Serum IGF‐1 Is Insufficient to Restore Skeletal Size in the Total Absence of the Growth Hormone Receptor

ABSTRACT States of growth hormone (GH) resistance, such those observed in Laron dwarf patients, are characterized by mutations in the GH receptor (GHR), decreased serum and tissue IGF‐1 levels, impaired glucose tolerance, and impaired skeletal acquisition. IGF‐1 replacement therapy in such patients increases growth velocity but does not normalize growth. Herein we combined the GH‐resistant (GHR knockout [GHRKO]) mouse model with mice expressing the hepatic Igf‐1 transgene (HIT) to generate the GHRKO‐HIT mouse model. In GHRKO‐HIT mice, serum IGF‐1 levels were restored via transgenic expression of Igf‐1, allowing us to study how endocrine IGF‐1 affects growth, metabolic homeostasis, and skeletal integrity. We show that in a GH‐resistant state, normalization of serum IGF‐1 improved body adiposity and restored glucose tolerance but was insufficient to support normal skeletal growth, resulting in an osteopenic skeletal phenotype. The inability of serum IGF‐1 to restore skeletal integrity in the total absence of GHR likely resulted from reduced skeletal Igf‐1 gene expression, blunted GH‐mediated effects on the skeleton that are independent of serum or tissue IGF‐1, and poor delivery of IGF‐1 to the tissues. These findings are consistent with clinical data showing that IGF‐I replacement therapy in patients with Laron syndrome does not achieve full skeletal growth.