In 2005, a Japanese epidemiological study showed that increase in plasma
glucose levels is a risk factor for
gastric cancer. However, no animal model has hitherto shown any association between
diabetes mellitus and
neoplasia in the stomach. Diabetic (db/db) mice have obese and diabetic phenotypes, including
hyperglycemia, because of disruption of the
leptin receptor. In the present study, effects of
hyperglycemia and/or
hyperinsulinemia on the development of proliferative lesions were therefore examined in db/db mice given
N-methyl-N-nitrosourea (MNU). A total of 120 mice were assigned to four groups: Group A, 40 db/db mice with MNU; Group B, 40 + /db mice with MNU; Group C, 30 misty (wild-type) mice with MNU; Group D, 10 db/db mice without MNU. MNU was given at 60 ppm in
drinking water for 20 weeks. Subgroups of animals were sacrificed at weeks 21 and 30 and blood samples were collected to measure
glucose,
insulin,
leptin, and
adiponectin concentrations. The removed stomachs were fixed in
formalin, and embedded in
paraffin for histological examination and immunohistochemistry. At week 30 in Groups A, B, C and D,
hyperplasia was observed in 100, 79, 57, and 0%, and dysplasia in 91, 43, 71, and 0%, respectively.
Adenocarcinomas and
pepsinogen-altered pyloric glands (PAPG), putative preneoplastic lesions, were observed only in Group A, at an incidence of 45%. The serum levels of
insulin and
leptin were also elevated in Group A. Gastric
carcinogenesis by MNU was enhanced in db/db mice, possibly in association with
hyperinsulinemia and hyperleptinemia.