The results of this study show that exogenous insulin leads to increased food intake, higher body weight and more abdominal fat, increased levels of plasma insulin and triglycerides, and reduced levels of plasma glucose. Insulin also increased the growth of aberrant crypt foci, with more crypts per ACF, and more large ACF per colon in insulin treated rats than in controls. Thus, insulin injections promoted colon carcinogenesis in this model. We also observed more sialomucin producing ACF in insulin treated rats than in controls. This might either suggest a more advanced phenotype (22
), or simply reflect the increased size of ACF.
A recent report by Tran et al. also shows that insulin is a colon tumor promoter in rats (24
). After azoxymethane initiation and daily injections of insulin, the fraction of rats with colon adenomatous polyps was greater in rats receiving insulin than in rats receiving saline (79% vs. 50% respectively, p<0.05). The number of tumors per rat was also greater in the insulin group (2.0 vs. 0.7, p<0.05). Insulin did not increase body weight gain (24
). Design differences between Tran’s study and this one may explain the discrepancies in body weight gain and tumor outcome. Tran et al. used male rats (vs. female here), starting at 240 g body weight (vs. 85 g), fed an AIN93M diet (vs. rodent chow), given medium-acting porcine insulin (vs. long-action bovine) at 15 U/kg for 132 days (vs. 20 U/kg for 100 d), after two 15 mg/kg azoxymethane injections (vs. a single dose 20 mg/kg), with a light cycle shifted 6 h earlier than daylight (24
). It is surprising that in Tran et al. study the insulin did not increase body weight, but it may be explained by differences in starting weight, gender, diet and insulin quickness. Although both studies show a significant promotion of carcinogenesis by insulin, at first glance the magnitude of effect appears smaller in the present study. However the crypt multiplicity increased here by a 1.11 factor, which may be compared to the 1.20 increase published by Zhang et al. (17
) and Magnuson et al. (19
). According to their data, the diets that increase the crypt multiplicity by 1.2 at 100 d also increase the adenocarcinoma incidence by 3 later (17
). This increase is higher than the 1.6 increased tumor incidence observed by Tran (24
). Thus, the promotion potency of insulin in both studies may be similar.
Previous reports show that insulin is a growth factor for rats and for tumors. Daily insulin injections (25 U/kg for 28 d) increase body weight, fat tissue weight, and fat cell size in female rats (25
). Daily insulin injections to hypophysectomized rats enable the growth of liver tumors, initiated by dietary methyldimethyl-aminobenzene (26
). Conversely, diabetes induced by alloxan in female rats previously initiated with dimethylbenzenthra- dimethylbenzenthracene produces the rapid regression of 90% of established mammary tumors. These tumors were shown to be insulin dependent in vitro (27
Exogenous insulin may promote tumor growth by at least three mechanisms.
- - First, exogenous insulin increases food intake and weight gain. Overfeeding and overweight increase, and caloric restriction decreases, carcinogenesis in many studies (28). Overfeeding modifies the hormonal balance and increases the energy available through the circulation for neoplastic cells.
- - Second, exogenous insulin leads to hyperinsulinemia, which may directly promote tumor growth (27), for instance by easing the uptake of nutrients by tumor cells.
- - Last, insulin may modify other blood-borne factor(s), for instance the insulin-like growth factor IGF1. Most colon cell lines have receptors for IGF1, and high fat diets induce both insulin and IGF1 resistance in rats (29).
A study in pair-fed rats receiving exogenous insulin, but as many calories as controls, might tell if hyperinsulinemia by itself can promote tumors. In human beings, however, hyperinsulinemia is always associated with hyperphagia.
Diets high in calories, fat, sucrose, fructose, amylopectin starch, and low in fibers, resistant starch and n-3 unsaturated lipids, favor the insulin resistance syndrome in rodents. These diets increase blood insulin, and lead to abdominal fat store, obesity, and non-insulinodependant diabetes in many animal models (30
), and probably in humans too (34
). These same diets are also known to promote experimental carcinogenesis in rodents, and are considered risk factors for colorectal cancer in human populations (5
). It is usually considered that bile acids in the fecal stream can explain the promoting effect of these diets on colon cancer, but blood insulin may also explain the promotion by these diets (4
). The present results support the idea that in humans, hyperinsulinemia and/or insulin resistance may explain the high risk of colorectal cancer associated with sedentary lifestyle, overfeeding, and nutriments cited above (4
This study is the second to show a promotion of colon carcinogenesis by exogenous insulin. If nutritional studies, in progress in our laboratory, also show the promoting effect of endogenous insulin, it will be necessary to study the protection afforded by interventions that reduce insulinemia in humans.