Melkonian SC, Daniel CR, Ye Y, Pierzynski JA, Roth JA, Wu X. Glycemic index, glycemic load, and lung cancer risk in non-Hispanic Whites. Cancer Epidemiol Biomarkers Prev. 2016;25(3):532-539.
To assess if glycemic index (GI) and glycemic load (GL) are associated with lung cancer risk in non-Hispanic whites, and whether lung cancer risk factors alter the association
Retrospective case-control study
Investigators compared 1,905 newly diagnosed lung cancer cases to 2,413 healthy controls. The controls had no prior history of cancer other than nonmelanoma skin cancers. Controls were matched to cases by age, gender, and ethnicity.
In the lung cancer group, participants’ mean age was 60.69 years; 52.81% were male and 47.19% female. In the control group the mean age was 60.78 years; 51.06% were male and 48.94% female.
Due to the small number of minority populations in the sample, the analysis was limited to non-Hispanic whites only.
GI and GL were calculated from food frequency questionnaires within the National Cancer Institute Health Habits and History Questionnaire. GI and GL were categorized into quintiles. GI was represented as both the overall GI and the GI available carbohydrate (GIac), which subtracts fiber content from total carbohydrates.
A number of other variables including socioeconomic status, physical activity (measured in metabolic equivalents), BMI, and smoking history were obtained through interviews and medical charts.
Primary Outcome Measures
Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for GI and GL quintiles and lung cancer risk using multivariable logistic regression.
Two modeling approaches were used to calculate ORs: A minimally adjusted model controlling for age, gender, education, and smoking status, and a fully adjusted model additionally controlling for physical activity, BMI, total caloric intake, alcohol intake, total meat intake, and fiber intake.
Higher GI and GIac was associated with an increased risk of lung cancer overall (GI: 5th vs 1st quintile, fully adjusted OR: 1.49; 95% CI: 1.21-1.83, Ptrend<0.001; GIac: 5th vs 1st quintile, fully adjusted OR:1.48; 95% CI: 1.20-1.81, Ptrend=0.001).
Glycemic load was not associated with overall lung cancer risk.
When stratified by histological subtype, higher GI was significantly associated with squamous cell carcinoma (SCC) (GI 5th vs 1st quintile OR: 1.92; 95% CI: 1.30-2.83; Ptrend<0.001), but not adenocarcinoma (AC). The effect estimates were more pronounced for SCC than AC. Results for GIac were consistent with GI findings.
Stratified analysis found more pronounced effects for lung cancer risk for highest versus lowest GI for never smokers (OR: 1.81; 95% CI: 1.11-2.93; Ptrend=0.02) compared to ever smokers (OR: 1.01; 95% CI: 0.80-1.26; Ptrend=0.94), and for those with less than 12 years of education (OR: 1.75; 95% CI: 1.19-2.58; Ptrend<0.001) compared to those with more than 12 years (results not significant). Results for GIac were consistent with GI findings.
All other stratified analyses (age, gender, and BMI) were consistent with overall results.
The glycemic index, developed by Dr. David Jenkins in the early 1980s,1 classifies carbohydrates based on their effect on postprandial blood glucose levels. The greater the elevation in blood glucose, the higher the GI of that particular food. White sugar and white bread are given a GI of 100, and are used as reference foods. International tables of GI and GL, last published in 2008, are available full-text online and are useful reference documents for clinicians.2 The effect of GI on a variety of chronic health conditions has been extensively studied, including diabetes, cardiovascular disease, obesity, and more recently cancer.3
The GI of food is altered by the rate of liberation and digestion of carbohydrates, which is affected by intrinsic factors as well as extrinsic factors such as the fiber, protein, and fat content of food.4 As an example, the addition of whey protein to a high GI food bolus decreases postprandial blood glucose levels.5
The concept of glycemic load was developed later and takes into account the GI and the total quantity of carbohydrate. A simple way to consider these related but different terms is that GI refers to the quality of the carbohydrate only, while GL also considers the quantity of carbohydrate.6
The present study found that GI but not GL was related to lung cancer development, indicating that in this case the quality of the carbohydrate is more important than the amount of carbohydrate consumed.
