Sexual difference in the incidence of diabetes mellitus in Otsuka-Long-Evans-Tokushima-Fatty rats: Effects of castration and sex hormone replacement on its incidence

Abstract

The incidence of non-insulin-dependent diabetes mellitus in a model rat (Otsuka-Long-Evans-Tokushima Fatty [OLETF]) has been shown to be much higher in males than in females. To evaluate the role of sex hormones in the development of diabetes in this model, we performed biochemical and morphological studies on the effects of castration and sex hormones on the development of non-insulin-dependent diabetes mellitus in these rats. The rats were randomly assigned to six groups of 10 rats each, three groups of males and three of females. Two of the male groups and two of the female groups were castrated at 5 weeks of age, and the third male and female groups received sham operations. From 9 to 30 weeks of age, one group of castrated males received testosterone enanthate (1 mg · wk −1) and one group of castrated females received estradiol valerate (1 mg · wk −1). The other castrated groups received an equal volume of vehicle only. At 30 weeks of age, the cumulative incidences of diabetes mellitus in the sham-operated male and female rats were 100% and 0%, respectively. Orchiectomy reduced the incidence of diabetes to 20%, whereas ovariectomy increased it to 30%. Administration of sex hormones restored the incidence to 89% in males and 0% in females. In vivo insulin-stimulated glucose uptake as measured with a euglycemic clamp was reduced in sham-operated males, castrated males with hormone replacement (HR), and castrated females without HR as compared with sham-operated females and castrated females with HR. Morphological studies on the pancreas of animals in groups showing reduced in vivo insulin-stimulated glucose uptake showed enlarged multilobulated fibrotic islets, whereas sections of islets from sham-operated females and castrated females with HR appeared normal. These results demonstrate that glucose intolerance associated with morphological changes of islets in OLETF rats is closely related to insulin insensitivity, and that sex hormones are directly or indirectly responsible for this condition.