A Novel Rat Model of Type 2 Diabetes: The Zucker Fatty Diabetes Mellitus ZFDM Rat

Abstract

The Zucker fatty (ZF) rat harboring a missense mutation (fatty, fa) in the leptin receptor gene (Lepr) develops obesity without diabetes; Zucker diabetic fatty (ZDF) rats derived from the ZF strain exhibit obesity with diabetes and are widely used for research on type 2 diabetes (T2D). Here we establish a novel diabetic strain derived from normoglycemic ZF rats. In our ZF rat colony, we incidentally foundfa/fahomozygous male rats having reproductive ability, which is generally absent in these animals. During maintenance of this strain by matingfa/famales andfa/+heterozygous females, we further identifiedfa/famale rats exhibiting diabetes. We then performed selective breeding using thefa/famale rats that exhibited relatively high blood glucose levels at 10 weeks of age, resulting in establishment of a diabetic strain that we designated Hos:ZFDM-Leprfa(ZFDM). Thesefa/famale rats developed diabetes as early as 10 weeks of age, reaching 100% incidence by 21 weeks of age, while none of thefa/+male rats developed diabetes. The phenotypic characteristics of this diabetic strain are distinct from those of normoglycemic ZF rats. ZFDM rat strain having high reproductive efficiency should serve as a more useful animal model of T2D.