Abstract & Commentary
Metabolic Dysregulation and the Risk of Obesity-related Cancers
By Traci Pantuso ND, MS
Adjunct Faculty, Bastyr University, Seattle, WA
Dr. Pantuso reports no financial relationships relevant to this field of study.
Synopsis: This study investigates the role of metabolic dysregulation of the insulin-glucose axis and the risk of obesity-related cancers in the Framingham Heart Study Offspring Cohort over approximately 37 years. The authors found that impaired fasting glucose exposure for a period greater than 10 years increased obesity-related cancer risk.
Source: Parekh N, et al. Metabolic dysregulation of the insulin-glucose axis and risk of obesity-related cancers in the Framingham heart study-offspring cohort (1971-2008). Cancer Epidemiol Biomarkers Prev 2013;22:1825-1836.
Thirty-five percent of adults meet the clinical criteria for obesity in the United States, which is considered a nationwide health epidemic. Excess adiposity is a well-established risk factor for several cancers, according to the World Cancer Research Fund/American Institute for Cancer Research Expert Panel Report.1 Excess adiposity is also an established risk factor for type 2 diabetes mellitus (T2DM). Recently, multiple meta-analyses have demonstrated that T2DM is an independent risk factor for particular types of cancer.2
Excess adiposity is known to secrete cytokines and other products that cause chronic inflammation and are thought to influence neoplastic processes.2 Biomarkers for insulin resistance and elevated blood glucose may indicate metabolic processes that increase cancer risk. The authors of this study investigated the relationship between a number of different clinical and laboratory metabolic biomarkers with the development of obesity-related cancers as an endpoint.
Methods. The study population for this study was the Framingham Offspring Cohort from the Framingham Health Study (FHS). The FHS is a three-generational study that is taking place in Framingham, Mass. The study population was > 20 years old and had no diagnosis of type 1 diabetes or cancer at onset of study. Clinic exams occurred on average every 4 years from 1971-2008. Data on women who were pregnant at the time of an exam were not included, as they would falsely elevate a number of the biomarkers for that exam.
The authors investigated a number of biomarkers to evaluate the insulin-glucose axis. Fasting blood glucose was measured at every exam while hemoglobin A1c and fasting insulin concentration were measured at select exams. The authors used blood glucose and insulin concentrations at exams 5 and 7 to calculate the homeostatic model assessment-insulin resistance (HOMA-IR). HOMA-IR measures pancreatic ß-cell function and insulin resistance. Blood pressure, height, and weight were measured at every exam visit. Waist circumference was measured at five of the eight exams. Physical activity was self-reported and a physical activity index (PAI) was calculated. The Harvard food frequency questionnaire was used to evaluate diet during exams 5 through 8. Other information that was collected during visits was occupation, education, ethnicity, multivitamin use, alcohol, smoking, medication, and medical history.
The authors evaluated the primary outcome of obesity-related cancers, which includes cancers of the thyroid gland, genitourinary organs, female reproductive tract, reticuloendothelial system (blood, bone, and spleen), and the gastrointestinal tract. Skin cancers were excluded from this analysis. The majority of cancers were confirmed primary cancers from pathology reports with the date of diagnosis. Less than 5% of cancers were confirmed by either death certificates or clinical reports without pathology reports. The authors used the Cox proportional hazards model with time dependent covariates to evaluate the risk of obesity-related cancer using all available data.
Results. There were a total of 4615 participants; 99% were Caucasian and 50% were female. The mean age at baseline was 37.5 years and 66.8 years at the last exam. Both body mass index (BMI) and waist circumference increased over time (see Table 1). There was no evidence of energy intake variability during the dietary follow-up period, and the physical activity index scores measured a moderate activity level with a range of scores from 34.6 to 37.7 units.
Table 1. BMI and Waist Circumference at Baseline and Endpoint
|
Baseline |
Endpoint |
P value |
BMI (kg/m2) |
25.6 |
28.3 |
P < 0.0001 |
Female waist circumference (inches) |
32.4 |
38.9 |
P < 0.0001 |
Male waist circumference (inches) |
38.5 |
41.4 |
P < 0.0001 |
Primary Outcome. There were 787 confirmed obesity-related cancers identified: 136 colorectal cancers, 219 prostate cancers, and 217 breast cancer.
Participants who had IFG detected 10-20 years and 20 + years had an increased risk (44% and 57%, respectively) of obesity-related cancers when adjusted for age and other covariates (see Table 2). There was no significance found for impaired fasting glucose (IFG) exposure 5-10 years prior to a cancer diagnosis even though the hazard ratio (HR) was > 1 (see Table 2).