As a prevention strategy, a low GI diet is a sound approach.
Several studies have looked at GI and cancer risk, but this is only the second study to evaluate the link between lung cancer and GI. A small case-control study in Uruguay7 found that an increased intake of sugar-rich foods, total sucrose intake, sucrose-to-fiber ratio, and GI were associated with lung cancer cases. Specifically, the OR for highest GI was 2.77 (95% CI: 1.28-5.97). An interesting study from 2006 looked at fruit and vegetable intake and mortality in 353 patients with lung cancer and found that while higher intake of fruits and vegetables had a nonsignificant trend toward decreased mortality, high intake of potatoes had a significant increased risk of mortality (HR: 1.51; 95% CI: 1.12-2.23).8 The GI of potatoes is 78+4,1 making them one of the highest GI foods. However, it is important to consider confounding factors with potato intake such as preparation method, and other dietary factors associated with potato intake. So while this does not demonstrate causation, it is interesting to note.
The GI has been studied in relation to other cancer types. A meta-analysis published in 20089 found that colorectal and endometrial cancers were significantly associated with GI and GL, while breast and pancreatic cancer were not. A meta-analysis published in 201510 found moderately increased risk for breast, endometrial, ovarian, prostate, esophageal, gastric, colorectal, liver, and pancreatic cancers with higher GI and GL diets.
Glycemic index and hyperinsulinemia
One possible mechanism by which lower GI diets may decrease the risk of lung cancer is through decreasing postprandial insulin levels and insulin resistance. High GI and GL diets increase the risk of developing diabetes mellitus (DM),11 which is characterized by hyperinsulinemia and insulin resistance. Adherence to a low GI diet improves glycemic control as measured by hemoglobin A1C.12 This is relevant, as a recent meta-analysis showed that DM is significantly associated with poorer overall survival among people with lung cancer (HR: 1.28; 95% CI: 1.10-1.49).13 Additionally, DM is an independent risk factor for the development of lung cancer when smoking status is controlled for.14 These findings suggest that better glycemic control may reduce lung cancer risk and mortality, and adherence to a low GI diet is a means to achieve this, thereby providing a possible mechanism of action.
Glycemic index and the IGF-1 pathway
To further explore the mechanism underlying a low GI diet, the role of insulin-like growth factor 1 (IGF-1) and its receptor are important considerations. Insulin-like growth factor 1 is produced in the liver and binds to the IGF-1 receptor (IGF-1R).15 The IGF binding proteins (IFGBPs) control IGF-1 activity, with IGFBP3 in particular decreasing the effect of IGF-1 on its receptor.16 The IGF-1R, a receptor tyrosine kinase, promotes malignant transformation, cell proliferation, and cell survival, and has been demonstrated to be highly expressed in non-small cell and small cell lung cancers.15 Therefore, IGF-1 and IGFBPs are of interest as they can potentially alter the expression and activation of IGF-1R and thus alter cancer growth and progression.
