Effects of hyperinsulinemia, insulin sensitivity, and other factors associated with the insulin resistance syndrome on colorectal epithelial proliferation and carcinogenesis in rats

The similar lifestyle risk factors for the development of colorectal cancer (CRC) and the insulin resistance syndrome, as noted by McKeown-Eyssen and Giovannucci, suggests common underlying pathogenic mechanisms. The hypothesis is: high levels of circulating insulin, glucose, non-esterified fatty acids (NEFA), and/or triglycerides, associated with insulin resistance, increase colorectal epithelial proliferation and promote carcinogenesis. This hypothesis was tested in three animal studies. (1) Carcinogen (azoxymethane)-initiated rats were given subcutaneous injections of insulin or saline. The number of colorectal tumours was increased in rats receiving insulin. (2) Initiated rats were fed diets containing a range of saturated fat as beef tallow. Insulin sensitivity was assessed directly with the hyperinsulinemic-euglycemic clamp, and indirectly with fasting and post-glucose load levels. Tumor promotion was assessed by multiplicity of aberrant crypt foci (ACF). Promotion was associated with direct measures of insulin sensitivity and post-load insulin levels. (3) Normal rats received intravenous infusions of insulin, glucose, and/or Intralipid. Insulin, alone or with Intralipid, increased proliferation. An integrative summary follows. (1) Studies investigating hyperinsulinemia demonstrated that: (i) injections of insulin promoted colorectal tumors; (ii) post-load insulin levels were correlated with multiplicity of ACF; and (iii) intravenous infusion of insulin increased proliferation. Thus, insulin appears to be a growth factor for colorectal epithelial cells in rats. (2) Hyperglycemia, as assessed by fasting and post-load levels or induced during intravenous infusions with insulin, did not appear to be important in proliferation or carcinogenesis. (3) Studies examining hyperlipidemia showed no association between ACF and fasting lipid levels, and no effect on proliferation after Intralipid infusion. However, lipids may indirectly affect proliferation and carcinogenesis through hyperinsulinemia and insulin resistance. (4) Insulin sensitivity, as assessed directly with a hyperinsulinemic-euglycemic clamp, and indirectly by post-load insulin levels, was associated with multiplicity of ACF. In conclusion, these results add biological plausibility to the hypothesis that hyperinsulinemia and insulin resistance may lead to increased colorectal epithelial proliferation and promotion of colorectal carcinogenesis.