Effect of elevated basal insulin on cancer incidence and mortality in cancer incident patients: the Israel GOH 29-year follow-up study

OBJECTIVE

Diabetes is associated with many forms of cancer. Recent evidence has suggested that some treatments for diabetes are associated with an increased cancer risk. Less is known about the association between endogenous insulin in the prediabetes state and cancer risk.

RESEARCH DESIGN AND METHODS

We investigated cumulative cancer incidence and cancer incidence density over 29 years, according to basal insulin, in a cohort of 1,695 nondiabetic men and women of four ethnic origins, aged 51.8 ± 8.0 years at baseline. Total mortality among the 317 subjects (18.7%) who developed cancer at least 2 years after baseline was assessed.

RESULTS

In a Cox proportional hazards model, the all-site hazard ratio of cancer incidence comparing the highest insulin quartile with the other three quartiles was 1.09 (95% CI 0.85–1.40), adjusted for age, sex, and ethnicity. BMI, smoking, and fasting blood glucose were not statistically significant in this model. Basal insulin level was not significantly associated with cancer of specific sites (breast, prostate, colon/rectum, or bladder). Fasting insulin in the upper quartile conferred a 37% increased risk for total mortality among cancer patients, adjusting for age, sex, and ethnic origin (95% CI 0.94–2.00, P = 0.097) compared with that of the lower quartiles. Male sex, older age, and North African origins were associated with a greater risk of mortality during follow-up time.

CONCLUSIONS

This long-term cohort study may suggest a role for basal elevated insulin levels, mainly as a negative predictor in cancer prognosis.The American Diabetes Association and the American Cancer Society recently issued a consensus report showing cancer incidence to be associated with diabetes (1). Type 2 diabetes has been associated with increased incidence, in the range of 1.2–2.5 of cancers of the pancreas (2), breast (3), colon (4), and bladder (5). In addition, a recent meta-analysis of 23 studies found diabetes to be associated with an increased mortality hazard ratio (HR) of 1.41 (95% CI 1.28–1.55) among individuals with cancer (6). Furthermore, some treatments for diabetes have been implicated in increasing the risk of malignancy (7). The development of some types of insulin has been discontinued secondary to increased mitogenic side effects (8). The affinity of binding to the IGF-1 receptor (IGF-1R) has been implicated.We and others have shown basal hyperinsulinemia to predict type 2 diabetes (9,10). Further, elevated levels of circulating insulin and C-peptide have been associated with an increased risk of colorectal and pancreatic cancers (11). Though the risk of breast cancer was less certain in the latter study, two recent analyses of the Women''s Health Initiative found a positive association between insulin levels and breast cancer (12,13).Studies in animals (14–17) and in vitro (18,19) suggest a role for insulin in tumor progression. Glucose tolerance status from 2-h glucose tolerance tests has been shown to associate with the risk of cancer mortality (4). However, the effect of elevated basal insulin on cancer prognosis has not been investigated in vivo.The current study examined the effect, up to 29 years later (mean follow-up time 21.7 ± 6.5 years), of elevated levels of basal insulin on the cumulative incidence of cancer and on cancer survival in a cohort of the Jewish population, representing the four main ethnic origins of immigration to Israel.