A prospective study of C-peptide, insulin-like growth factor-1, insulin-like growth factor binding protein-1, and the risk of colorectal cancer in women

Hyperinsulinemia, hyperglycemia, and elevated insulin-like growth factor (IGF)-1 levels have been implicated in the etiology of colorectal cancer. However, the joint effects of insulin and IGF-1 have not been considered, and whether hyperinsulinemia or hyperglycemia is more etiologically relevant is unclear. IGF binding protein-1 (IGFBP-1) has been hypothesized to mediate the effects of insulin, but epidemiologic data on IGFBP-1 are sparse. We conducted a nested case-control study among the 32,826 women of the Nurses' Health Study who provided a blood sample in 1989 to 1990. After excluding diabetics, we confirmed 182 incident colorectal cancer cases over 10 years of follow-up and 350 controls. Cases were matched to two controls on year of birth, date of blood draw, and fasting status. C-peptide levels were weakly associated with risk of colon cancer [top quartile (Q4) versus bottom quartile (Q1): multivariable relative risk (MVRR), 1.76; 95% confidence interval (95% CI), 0.85-3.63]. Fasting IGFBP-1 was inversely associated with risk of colon cancer (MVRR, 0.28; 95% CI, 0.11-0.75). We observed no clear association between glycosylated hemoglobin and risk for colorectal cancer. The IGF-1 to IGFBP-3 molar ratio was associated with colon cancer risk (MVRR, 2.82; 95% CI, 1.35-5.88), and women with low levels of both IGF-I/IGFBP-3 and C-peptide (or high IGFBP-1) were at low risk, and elevation of either was sufficient to increase risk. Although altering IGF-1 levels may not be practical, the growing burden of obesity and consequently hyperinsulinemia, which seems increasingly important for colon cancer, may be a target for effective prevention.