549.[CrossRef][ISI][Medline]
30. La Vecchia C, Negri E, Franceschi S et al. A case-control study of diabetes mellitus and cancer risk. Br J Cancer 1994; 70: 950953.[ISI][Medline]
31. Saydah SH, Loria CM, Eberhardt MS, Brancati FL. Abnormal glucose tolerance and the risk of cancer death in the United States. Am J Epidemiol 2003; 157: 10921100.
32. Bjork J, Nilsson J, Hultcrantz R, Johansson C. Growth-regulatory effects of sensory neuropeptides, epidermal growth factor, insulin, and somatostatin on the non transformed intestinal epithelial cell line IEC-6 and the colon cancer cell line HT 29. Scand J Gastroenterol 1993; 28: 879884.[ISI][Medline]
33. Tran TT, Medline A, Bruce RW. Insulin promotion of colon tumors in rats. Cancer Epidemiol Biomarkers Prev 1996; 5: 10131015.[Abstract]
34. Yi HK, Hwang PH, Yang DH et al. Expression of the insulin-like growth factors (IGFs) and the IGF-binding proteins (IGFBPs) in human gastric cancer cells. Eur J Cancer 2001; 37: 22572263.[CrossRef][ISI][Medline]
35. Lee DY, Yi HK, Hwang PH, Oh Y. Enhanced expression of insulin-like growth factor binding protein-3 sensitizes the growth inhibitory effect of anticancer drugs in gastric cancer cells. Biochem Biophys Res Commun 2002; 294: 480486.[CrossRef][ISI][Medline]
36. Franciosi CM, Piacentini MG, Conti M et al. IGF-1 and IGF-1BP3 in gastric adenocarcinoma. Preliminary study. Hepatogastroenterology 2003; 50: 297300.[ISI][Medline]
37. DAvanzo B, La Vecchia C, Katsouyanni K et al. An assessment, and reproducibility of food frequency data provided by hospital controls. Eur J Cancer Prev 1997; 6: 288293.[ISI][Medline]