Physiologic and clinical relevance of the insulin-like growth factor binding proteins

The insulin-like growth factors (IGFs) are potent mitogenic agents that have been recognized for three decades. Recently, however, the complex milieu in which they operate has begun to be unraveled. Endocrine and autocrine patterns of IGF secretion have been identified and specific receptors that bind IGFs and mediate their biologic actions have been characterized. A family of six peptides, which bind IGFs with high affinity, the IGF binding proteins (IGFBPs), have been recognized as a new class of growth modulators. The IGFBPs can inhibit IGF actions, enhance IGF actions, or function as independent cell regulatory factors, possibly by interacting with their own receptors on the cell membrane. The IGFBPs, in turn, are regulated by a group of proteolytic enzymes, which are capable of cleaving IGFBPs into smaller fragments with lower affinity for the IGFs, thus enhancing IGF action. The size IGFBPs, although similar, have unique biologic properties, and appear to have specific patterns of expression and function. Radioimmunoassay for IGFBP-1, -2, and -3 are currently commercially available and information is accumulating on their diagnostic usefulness. This includes several clinical situations, such as growth disorders, where serum IGFBP-3 is a highly specific screening tool for growth hormone deficiency, various malignancies in which serum IGFBP-2 levels are elevated, and disorders of carbohydrate metabolism that display an inverse relationship between serum IGFBP-1 and insulin-secretion. Current clinical practice may include the judicious use of these tests for the diagnosis and for monitoring the therapeutic response of such disorders.