Insulin-like growth factor binding proteins

Abstract

Although insulin-like growth factor I (IGF-I) may be useful in the therapy of diabetes, the IGFs also may contribute to some diabetic complications. The biological activity of IGFs is determined by its interaction IGF-I receptors and with IGF binding proteins (IGFBPs). Almost all circulating and tissue IGFs are bound to one of the six members of a family of structurally related IGFBPs (IGFBPs 1-6). In plasma, most IGF is bound in a 150 kDa ternary complex with IGFIBP-3 and an acid-labile subunit. The 150 kDa complex is unable to leave the vasculature and acts as a circulating reservoir for IGPs. By restricting access of circulating IGFs to tissues, the 150 kDa complex prevents tile intrinsic insulin like activity of the IGFs from causing hypoglycemia. In the syndrome of non-islet cell tumor hypoglycemia, formation of the 150 kDa complex is decreased, and this homeostatic mechanism fails. At a tissue level, IGFBPs may inhibit IGF action by preventing them from binding to receptors. Inhibition is relieved when the affinity of the IGFBP for IGF is decreased, as by proteolysis by a specific protease. Under some experimental conditions, IGFBPs 1, 3, and 5 potentiate IGF activity mechanisms that are unknown but which may include cell association and reduction in binding affinity, IGFBPs are synthesized in all tissues, although expression of specific IGFBPs may he restricted, IGFBPs are subject to post translational modifications such as phosphorylation and glycosylation, and these may alter their characteristics, Specific IGFBPs are regulated by different developmental, hormonal, and metabolic factors, such ss diabetes. Some IGFBPs bind IGB-I and IGF-II with equal affinity whereas others (notably IGFBP-6 preferentially bind IGF-II. The family of IGFBPs represents a versatile and finely tuned mechanism for the regulation of IGF activity. Understanding the nuances of this control will enable the therapeutic potential of IGF-I to be safely harnessed ill the treatment of diabetes.