In order to explore the limitations of liver-specific IGF-I gene deficient (LID) model and to further evaluate the role of endocrine IGF-I in early postnatal life as well as in old age, we have studied these mice during the pre-pubertal period (from birth to 3 weeks of age) and when they are 2 years old. During the first 2 weeks of life, IGF-I gene deficiency and the resulting reduction in serum IGF-I levels in LID mice did not reach sufficiently low levels when mice experience the most rapid and GH-independent growth. It suggests that the role of liver-derived IGF-I in pre-pubertal, GH-independent postnatal growth cannot be established. From our previous studies, liver IGF-I mRNA level was abolished in adult LID mice, which causes elevated GH level, insulin resistance, pancreatic islet enlargement and hyperinsulinemia. Interestingly in 2-year-old LID mice, although liver IGF-I mRNA and serum IGF-I levels were still suppressed, serum insulin and GH levels had returned to normal. Compared to same-sex control littermates, aged male LID mice had significantly reduced body weight and fat mass and exhibited normal insulin sensitivity. On the other hand, aged female LID mice exhibit normal weight and marginal resistance to insulin actions. The pancreatic islet percentage (reflecting islet cell mass) was also restored to normal level in aged LID mice. Thus, although the IGF-I gene deficiency is well maintained into old age, the insulin sensitivity, islet enlargement and hyperinsulinemia that occurred in young adult mice have been mostly restored to normal levels, further supporting the age-dependent and sexual dimorphic features of the LID mice.