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

The incidence of non-insulin-dependent diabetes mellitus in a model ra t (Otsuka-Long-Evans-Tokushima Fatty [OLETF]) has been shown to be muc h higher in males than in females. To evaluate the role of sex hormone s in the development of diabetes in this model, we performed biochemic al and morphological studies on the effects of castration and sex horm ones on the development of non-insulin-dependent diabetes mellitus in these rats. The rats were randomly assigned to six groups of 10 rats e ach, three groups of males and three of females. Two of the mate group s and two of the female groups were castrated at 5 weeks of age, and t he third male and female groups received sham operations. From 9 to 30 weeks of age, one group of castrated males received testosterone enan thate (1 mg . wk(-1)) and one group of castrated females received estr adiol valerate (1 mg . wk(-1)). The other castrated groups received an equal volume of vehicle only. At 30 weeks of age, the cumulative inci dences of diabetes mellitus in the sham-operated male and female rats were 100% and 0%, respectively. Orchiectomy reduced the incidence of d iabetes to 20%, whereas ovariectomy increased it to 30%. Administratio n of sex hormones restored the incidence to 89% in males and 0% in fem ales. In vivo insulin-stimulated glucose uptake as measured with a eug lycemic clamp was reduced in sham-operated males, castrated mates with hormone replacement (HR), and castrated females without HR as compare d with sham-operated females and castrated females with HR. Morphologi cal studies on the pancreas of animals in groups showing reduced in vi vo insulin-stimulated glucose uptake showed enlarged multilobulated fi brotic islets, whereas sections of islets from sham-operated females a nd castrated females with HR appeared normal. These results demonstrat e that glucose intolerance associated with morphological changes of is lets in OLETF rats is closely related to insulin insensitivity, and th at sex hormones are directly or indirectly responsible for this condit ion. Copyright (C) 1994 by W.B. Saunders Company