Metabolic dysregulation of the insulin-glucose axis and risk of obesity-related cancers in the Framingham heart study-offspring cohort (1971-2008).
BACKGROUND
Obesity-related dysregulation of the insulin-glucose axis is hypothesized in carcinogenesis. We studied impaired fasting glucose (IFG) and other markers of insulin-glucose metabolism in the Framingham Heart Study-Offspring Cohort, which uniquely tracks these markers and cancer >37 years.


METHODS
Participants were recruited between 1971 and 1975 and followed until 2008 (n = 4,615; mean age 66.8 years in 2008). Serum glucose, insulin, and hemoglobin A1c were determined from fasting blood in quart-annual exams. Lifestyle and demographic information was self-reported. HRs and 95% confidence intervals (CI) of cancer risk were computed using time-dependent survival analysis (SASv9.3), while accounting for temporal changes for relevant variables.


RESULTS
We identified 787 obesity-related cancers, including 136 colorectal, 217 breast, and 219 prostate cancers. Absence versus presence of IFG 10 to 20 years and 20+ years before the event or last follow-up was associated with 44% (95% CI, 1.15-1.79) and 57% (95% CI, 1.17-2.11) increased risk of obesity-related cancers, respectively. When time-dependent variables were used, after adjusting for age, sex, smoking, alcohol, and body mass index, IFG was associated with a 27% increased risk of obesity-related cancer (HR = 1.27; CI, 1.1-1.5). Associations were stronger in smokers (HR = 1.41; CI, 1.13-1.76). Increased risk was noted among persons with higher insulin (HR = 1.47; CI, 1.15-1.88) and hemoglobin A1c (HR = 1.54; CI, 1.13-2.10) for the highest (≥ 5.73%) versus lowest (≤ 5.25%) category. A >2-fold increase in colorectal cancer risk was observed for all blood biomarkers of insulin-glucose metabolism, particularly with earlier IFG exposure. Nonsignificant increased risk of breast and prostate cancer was observed for blood biomarkers.


CONCLUSIONS
Earlier IFG exposure (>10 years before) increased obesity-related cancer risk, particularly for colorectal cancer.


CONCLUSIONS
Our study explicitly recognizes the importance of prolonged IFG exposure in identifying links between glucose dysregulation and obesity-related cancers.
Authors' Affiliations: Nutrition, Food Studies, and Public Health, Steinhardt School, New York University; Population Health, Langone School of Medicine, New York University, New York, New York; Biostatistics, School of Public Health, Rutgers University; Medicine, Rutgers University-Robert Wood Johnson Medical School, Piscataway; and Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
Niyati
N
Parekh
Yong
Y
Lin
Maya
M
Vadiveloo
Richard B
RB
Hayes
Grace L
GL
Lu-Yao
D000368:Aged; D001786:Blood Glucose / Q000378:metabolism*; D015992:Body Mass Index; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D008297:Male; D053858:Metabolic Networks and Pathways; D009369:Neoplasms / Q000097:blood / Q000453:epidemiology / Q000378:metabolism*; D009765:Obesity / Q000453:epidemiology / Q000378:metabolism*; D015995:Prevalence; D011446:Prospective Studies; D012307:Risk Factors; D016896:Treatment Outcome; D014481:United States / Q000453:epidemiology
D001786:Blood Glucose; D007328:Insulin