Two case-control studies have found higher plasma levels of IGF-1 in lung cancer cases,17,18 and 1 of the studies found that IGF-1 levels were significantly higher in stage III and IV lung cancer cases compared to stage I and II, suggesting IGF-1 may be implicated in the development and progression of lung cancer.12 Another study found that genetic variations in the IGF-1-IGF-1R-IGFBP pathway increases risk of developing lung cancer.19 However, other studies have failed to find an association between IGF-1 and lung cancer risk or mortality.20,21 Monoclonal antibodies targeting IGF-1R have been developed; however results have not favored the drug.22,23
The impact that GI and GL have on the IGF axis has been studied with conflicting results. One study in 84 healthy individuals found that a 28-day low GL diet led to 4% lower fasting concentrations of IGF-1 and 4% lower IGF-1:IGFBP3 levels compared to a high GL diet.24 Another study comparing the response of a low GI and high GI carbohydrate source on IGF-1 and IGFBPs found that the low GI carbohydrate resulted in higher levels IGFBP3, but that GI had minimal effect on IGF-1 as measured over a 4-hour period.25
In summary, the IGF-1 axis is complex, and research is ongoing. Although there is a growing body of evidence supporting the role of the IGF axis in lung cancer development and progression, the impact that GI and GL have on this pathway is unclear. The GI may provide a method of targeting the pathway through modulating postprandial secretion of insulin, IGFBPs, and possibly IGF-1, although further research is warranted to clarify.
Glycemic index of common dietary approaches
The low GI diet aligns well with the Mediterranean diet, which encourages consumption of low GI foods such as vegetables and fruit, legumes, fish, poultry, whole grains, olive oil, and red wine. The diet limits the intake of higher GI foods such as refined grains, sweetened beverages, and desserts. High adherence to the Mediterranean diet is inversely associated with GI and GL.7 A recent study found adherence to a Mediterranean diet decreased risk of lung cancer in heavy smokers.26 The most recent meta-analysis of the Mediterranean diet for cancer mortality found a significant inverse association between the two, and the relative risk for mortality from respiratory cancers was an impressive 0.10 (95% CI: 0.01-0.70).27 Of course, not all of this can be attributed to the GI alone, as many components of the Mediterranean diet have health-promoting benefits, such as fish and olive oil.
Low carbohydrate diets may be low GI, but the definition of what constitutes low carbohydrate varies widely and ranges from 5% to 40% of total caloric intake.28 Additionally, the quantity of carbohydrate refers more to the GL, and attention should be paid to the type of carbohydrate to ensure the diet is also low GI. The ketogenic diet would of course have an extremely low GI. This diet is very low in carbohydrates, with a typical ketogenic diet containing approximately 5% of daily calories from carbohydrate, 80% from fat, and 15% from protein. Although interest in the ketogenic diet has been growing, particularly for glioblastoma, it has yet to be studied in lung cancer.
Juicing is a popular practice among patients. Clinicians should be aware of the high GI potential of juicing due to the complete removal of fiber and the absence of fat or protein. Any fruits or root vegetables will create a very high GI juice. With the exception of low residue diets, encouraging patients to blend or eat whole fruits and vegetables may be preferable.
The GI allows for flexibility in dietary choices and can be applied to a variety of culturally and ethnically appropriate cuisines, making a low GI diet a feasible choice.
The present study looked only at GI/GL and its association with lung cancer incidence. Future studies looking at GI/GL and lung cancer survival are warranted. Until then, one can apply Special Recommendation 2 of the World Cancer Research Fund, which encourages cancer survivors to “follow the recommendations for cancer prevention.”29 This allows the extrapolation of these results to lung cancer treatment and survivorship, since what provides benefit for prevention is considered supportive both during treatment and for secondary prevention.
As a prevention strategy, a low GI diet is a sound approach. As with most dietary approaches during active cancer treatment, it is important that clinicians allow for some flexibility with patients. Patients with lung cancer, especially if undergoing conventional treatment, may experience nausea, vomiting, food aversions, and fatigue, making meal preparation difficult. Compiled with the high risk of cachexia in lung cancer patients30 and high prevalence of malnutrition in this population,31 clinicians should modify their dietary recommendations to suit the needs of the individual. One might consider the primary goal to be caloric and macronutrient sufficiency and, once achieved, shift the focus to the GI of foods.
Since its inception in the early 1980s, the GI has been extensively studied for a variety of chronic health conditions. The last decade has seen the GI more widely studied in relation to cancer, but this paper is only the second to look at the association of GI with risk of lung cancer incidence. Although the mechanism by which GI may impact cancer development and progression is far from clear, the potential benefit of weighing the quality of carbohydrates is proving to be an important consideration for cancer prevention and treatment.
