McKeown-Eyssen and Giovannucci have proposed a mechanism for colon carcinogenesis based on the similarity of the risk factors for colorectal cancer and non-insulin-dependent diabetes. They note that diets high in fat and energy and low in complex carbohydrates and a sedentary lifestyle lead to insulin resistance and hyperinsulinemia and propose that the hyperinsulinemia promotes colon carcinogenesis. In this study, we directly tested for a promoting effect of insulin on colon carcinogenesis in F344 rats. After azoxymethane initiation and injections of insulin given 5 times/week for 17 weeks, the fraction of rats with colon tumors was greater in rats receiving insulin than in rats receiving saline (79 versus 50%, respectively; P < 0.05 for tumors with maximum diameters > or = 2 mm), and the average number of tumors/ rat was also greater (2.00 versus 0.73; P < 0.001). There was no effect on body weight. Our results demonstrate that insulin in a colon tumor promoter in this rat model and support the proposed mechanism linking lifestyle factors and colon carcinogenesis.