The History of the Insulin-Like Growth Factor System

Abstract

The growth hormone (GH)–insulin-like growth factor (IGF) cascade is central to the regulation of growth and metabolism. This article focuses on the history of the components of the IGF system, with an emphasis on the peptide hormones, IGF-I and -II, their cell surface receptors, and the IGF binding proteins (IGFBPs) and IGFBP proteases that regulate the availability of the peptide hormones for interaction with their receptors in relevant target tissues. We describe landmark events in the evolution of the somatomedin hypothesis, including evidence that has become available from experiments at the molecular and cellular levels, whole animal and tissue-specific gene knockouts, studies of cancer epidemiology, identification of prismatic human cases, and short- and long-term clinical trials of IGF-I therapy in humans. In addition, this new evidence has expanded our clinical definition of GH insensitivity (GHI) beyond growth hormone receptor mutations (classic Laron syndrome) to include conditions that cause primary IGF deficiency by impacting post-receptor signal transduction, IGF production, IGF availability to interact with the IGF-I receptor (IGF-1R), and defects in the IGF-1R, itself. We also discuss the clinical aspects of IGFs, from their description as insulin-like activity, to the use of IGF-I in the diagnosis and treatment of GH deficiency, and to the use of recombinant human IGF-I for therapy of children with GHI.

Phospholysine phosphohistidine inorganic pyrophosphate phosphatase suppresses insulin‐like growth factor 1 receptor expression to inhibit cell adhesion and proliferation in gastric cancer

“…IGF1R plays a crucial role in cell biology processes such as cell proliferation, metabolism, and tumor development by activating downstream signaling pathways upon binding to insulin‐like growth factor 1 (IGF‐1) or insulin‐like growth factor 2 (IGF‐2) 37,38 . Recently, IGF1R has been reported to promote cancer metastasis and drug resistance 39,40 .…”

Ablation of specific insulin‐like growth factor I forms reveals the importance of cleavage for regenerative capacity and glycosylation for skeletal muscle storage

“…IGF-I activity is important for organismal growth, as loss of Igf1 expression, IGF-I production, or IGF-I receptors significantly impair postnatal growth and survival in murine models and in humans. 13,14,34,35 However, it remains unknown whether it is the amount of total IGF-I, or its available form, that supports postnatal growth. Both mutant mouse lines displayed normal litter sizes with no prenatal deaths, supporting that loss of IGF-I N-glycosylation or cleavage did not affect fertility or viability.…”

Cell non-autonomous regulation of cerebrovascular aging processes by the somatotropic axis

“…GH is secreted from the anterior pituitary gland in response to GH releasing hormone, and acts on the liver and other tissues to promote the secretion of IGF-1 ( 86 ). The GH/IGF-1 axis is essential for proper growth and development ( 87 – 89 ) and confers multifacteed pro-survival, anabolic and cellular protective effects. Levels of GH decrease by ~14%/decade after approximately the third decade of life ( 90 , 91 ), and as a result levels of circulating IGF-1 also significantly decrease with age ( 92 – 95 ).…”