Cancer susceptibility in two rat models of spontaneous diabetes

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Recent epidemiological data suggest that type 2 diabetes is a risk factor of total cancer including colorectal cancer. We found that whole body X-irradiation accelerated the onset of diabetes and decreased plasma insulin level both in Long-Evans Agouti (LEA) and Otsuka Long-Evans Tokushima Fatty (OLETF) rats, animal models of diabetes. In the present study, we examined X-irradiation and N-methyl-N-nitrosourea (MNU)-induced cancer susceptibilities in diabetes-prone rats, LEA and OLETF strains. Six-week-old male F344, Long-Evans Cinnamon (LEC), LEA, Long-evans Tokushima Otsuka (LETO) and OLETF rats (n=15) were whole body X-irradiated (2 or 4 Gy) and killed at 72 weeks. Next. Male F344, LEC and LEA (n=21) were i.p. injected 50 mg/kg MNU at 6, 8, 10 and 12 weeks and killed at 32 weeks. Incidences of small intestine tumors (adenocarcinoma) in 2 Gy-irradiated F344, LEC and LEA rats were 0%, 0% and 7%, respectively, and those of cecum/colon tumors were 0%, 7% and 14%, respectively. Incidences of small intestine tumors in 4 Gy-irradiated F344 and LEC rats were 7%, respectively, and those of cecum/colon tumors were 0% and 14%, respectively. Most of the 4 Gy-irradiated LEA rats died of diabetes by 20 weeks. Incidences of small intestine tumors in 4 Gy-irradiated LETO and OLETF rats were 0% and 30%, respectively, and no cecum/colon tumors developed in both strains. Incidences of small intestine tumors in MNU-induced F344, LEC and LEA rats were 14%, 0% and 38% (P<0.01, versus LEC), respectively. Those in cecum/colon tumors were 10%, 47% (P<0.01, versus F344) and 24%, respectively. High susceptibility of cecum/colon carcinogenesis in LEC rats depends on spontaneous and X-irradiation-induced colitis in this strain (data not shown). These data suggest that diabetic rats are susceptible to small intestine carcinogenesis. Our recent study demonstrated that one of the quantitative trait loci responsible for X-irradiation-induced hyperglycemia in LEA rats was mapped near D20Mgh4 region on chromosome 20 (LOD score=4.1). Further experiments using non-diabetic congenic strains are necessary to confirm the present data.