Table 2. Risk of Obesity-Related Cancers and IFG Exposure Time
Time from IFG |
Risk % |
Adjusted HR |
|
5-10 years |
|
1.13 (0.91-1.41) |
Not significant |
10-20 years |
44% |
1.44 (1.15-1.79) |
|
20+ years |
57% |
1.57 (1.17-2.11) |
|
Ptrend |
|
0.1477 |
|
Compared to individuals without IFG, there was a 27% higher risk of developing obesity-related cancer among participants with IFG (HR, 1.27; 95% confidence interval [CI], 1.06-1.53) after adjusting for age, sex, alcohol, smoking, and BMI.
Homeostatic model assessment-insulin resistance (HOMA-IR), first reported in 1985, assesses insulin sensitivity and ß-cell function. A 45% increase in risk of obesity-related cancers was noted with a HOMA-IR score of > 2.6 (HR, 1.45; CI, 1.18-1.78).
There was a 54% increased risk of developing obesity-related cancers among persons within the highest vs the lowest category of HbA1c levels (CI, 1.13-2.1). A 47% increased risk of obesity-related cancers among participants within the highest (≥ 9.94 pmol/L) compared to the lowest (< 4.94 pmol/L) group of blood insulin concentrations was also found (CI, 1.15-1.88).
Many participants quit smoking, which was indicated by the increase in the number of past smokers over time (20.2-51.3%; P < 0.0001). There was an increased risk of obesity-related cancers among past or current smokers who also had higher glucose concentrations (HR, 1.41; CI, 1.13-1.76).
Specific Obesity-Related Cancers. There was a significant increased risk for developing colorectal cancer with the increased IFG exposure time (Ptrend = 0.0196). Participants who were exposed to IFG for more than 20 years had a risk estimate over 3. No significant association between IFG exposure time and risk of breast or prostate cancer were found.
An increased risk of colon cancer that was more than two-fold was found when participants had higher concentrations of the glucose metabolism biomarkers but not higher waist circumference.
The authors also point out that there was a trend of increased risk of breast cancer with all of the glucose metabolism biomarkers, with HRs ranging from 1.23-1.95, but not with waist circumference. A nonsignificant HR for developing prostate cancer that ranged from 1.10-1.52 was also reported.
Commentary
This study has demonstrated that IFG time exposure increases the risk of obesity-related cancers, particularly colorectal cancer. This study is unique in that the researchers were able to also investigate the time variable in relation to IFG and the association to obesity-related cancers. This research study had a number of strengths and a few weaknesses. The strengths of this study are the large participant group, of which 50% were female, and a 37-year follow-up period with exams occurring approximately every 4 years. The diagnosis of cancer was provided by the participant’s doctor and confirmed with the pathology reports in most cases. There were also dietary, medication, anthropometric, physical activity, and demographic data that allowed the researchers to control for variables that are known risk factors of cancer.
The limitations of this study include the lack of generalizability to other ethnicities, as the population was 99% Caucasian. Also, family medical history of cancer was not available and is a known risk factor. Another issue with this study that the authors point out is with the risk of prostate cancer in men with IFG. The authors mention that they believe the lack of an association between IFG and the risk of prostate cancer may be underestimated due to decreased rate of diagnosis in this population. The authors make the argument that prostate-specific antigen concentrations may be decreased in men who are obese and have glucose abnormalities leading to a lack of follow-up prostate biopsies.
Obesity has reached epidemic proportions in the United States.2,4 Recently, the American Medical Association categorized obesity as a disease and with this recognition it is believed it will be treated as a disease. Obesity is a multifactorial disease that must be addressed on a number of levels including the mental, emotional, and physical health of an individual. The best treatment for obesity is through diet and lifestyle modifications, which are preventive measures. This study demonstrates the important connections between IFG and obesity-related cancers. More research needs to be performed to understand the best way to recommend and follow up with diet and lifestyle recommendations so that patients are able to implement them successfully and reduce obesity and fasting glucose levels.
References
1. 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.
2. Garg SK, et al. Diabetes and cancer: Two diseases with obesity as a common risk factor. Diabetes Obes Metab 2014;16:97-110.
3. World Health Organization/IDF Consultation. Definition and Diagnosis of Diabetes Mellitus and Intermediate Hyperglycemia. Geneva; 2006.
4. Haslam DW, James WP. Obesity. Lancet 2005;366:1197-1209.
- Individuals with impaired fasting glucose (IFG) had a 27% higher risk of developing obesity-related cancers compared to those who did not have IFG.
- A 44% increased risk of obesity-related cancer in participants who had IFG detected 10-20 years prior was observed. This risk increased to 57% for participants who had IFG detected > 20 years prior.
- A risk estimate for colorectal cancer > 3 was observed in participants who were exposed to IFG for more than 20 years.
