Christoph Schmid

Metabolic Effects of IGFs

The relationship between insulin-like growth factors (IGFs) and insulin has been known since the discovery of nonsuppressible insulin-like activity (NSILA) in serum at the beginning of the 1960s (1), and was derived from the similarities of their biological actions. In the mid-1970s it was found that NSILA consisted of two polypeptides termed IGF-I and IGF-II. They turned out to be not only biologically but also structurally closely related to insulin (2,3). This finding was at first surprising, because the discovery of NSILA had been based on a most prominent feature that essentially distinguished it from insulin: its complete lack of cross-reactivity with insulin antibodies. However, after the elucidation of the primary and tertiary structures of IGF-I and -II (2–4),the reason for this lack of cross-reactivity became apparent (Fig. 1). Insulin contains two main antibody binding sites. One of them comprises the amino (N)-terminal region of the B chain (B2, B3, and B4) plus an adjacent region of the A chain (A8, A9, and A10). This region is completely different in the IGFs. The second antibody binding site of insulin comprises residues Al and A19–A21 and the carboxyl (C)-terminal region of the B chain, but this region is covered in the IGFs by the C domain and by a C-terminal extension called the D domain.