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

Abstract

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 technician; 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. 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 technician; 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. 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 technician; 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. 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 technician; 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. 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 technician; 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. 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 primates ( Howard, 1982 ). No single model can answer all the research questions related to a disease being investigated; 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 produced 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 and Coleman, 1977 ), although they have demonstrated a reduced glucose tolerance and other indications of insulin 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 hyperglycem