Few studies have been done to examine gender differences in diabetic mouse models. Here we examined a gender difference in Inducible cAMP Early Repressor (ICER) transgenic (Tg) mice, a diabetic mouse model. Longitudinal changes in diabetes and nephropathy were investigated in male and female Tg mice. Both male and female Tg mice developed severe diabetes early in life due to severely impaired insulin synthesis and decreased beta-cell numbers, but only female Tg mice became less hyperglycemic later in life, and most female Tg mice did not develop diabetic nephropathy. Even some female Tg mice that remained hyperglycemic showed less renal expansion than age-matched male Tg mice. Thus the gender difference in the severity of diabetes and diabetic nephropathy was evident with age in this model. This study indicates that sex hormones may play a role in glucose metabolism in diabetic conditions.