INSULIN-RESISTANCE AND PROMOTION OF ABERRANT CRYPT FOCI IN THE COLONSOF RATS ON A HIGH-FAT DIET

McKeown-Eyssen and Giovannucci recently proposed that the etiology of insulin resistance (IR) and colorectal cancer (CRC) are related. They suggested that diets high in fat and energy and low in complex carbohy drates and a sedentary life-style lead to IR and that the associated h yperinsulinemia, hypertriglyceridemia, and glycemia lead to increased CRC risk through the growth-promoting effect of insulin or the increas ed availability of energy. We reasoned that if diet affects colon carc inogenesis through its effect on IR, evidence of colon cancer promotio n would be preceded by evidence of IR. To test this expectation, we co mpared the effects of a high-fat (HF, 59% energy) diet and a low-fat ( LF, 11% energy) diet on indirect measures of IR and promotion in azoxy methane-initiated F344 rats. Promotion was assessed as growth of aberr ant crypt foci (ACF) at 100 days after initiation. The HF diet increas ed ACF size 1.4 times (95% confidence interval = 1.30-1.58) that of th e LF diet. The HF diet also led to impaired oral glucose tolerance tes ts measured at 4, 32, 60, and 88 days and characterized by an average increased glucose concentration of 0.78 +/- 0.17 mmol/l (p < 0.001). I t also resulted in an impaired intravenous glucose tolerance test and elevated levels of serum insulin after a glucose gavage. We concluded that with this model a high-fat diet leads to evidence of IR before is is possible to demonstrate CRC promotion, thus providing support, nec essary but not sufficient, for the causal hypothesis linking IR and CR C. Possible mechanisms linking diet, IR, and promotion are considered.