Glycemic index, glycemic load and risk of gastric cancer

L. S. A. Augustin1,2, S. Gallus3,*, E. Negri3 and C. La Vecchia3,4

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 Michael’s 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


    ABSTRACT
 Top
 ABSTRACT
 Introduction
 Materials and methods
 Results
 Discussion
 REFERENCES
 
Background:

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 case–control 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) 1.11–1.87], 1.62 (95% CI 1.24–2.12) and 1.94 (95% CI 1.47–2.55). 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


    Introduction
 Top
 ABSTRACT
 Introduction
 Materials and methods
 Results
 Discussion
 REFERENCES
 
Gastric cancer incidence and mortality have been traditionally higher in several areas of Italy compared with other European countries [1]. Case–control studies conducted in the Greater Milan area [2] and in several areas of Italy with high and low incidence [3] have shown an association between starchy foods, including pasta or rice, polenta or traditional soups, and gastric cancer risk. Studies in the United States [4, 5], Israel [6], Canada [7], Greece [8] and Belgium [9] support the hypothesis of an increased risk of gastric cancer with high carbohydrate intake. In these studies, selected starchy foods were considered as general indicators of a poor diet, which is a recognized risk factor for gastric cancer [10, 11].

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 case–control study conducted in northern Italy [2, 20].


    Materials and methods
 Top
 ABSTRACT
 Introduction
 Materials and methods
 Results
 Discussion
 REFERENCES
 
Data were derived from a case–control study conducted in the major teaching and general hospitals in the Greater Milan area. The design of the study was described previously [20]. Briefly, 769 incident, histologically confirmed cases of stomach cancer (469 men and 300 women; median age 61 years, range 19–79 years) were interviewed between January 1985 and December 1997. The control group included 2081 subjects (1220 men, 861 women; median age 55 years, range 19–79 years) admitted to the same hospital network as cases for acute conditions not related to neoplastic or digestive tract diseases and unrelated to long-term diet modification (46% traumas, 20% other orthopaedic conditions, 19% acute surgical, 15% other miscellaneous disorders). Less than 4% of identified cases and controls refused to be interviewed.

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].


    Results
 Top
 ABSTRACT
 Introduction
 Materials and methods
 Results
 Discussion
 REFERENCES
 
Table 1 shows the multivariate ORs of gastric cancer according to quartiles of GI and GL. The ORs were 1.44, 1.62 and 1.94 in subsequent quartiles of GL, after allowance for non-carbohydrate energy, fruit and vegetables, besides main non-dietary risk factors. The trend in risk for GL was significant. In contrast, no consistent pattern of risk across subsequent quartiles of GI was observed.


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Table 1. Odds ratios (OR) and 95% confidence intervals (CI) of 769 cases of gastric cancer and 2081 controls, according to glycemic index and glycemic load (Italy, 1985–1997)
 
Table 2 considers the relation of GL and gastric cancer risk in separate strata of age, sex, education and BMI. The ORs for subsequent quartiles were above unity in all strata, in the absence of an apparent heterogeneity for all covariates considered except for sex, since the association was significantly stronger in women.


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Table 2. Odds ratios (OR) and 95% confidence intervals (CI)a of 769 cases of gastric cancer and 2081 controls, by glycemic load in strata of age, sex, education and body mass index (BMI) (Italy, 1985–1997)
 

    Discussion
 Top
 ABSTRACT
 Introduction
 Materials and methods
 Results
 Discussion
 REFERENCES
 
We reported previously that gastric cancer was associated with a poor diet [2] as indicated by low consumption of fruit and vegetables and micronutrients, including vitamin C and beta-carotene [20]. Elevated dietary GI and GL may indeed reflect a high intake of refined carbohydrates [25], which are often low in vitamins, minerals, antioxidants and fiber, as well as to low intakes of legumes, fruit, vegetables and whole grains, which have been inversely related to gastric cancer risk [2, 10, 11, 2529].

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.


    Acknowledgements
 
The authors wish to thank Mrs Ivana Garimoldi for editorial assistance. This work was supported by the Italian Association for Cancer Research (AIRC), Milan, and the Italian League against Cancer.


    FOOTNOTES
 
* Correspondence to: Dr S. Gallus, Istituto di Ricerche Farmacologiche ‘Mario Negri’, Via Eritrea 62, 20157 Milano, Italy. Tel: +39-02-39014-526; Fax: +39-02-33200-231; E-mail: gallus{at}marionegri.it Back


    REFERENCES
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 ABSTRACT
 Introduction
 Materials and methods
 Results
 Discussion
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