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Clinical relevance of systemic and local IGF-I: lessons from animal models.

Since the original somatomedin hypothesis was first put forward, several major revisions have been made. These include the identification of the insulin-like growth factors (IGF-I and IGF-II) and, importantly, the finding that these substances have local (autocrine/paracrine) as well as endocrine effects. Differentiating the roles of IGF-I at these different levels has been an ongoing challenge. However, knowledge in this area has been advanced by studies of knockout mice with specific gene deletions of liver IGF-I as well as IGF binding proteins (IGFBPs). Targeting IGFBP and the acid-labile subunit, in gene deletion studies, has made it possible to almost completely eliminate circulating IGF-I. Finally, animal models looking at IGFBPs have begun to provide insights into the numerous and often surprising effects these proteins themselves have. Despite the advances in knowledge made through these animal models, our understanding of the IGF-I system is still incomplete.