High Glycemic Index Diet Associated with Lung Cancer

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 (GI_ac), 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.

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 GI_ac was associated with an increased risk of lung cancer overall (GI: 5^th vs 1^st quintile, fully adjusted OR: 1.49; 95% CI: 1.21-1.83, P_trend<0.001; GI_ac: 5^th vs 1^st quintile, fully adjusted OR:1.48; 95% CI: 1.20-1.81, P_trend=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 5^th vs 1^st quintile OR: 1.92; 95% CI: 1.30-2.83; P_trend<0.001), but not adenocarcinoma (AC). The effect estimates were more pronounced for SCC than AC. Results for GI_ac 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; P_trend=0.02) compared to ever smokers (OR: 1.01; 95% CI: 0.80-1.26; P_trend=0.94), and for those with less than 12 years of education (OR: 1.75; 95% CI: 1.19-2.58; P_trend<0.001) compared to those with more than 12 years (results not significant). Results for GI_ac 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. 

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.

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 A_1C.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. 

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. 

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.