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.