Enhanced tumorigenesis of forestomach tumors induced by N‐Methyl‐N′‐nitro‐N‐nitrosoguanidine in rats with hypoinsulinemic diabetes

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.