C-peptide and leptin levels were positively and IGF-I negatively related to higher categories of BMI (p < .0001); whereas c-peptide and leptin were negatively and IGF-I positively related to lower levels of sports/recreational physical activity among breast cancer survivors (p < .05). While the BMI and C-peptide, leptin, and IGF-I associations remained statistically significant even after adjustment for potential confounders including physical activity, the physical activity and C-peptide, leptin, and IGF-I associations became less statistically significant, or nonsignificant in the case of C-peptide, after adjusting for BMI. Our findings imply that BMI explains more of the variation in these hormones and peptides than physical activity.
Our insulin and leptin associations with BMI and physical activity are consistent with studies conducted among healthy women (4
), and the one study conducted among cancer survivors (23
). Published studies in healthy, overweight/obese vs. normal-weight women have reported IGF-I concentrations to be high, normal, or reduced (28
); inconsistent findings have also been observed between physical activity and IGF-I concentrations in studies among healthy women (21
). The observation of higher IGF-I levels with lower BMI and higher physical activity levels implies that IGF-I is regulated by a complex system, most notably IGFBP-3 (1
). Because IGFBP-3 can either suppress IGF-I by blocking its binding to the IGF-I receptor or enhance the action of IGF-I by protecting it from proteolysis and clearance (40
), it is difficult to determine the actual association of IGF-I with obesity and physical activity. Although in vitro studies show both inhibition and potentiation of IGF-I activity (1
), in vivo studies largely support the concept that IGFBP-3 provides a stable serum reservoir of bioactive IGF-I, thereby enhancing its growth-inducing effects (41
). Further, in hyperinsulinemic states such as obesity, insulin inhibits the synthesis of IGFBP-3 and increases free IGF-I (27
). The increase in free IGF-I, in turn, exerts a negative feedback on pituitary growth hormone secretion and causes a decrease in total IGF-I (27
). This mechanism would explain our findings in relation to BMI, physical activity, and IGF-I levels.
In our study, higher levels of IGFBP-3 were associated with higher levels of physical activity, but no association was observed between IGFBP-3 levels and BMI. This physical activity and IGFBP-3 association is intriguing because it may indicate some functional changes in the IGF system and in insulin levels occurring with physical activity independent of body weight or body fat. It is known that exercise training may decrease insulin resistance by a number of mechanisms independent of changes in body fat including increased post-receptor insulin signaling, increased glucose transporter protein and mRNA, decreased release and increased clearance of free fatty acids, increased muscle glucose delivery, and changes in muscle composition favoring increased glucose disposal (42
). This exercise-induced reduction in insulin resistance may lower circulating levels of insulin, which, in turn, may decrease circulating IGF-I levels via increases in insulin-mediated changes in IGFBP-3 concentrations.
In healthy individuals, physical activity may not alter certain hormones that are already at “normal” levels. Thus, in post-hoc analyses we examined whether the associations between physical activity and C-peptide, leptin, and IGFs differed when only women at the upper half of the hormone and peptide distributions were included in the analyses. We also examined these associations in women in the upper half of the BMI distribution, and in women diagnosed with type 2 diabetes. The only difference between physical activity and the hormones/peptide associations when including only women at the upper half of the hormone/peptide distribution was for physical activity and IGF-I where no association was observed compared to a positive association observed in the whole sample of N = 710. Similar associations were observed between physical activity and the hormones/peptides in women at the upper half of the BMI distribution compared to the whole sample. In women diagnosed with type 2 diabetes (n = 69), higher levels of physical activity were associated with lower IGF-I levels. The mean IGF-I levels for < 2.6, 2.6–13.2, and ≥ 13.3 METhr/week of sports/recreational physical activity were 129.0 ± 10.9 ng/mL, 110.5 ± 15.4 ng/mL, and 109.9 ± 12.8 ng/mL), respectively. However, because of small sample sizes, the association was not statistically significant (p for trend = 0.29).
Because IGFs have been associated with estrogen levels (43
), and both IGFs and estrogens are associated with breast cancer risk, we examined associations between BMI and physical activity with IGFs, c-peptide, and leptin levels stratified by menopausal status. In our study, a statistically significant positive association was observed between physical activity and IGFBP-3 levels among premenopausal women, but not postmenopausal women; and, while nonsignificant, a positive association between BMI and IGFBP-3 was observed in premenopausal women, yet a negative association in postmenopausal women. The associations between physical activity and BMI with IGF-I did not differ by menopausal status.
Very little is known about whether differences in BMI, physical activity, and/or the hormones/peptides examined in this analysis contribute to the disparities in breast cancer risk and prognosis between Black and White women (44
). In our study, similar associations were observed between BMI and physical activity with c-peptide, leptin, IGF-I, and IGFBP-3 levels when stratifying by ethnic group. However, Black women were heavier, reported lower physical activity levels, had higher leptin levels, and lower C-peptide levels, IGF-I, and IGFBP-3 levels than non-Hispanic White women and Hispanic women. Other studies have also reported higher BMI and lower physical activity levels among healthy Black women compared to White women (45
). Few studies have examined whether differences exist in insulin, leptin, and IGF levels by ethnic group in healthy women or in cancer patients.
The HEAL Study has several limitations and strengths. While the HEAL Study is a prospective cohort study, this analysis is cross-sectional in design. Another limitation of our study is that we cannot be sure that these findings pertain to all breast cancer survivors because our sample only included women with in situ to Stages IIIA breast cancer living in Los Angeles, Western Washington, and New Mexico. Major strengths of our study are that the HEAL Study is a well-characterized population-based cohort of breast cancer survivors; the quality of the physical activity data was obtained from a reliable and valid 29-item interview-administered questionnaire; we measured body weight and followed standardized blood collection protocols; and we recruited non-Hispanic and Hispanic White and Black women.
In conclusion, there are few modifiable factors known to be associated with breast cancer recurrence and mortality that might provide opportunities for 20 improving prognosis in breast cancer patients. If insulin and BMI, and potentially leptin, are associated with an increased risk of breast cancer recurrence or mortality, then their responsiveness to lifestyle changes are key to novel strategies for improving prognosis. Physical activity is a modifiable behavior with a multitude of health benefits, including most recently a favorable association with breast cancer survival (16
). Increasing physical activity and decreasing body fat may be a reasonable intervention approach towards decreasing breast cancer recurrence and increasing survival.