Introduction of New Recombinant Insulin-like Growth Factor - Current and Future Perspectives

Michael B Ranke
European Endocrinology, 2008;4(1):52-6
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The past 50 years have seen extraordinary developments, from the somatomedin hypothesis1 to a broad understanding of the insulin-like growth factor (IGF) system with its varied components and diverse actions.2 At the centre of the system is IGF-1, the insulin-like peptide with major effects on metabolism and cellular function. The fundamental physiological effects of IGF-1 on glucose metabolism and growth were discovered in the 1980s,3,4 when it was proved that the most important similarities between insulin and IGF-1 involved their metabolic effects on cellular glucose, amino acid uptake, glycogen synthesis, lipogenesis and mitogenesis. In 1983, the cloning of recombinant human IGF-1 (rhIGF-1) laid the foundation for the production of sufficient amounts of recombinant material for clinical use.5 The resulting industrial production enabled the exploration of this new drug within the framework of clinical trials involving various disorders. The main focus in the 1990s was the investigation of the growth-promoting and insulin effects of IGF-1, while current experimental and clinical trials deal with the neuroprotective potential of IGF-1.6–9 Clinical studies were brought to an abrupt halt in the 1990s owing to suggestions in cohort studies of an association between high levels of IGF-1 and malignancies.10 Consequently, on the grounds of risk–benefit assessments and economic considerations, manufacturers of IGF-1 decided to discontinue their involvement in clinical research. This negative outlook changed after expanding knowledge in the field led to a rational re-assessment of the therapeutic potential of IGF-1 (see Table 1). More recently, rhIGF-1 (Increlex®) received marketing authorisation in the US in 2006, and in 2007 the EU approved IGF-1 in the treatment of severe primary IGF deficiency.

This brief article aims at summarising clinical experience with regard to the efficacy and safety of IGF-1, focusing on the role of IGF-1 in the treatment of growth disorders, diabetes and insulin resistance, as these diagnoses serve as the empirical basis for the knowledge we have gained.

The Insulin-like Growth Factor–Growth Hormone System

In 1957, Salmon and Daughaday found proof of a growth hormone (GH)- dependent factor that had a growth-promoting effect on epiphyseal cartilage. They called it the ‘sulphation factor’ owing to its mediation of sulphate. Subsequently, the more general term ‘somatomedin’ was proposed1 in view of the diverse metabolic effects of this factor and its insulin-like nature. Somatomedin was found to have two proteins, which due to their structural resemblance to insulin were termed ‘insulin-like growth factors’ (IGF-1 and IGF-2).11,12 Through binding studies and molecular investigations it became evident that there were specific cell membrane (type 2 kinase) receptors: IGF-1-R and IGF-2-R. It is possible for both IGF-1 and IGF-2 to bind with the insulin receptor; the binding affinity of IGF-1 with the insulin receptor represents only one-hundredth that of insulin.13 The ‘insulin-like’ effects of the IGFs are thus related to the cellular uptake of glucose and amino acids, glycogen synthesis, lipogenesis and mitogenesis.14,15 Specific effects include their function in cell differentiation, cell proliferation and apoptosis. The complexity of the IGF system is enhanced by the fact that certain proteins specifically bind IGFs; these proteins are known as ‘IGF-binding proteins’ (IGFBP-1–6).16 Although structurally similar, these proteins can be modified individually by phosphorylation, glycosylation and proteolysis, and this in turn can affect their ability to bind IGFs. IGFs and IGFBPs can be expressed in almost every type of tissue.17 The IGFs and IGFBPs found in the blood circulation are mainly synthesised in the liver. The secretion of GH, insulin and sex steroids, liver function and nutritional status are major determinants of circulating levels of IGFs and IGFBPs.18 The degradation of IGF is impeded through association with binding proteins and the acidlabile subunit (ALS), and its half-life is prolonged by hours.19,20 Only about 1–2% of IGF-1 in the circulation is ‘free’ (according to the law of mass action). IGF in the circulation is transported to various peripheral target organs through binding protein cascades. Thus, several biological functions can be attributed to IGFBPs.17

GH is a peptide hormone expressed in a pulsatile way in the somatotrope cells of the anterior pituitary.21 The growth-promoting effect of GH occurs either indirectly, via the stimulation of IGF-1 in the liver, or directly, on the epiphyseal growth plate or by means of IGF-independent effects. GH stimulates the expression of IGF-1, IGFBP-3 and ALS in the liver; these then reach the epiphyseal plate through the blood circulation. GH in the epiphyseal plate stimulates the expression of pre-chondrocytes and the local synthesis of IGF-1.22 GH and IGF-1 are both prerequisites for the optimal longitudinal growth of bones. IGF-1 and GH have a synergistic effect on growth and anabolic metabolism; they have an antagonistic effect on the metabolism of glucose and fat due to the antiinsulin effect of GH23 and the insulin-like effect of IGF-1.4

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