This study has several limitations. First, retrospective case-control studies carry the risk of selection and recall bias. The results rely on participants’ ability to accurately recall and report on their diet, and healthy controls are more likely to recall healthy habits. Second, retrospective studies cannot demonstrate causality. Third, the study did not control for diabetes, which may be a large confounding factor (see commentary for further discussion of this). Finally, because the analysis was limited to non-Hispanic whites, the generalizability of these results is limited.
Prospective studies are recommended to further elucidate the relationship between GI and cancer risk. Furthermore, the relationship between GI and lung cancer mortality is yet unknown and cannot be determined from this study.
- Jenkins DJ, Wolever TM, Taylor RH, et al. Glycemic index of foods: a physiological basis for carbohydrate exchange. Am J Clin Nutr. 1981;34(3):362-366.
- Atkinson FS, Foster-Powell K, Brand-Miller JC. International tables of glycemic index and glycemic load values: 2008. Diabetes Care. 2008;31(12):2281-2283.
- Augustin LSA, Kendall CW, Jenkins DJ, et al. Glycemic index, glycemic load and glycemic response: an International Scientific Consensus Summit from the International Carbohydrate Quality Consortium (ICQC). Nutr Metab Cardiovasc Dis. 2015;25:795-815.
- Jenkins DJ, Kendall CW, Augustin LS, et al. Glycemic index: overview of implications in health and disease. Am J Clin Nutr. 2002;76(1):266S-73S.
- Petersen BL, Ward LS, Bastian ED, Jenkins AL, Campbell J, Vuksan V. A whey protein supplement decreases post-prandial glycemia. Nutr J. 2009;8:47.
- Rodríguez-Rejón AI, Castro-Quezada I, Ruano-Rodríguez C, et al. Effect of a Mediterranean diet intervention on dietary glycemic load and dietary glycemic index: The PREDIMED Study. J Nutr Metab. 2014;2014:985373.
- De Stefani E, Deneo-Pellegrini H, Mendilaharsu M, Ronco A, Carzoglio JC. Dietary sugar and lung cancer: a case-control study in Uruguay. Nutr Cancer. 1998;31(2):132-137.
- Skuladottir H, Tjoenneland A, Overvad K, Stripp C, Olsen JH. Does high intake of fruit and vegetables improve lung cancer survival? Lung Cancer. 2006;51(3):267-273.
- Gnagnarella P, Gandini S, La Vecchia C, Maisonneuve P. Glycemic index, glycemic load, and cancer risk: a meta-analysis. Am J Clin Nutr. 2008;87(6):1793-1801.
- Turati F, Galeone C, Gandini S, et al. High glycemic index and glycemic load are associated with moderately increased cancer risk. Mol Nutr Food Res. 2015;59(7):1384-1394.
- Bhupathiraju SN, Tobias DK, Malik VS, et al. Glycemic index, glycemic load, and risk of type 2 diabetes: results from 3 large US cohorts and an updated meta-analysis. Am J Clin Nutr. 2014;100(1):218-232.
- Wang Q, Xia W, Zhao Z, Zhang H. Effects comparison between low glycemic index diets and high glycemic index diets on HbA1c and fructosamine for patients with diabetes: A systematic review and meta-analysis. Prim Care Diabetes. 2015;9(5):362-269.
- Zhu L, Cao H, Zhang T, et al. The effect of diabetes mellitus on lung cancer prognosis: a PRISMA-compliant meta-analysis of cohort studies. Medicine (Baltimore). 2016;95(17):e3528
- Lee J-Y, Jeon I, Lee JM, Yoon J-M, Park SM. Diabetes mellitus as an independent risk factor for lung cancer: a meta-analysis of observational studies. Eur J Cancer. 2013;49(10):2411-2423.
