Effects of obesity and inheritance on the development of non-insulin-dependent diabetes mellitus in Otsuka-Long-Evans-Tokushima fatty rats

Abstract

We studied whether obesity or inheritance was the more important factor in the development of non-insulin-dependent diabetes mellitus (NIDDM) using female Otsuka-Long-Evans-Tokushima Fatty rats (OLETF) possessing one of the diabetic genes, ODB-1, and male Long-Evans-Tokushima-Otsuka rats (LETO) possessing no ODB-1, neither of which were diabetic when bred normally. Diabetes-resistant male LETO rats and female OLETF rats (4 weeks old) were assigned to three groups of 6 rats each, respectively; two groups in which obesity was induced by high calorie 'cafeteria' diet (D), or ventromedial hypothalamus lesions (V) with normal chow diet and a control group fed on normal chow (C). Six male OLETF rats were used as NIDDM positive controls. The mean daily energy intakes of obese male LETO and female OLETF rats were higher than those of the respective C groups. At 27 weeks of age, the average body weights of the obese LETO and female OLETF rats were significantly higher than those of the respective C groups and similar to that of the male OLETF group. Abdominal fat deposits of the obese groups were significantly higher than those of the respective C groups. At 28 weeks of age, the cumulative incidence of diabetes mellitus in obese LETO rats was 0% in group D and 17% in group V, while that of obese female OLETF rats in groups D and V were 100%. At 29 weeks of age, the plasma immunoreactive insulin (IRI) responses to glucose in obese female OLETF rats, groups D and V, were higher than that in group C. In obese LETO rats, insulin-stimulated glucose disposal in vivo was similar to that in group C, but in obese female OLETF rats, it was reduced to 41% in group D and 37% in group V of that in group C. Sections of islets of the pancreas of obese LETO rats appeared histologically normal, whereas those of obese female OLETF rats showed enlarged multilobulated fibrotic islets. These results demonstrate that obesity is necessary, but not sufficient alone for the development of NIDDM in these rat models.