Liver-specific IGF-I gene deficient (LID) mice exhibit pancreatic islet hyperplasia and insulin resistance. To clarify their causal relationship, we studied age-dependent changes in these two aspects and the response to beta-cell damage caused by streptozotocin in adult mice. As a result, the onset of insulin resistance in LID mice was detectable as early as 1-month of age, while hyperinsulinemia was developed after a significant delay at 2.5-month. Upon streptozotocin administration, control mice exhibited significant hyperglycemia after 9 days, and glucose levels continued to rise at 12-15 days. LID mice developed diabetes much more rapidly, with hyperglycemia after 6 days and higher glucose levels up to 15 days. They also exhibited significant weight loss and 6/19 died. Serum insulin assay, insulin mRNA analysis and immunohistochemistry revealed that the more severe diabetes in LID mice was not due to more damage to their beta-cells. Thus LID mice are more sensitive to streptozotocin-induced beta-cell damage, due to a primary defect in insulin responsiveness. The pancreatic islet hyperplasia observed in these mice seems to represent a compensatory response to insulin resistance, therefore, offers no protection against beta-cell damage.