From insulin and insulin-like activity to the insulin superfamily of growth-promoting peptides: a 20th-century odyssey.

In 1941, Gellhorn reported that administration of human blood to hypophysectomized/adrenodemedullated rats caused a fall in blood sugar. This was among the early demonstrations that human blood possesses glucose-lowering or insulin-like activity (ILA). Gellhorn assumed he had detected only insulin. During the 1960s, however, it became evident that plasma ILA contained at least two components: one, suppressible ILA (SILA), was inactivated by anti-insulin antibody and was therefore considered to be indistinguishable from pancreatic insulin; the other, nonsuppressible ILA (NSILA), was unaffected by anti-insulin antibody. Subsequent work resolved NSILA into insulin-like growth factors I and II (IGF-I and IGF-II), two 7.5 kilodalton peptides with potent mitogenic properties; established their identity with the somatomedins; and investigated both their therapeutic potential and role in the pathogenesis of neoplastic and other human diseases. Insulin and the IGFs exhibit striking homologies in amino acid composition and some degree of overlap in their signaling pathways and actions. Moreover, insulin-like proteins have been identified not only in all vertebrate classes but also in molluscs, insects, and worms. These observations are the basis for the hypothesis that the genes encoding vertebrate insulins and IGFs and invertebrate insulin-like molecules evolved from a common ancestral gene, and for the concept of an insulin superfamily of growth-promoting peptides.

Current concepts of somatomedin and other biologically related growth factors.

Since the discovery 20 years ago that the growth-promoting effects of somatotropin are mediated through a serum factor(s), research in this area has rapidly expanded. It is the purpose of this review to bring this area of scientific endeavor into perspective. The first part of this review will deal with aspects of total serum somatomedin activity and its biologic actions and measurements in health and disease. The last part of this review will summarize some of the physical and biologic characteristics of the recently purified "somatomedin-like" substances: somatomedin A, B, and C, NSILA-S (nonsuppressible insulin-like activity-soluble in acid ethanol) and MSA (multiplication-stimulating activity).

Somatomedins and other serum growth factors: a review of current concepts.

Growth hormone is essential for sustaining longitudinal growth in man. However, during the last 20 years, it has become evident that the actions of growth hormone, at a cellular level, are mediated by specific growth promoting factors. This paper describes the nature and actions of mammalian growth factors and summarises the immense contribution that the measurement of these substances has made towards the elucidation of many problems in the science of human growth and development.

[Recent data on somatomedins (insulin-like growth factors) (author's transl)]. / Données récentes sur les somatomédines (insulin-like growth factors).

Data on somatomedins have resulted from the convergence of two initially distinct lines of research relating to the two major aspects of their biological activities, their effects on cartilage growth and their insulin-like action. Human serum has yielded three factors, SM-A, SM-C and NSILA-S. The latter comprises two very similar polypeptides, IGF I and IGF II which structurally closely resemble proinsulin. A fourth factor, MSA, has been isolated from calf serum and from conditioned medium of a rat liver cell strain. All these chemically and biologically closely related factors have a molecular weight of approximately 7 500 but circulate in a form with much higher molecular weight owing to their binding to specific carrier proteins. Over the past five years, the use of purified somatomedins has led to rapid progress in the elucidation of the physiology of these hormones. In this review, present knowledge of somatomedins is analysed in the following terms: physiochemical properties, circulating forms, action on growth, insulin-like activity, interaction with receptors, immunological characteristics, biosynthesis and hormonal regulation of their blood level. Results obtained in our laboratory from rat liver organ culture are discussed: the action of culture media on cartilage sulphation, the detection of a protein which specifically binds NSILA-S and SM-A and its use in a competitive protein binding assay for somatomedins in biological fluids.

Insulin-like growth factor II and nonsuppressible insulin-like activity levels in newborns.

We measured insulin-like growth factor II and nonsuppressible insulin-like activity levels in the sera of newborn infants with different birth weights and gestational ages to determine the significance of these peptides in fetal growth. Our results obtained by use of one-way analysis of variance showed that the insulin-like growth factor II and nonsuppressible insulin-like activity levels in premature, average-weight-for-gestational-age, large-for-gestational-age, and small-for-gestational-age newborns were significantly different (p less than 0.01). Although levels in the premature neonates were less than the other three groups and large-for-gestational-age neonates had a higher insulin-like growth factor II level than the other three groups, maternal insulin-like growth factor II levels in all groups were similar. These results suggest that insulin-like growth factor II may play a major role in fetal growth.

[Somatomedins (author's transl)]. / Somatomédines.

Research on somatomedins (insulin-like growth factors) has progressed greatly over the past few years. In the present review we summarize, in addition to our own results, some recent findings concerning the structure of these factors, their carrier protein, their biosynthesis and hormonal regulation. We also stress the interest of specific assays for their use in clinical investigation.

Similarities between the insulin-like stimulatory effect of human IgG and NSILP.

Since the insulin-like stimulatory effect of human IgG on adipocyte lipogenesis, exerted through its Fc moiety, is not neutralized by anti-insulin antisera, IgG may contribute significantly to the non-suppressible insulin-like activity (NSILA) of plasma. 91% of NSILA has been shown previously to be associated with a high mol. wt. protein (NSILP). The purpose of this investigation was to assess whether IgG and NSILP have similar stimulatory effects on adipocyte lipogenesis and whether this effect can be neutralized by preincubation with gamma-chain specific anti-IgG antiserum; whether IgG stimulates 35S-sulphate uptake by porcine cartilage, known to be stimulated by insulin-like growth factors but not NSILP; and whether gamma-chain specific anti-IgG antisera precipitate IgG in a fashion similar to that with IgG preparations. Our investigations show that both IgG and NSILP have similar dose response relationships with respect to the stimulation of adipocyte lipogenesis and that both lose their adipocyte stimulating effect following preincubation with anti-IgG antiserum; neither IgG nor NSILP stimulate 35S-sulphate uptake by porcine cartilage, unlike serum somatomedin and crude NSILA-s preparations; and that gamma-chain specific anti-IgG antisera form precipitin lines with NSILP. Therefore, NSILP and IgG molecules have immunological and biological similarities; there may occur a homology between the Fc fragment of IgG and the NSILP molecule.