Zucker Diabetic Fatty Rat as a Model for Non-insulin-dependent Diabetes Mellitus

Abstract

A number of animal models for non-insulin-dependent diabetes mellitus (NIDDM) have been described over the years. These include common laboratory animals such as mice (Coleman, 1982a), rats (Greenhouse et al., 1988; Peterson et al., 1988a,b), other rodents (Coleman, 1982b), dogs (Engerman and Kramer, 1982), as well as more unusual animals such as Chinese hamsters (Gerritson, 1982), swine (Phillips et al., 1982), and nonhuman pri- mates (Howard, 1982). No single model can answer all the research questions related to a disease being investi- gated; however, models that resemble the disease under study in onset, course, and symptoms do have a very significant role. Two frequently used mouse models for NIDDM are the models containing the db and ob genes (Coleman, 1982a). These genes have been placed in several inbred strains, the result being a number of variations in the severity of diabetes (Coleman, 1982a). Rat models for NIDDM have been developed more recently using strains primarily involving the fa and the cp genes. The fa gene was first described in the Zucker rat (Zucker and Zucker, 1961), and the cp gene appeared spontaneously in a colony pro- duced as a result of a cross between the SHR/N strain and the SD rat (Koletsky, 1973). These genes have been maintained and backcrossed into a number of strains (Greenhouse et al., 1988; Peterson et al., 1988a). Again, variations of the level of diabetes are evident. To date, the model that appears to be most consistently diabetic is the male Wistar diabetic fatty (WDF) rat (Ikeda et al., 1981; Peterson et al., 1988a). Most of these rat models can be described as having a moderate degree of hyperglycemia. As a general rule, Zucker fatty rats have not displayed hyperglycemia when fed ad libitum (Bray, 1977; Herberg Richard G. Peterson is professor of anatomy at Indiana University School of Medicine, Indianapolis. Walter N. Shaw is a senior research scientist at Lilly Research Laboratories, Indianapolis. Mary-Ann Neel is a senior research technician and Leah A. Little is a research techni- cian; they carried out all breeding and animal care protocols. J. Eichberg is professor of biochemical and biophysical science, University of Houston, Texas. This project was partially supported by PHS Grant RO1DK30577. Address all correspondence to Richard G. Peterson at 635 Barnhill Dr. MS 258, Indianapolis, IN 46202-5120. 16 and Coleman, 1977), although they have demonstrated a reduced glucose tolerance and other indications of insu- lin resistance (Rohner-Jeanrenaud et al., 1986). Several years ago, an unusually high level of blood glucose and intolerance to glucose were observed in a few animals in the colony of Zucker rats from which the rats described in this paper were originally derived (Clark and Palmer, 1981, 1982; Clark et al., 1983). Although this trait was difficult to follow in the intervening years, it continued to appear in a number of fatty male rats. About three years ago, we began selectively inbreeding for this trait and have been successful in maintaining a very high level of hyperglycemia in fatty male rats for the last eight generations. This paper describes the characteristics of the resulting model. Diabetic fatty rats and lean rats with a high degree of diabetes in their background were initially chosen for breeding. Male fatty-diabetic breeders were used at each generation when available. Inbreeding has continued for 10 generations. In all but one instance in which the mat- ing was parent x offspring, inbreeding was by brother x sister mating. As a result of this inbreeding, every fatty male rat has been very hyperglycemic and has remained diabetic for as long as they have been followed (up to 42 weeks). The phenotype has been consistently expressed since the F2 generation. Fed hyperglycemia (blood glu- cose >175 mg percent) was observed in most fatty male rats at 7 weeks of age. All fatty male rats were above 200 mg percent by 9 weeks of age, and by 10 weeks the average level was above 400 mg percent. The average blood glucose levels then gradually increased to above 500 mg percent where they remained for the life of the rat. HbAl, free fatty acids, triglycerides, and cholesterol levels were also significantly higher than control. This partially inbred strain is being referred to as Zucker dia- betic fatty (ZDF/Drt-/a) and appears to be a very good model for NIDDM. Materials