Abstract
Hyperinsulinemia and hyperglycemia in prediabetic and diabetic patients are thought to increase the risk of developing neoplasms because insulin is a growth factor with pre-eminent metabolic but also mitogenic effects. To determine the effect of hypoinsulinemic diabetic conditions on carcinogenesis, we examined N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced forestomach carcinogenesis in hypoinsulinemic diabetic WBN/Kob rats aged about 45 weeks (DM) compared with non-diabetic younger WBN/Kob rats (C1), non-diabetic Wistar rats age-matched to DM (C2), and non-diabetic Wistar rats age-matched to C1 (C3). All rats were treated with MNNG by gavage and were killed at 40 weeks after dosing. Various-sized tumors were disseminated throughout the forestomach of all rats, and the ratio of the area of tumors to the whole forestomach area was 23.3% in the DM group and was higher than in the C1-3 (4.2-14.3%) groups. The incidence of carcinoma was much higher in the DM group (36.8%) than in the C1-3 (7.1-16.7%) groups, and the incidence of papilloma was also significantly higher in the DM group (84.2%) than in the C1-3 (28.5-50.0%) groups. The average thickness of the squamous epithelium in the non-neoplastic mucosa was significantly greater in the DM group (50.8 mum) than in the C1-3 (29.6-37.9 microm) groups. Immunohistochemically, the Ki-67-positive index in the non-tumorous mucosa of the DM group (42.0%) was significantly higher than that of the C1-3 groups (18.8-33.3%). These results suggest that prolonged hyperglycemic conditions without hyperinsulinemia enhance tumorigenesis of MNNG-induced tumors by enhanced proliferative activity of the squamous epithelium in the rat forestomach.