- Nurwidya F, Andarini S, Takahashi F, Syahruddin E, Takahashi K. Implications of Insulin-like Growth Factor 1 Receptor Activation in Lung Cancer. Malays J Med Sci. 2016;23(3):9-21.
- Zhao S, Qiu Z, He J, Li L, Li W. Insulin-like growth factor receptor 1 (IGF1R) expression and survival in non-small cell lung cancer patients: a meta-analysis. Int J Clin Exp Pathol. 2014;7(10):6694-6704.
- Yu H, Spitz MR, Mistry J, Gu J, Hong WK, Wu X. Plasma levels of insulin-like growth factor-I and lung cancer risk: a case-control analysis. J Natl Cancer Inst. 1999;91(2):151-156.
- Zhang M, Li X, Zhang X, Yang Y, Feng Z, Liu X. Association of serum hemoglobin A1c, C-peptide and insulin-like growth factor-1 levels with the occurrence and development of lung cancer. Mol Clin Oncol. 2014;2(4):506-508.
- Huang XP, Zhou WH, Zhang YF. Genetic variations in the IGF-IGFR-IGFBP axis confer susceptibility to lung and esophageal cancer. Genet Mol Res. 2014;13(1):2107-2119.
- Spitz MR, Barnett MJ, Goodman GE, Thornquist MD, Wu X, Pollak M. Serum insulin-like growth factor (IGF) and IGF-binding protein levels and risk of lung cancer: a case-control study nested in the beta-Carotene and Retinol Efficacy Trial Cohort. Cancer Epidemiol Biomarkers Prev. 2002;11(11):1413-1418.
- Tas F, Bilgin E, Tastekin D, Erturk K, Duranyildiz D. Serum IGF-1 and IGFBP-3 levels as clinical markers for patients with lung cancer. Biomed reports. 2016;4(5):609-614.
- Scagliotti GV, Bondarenko I, Blackhall F, et al. Randomized, phase III trial of figitumumab in combination with erlotinib versus erlotinib alone in patients with nonadenocarcinoma nonsmall-cell lung cancer. Ann Oncol. 2015;26(3):497-504.
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- Runchey SS, Pollak MN, Valsta LM, et al. Glycemic load effect on fasting and post-prandial serum glucose, insulin, IGF-1 and IGFBP-3 in a randomized, controlled feeding study. Eur J Clin Nutr. 2012;66(10):1146-1152.
- Brand-Miller JC, Liu V, Petocz P, Baxter RC. The glycemic index of foods influences postprandial insulin-like growth factor-binding protein responses in lean young subjects. Am J Clin Nutr. 2005;82(2):350-354.
- Maisonneuve P, Shivappa N, Hébert JR, et al. Dietary inflammatory index and risk of lung cancer and other respiratory conditions among heavy smokers in the COSMOS screening study. Eur J Nutr. 2016;55(3):1069-1079.
- Schwingshackl L, Hoffmann G. Adherence to Mediterranean diet and risk of cancer: an updated systematic review and meta-analysis of observational studies. Cancer Med. 2015;4(12):1933-1947.
- Wylie-Rosett J, Aebersold K, Conlon B, Isasi CR, Ostrovsky NW. Health effects of low-carbohydrate diets: where should new research go? Curr Diab Rep. 2013;13(2):271-278.
- World Cancer Research Fund / American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective. Washington DC: AICR, 2007.
- Jafri SHR, Previgliano C, Khandelwal K, Shi R. Cachexia index in advanced non-small-cell lung cancer patients. Clin Med Insights Oncol. 2015;9:87-93.
- Mohan A, Poulose R, Kulshreshtha I, et al. High prevalence of malnutrition and deranged relationship between energy demands and food intake in advanced non-small cell lung cancer [published online ahead of print April 21, 2016]. Eur J Cancer Care (Engl).