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The involvement of insulin, the insulin-like growth factors (IGF1, IGF2) and their receptors in central nervous system development and function has been the focus of scientific interest for more than 30 years. The insulin-like peptides, both locally-produced proteins as well as those transported from the circulation into the brain via the blood-brain barrier, are involved in a myriad of biological activities. These actions include, among others, neuronal survival, neurogenes, angiogenesis, excitatory and inhibitory neurotransmission, regulation of food intake, and cognition. In recent years, a linkage between brain insulin/IGF1 and certain neuropathologies has been identified. Epidemiological studies have demonstrated a correlation between diabetes (mainly type 2) and Alzheimer׳s disease. In addition, an aberrant decline in IGF1 values was suggested to play a role in the development of Alzheimer׳s disease. The present review focuses on the expression and function of insulin, IGFs and their receptors in the brain in physiological and pathological conditions., (Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.)

Although very similar to insulin and its receptor; the modus operandi of the insulin-like growth factors (IGFs) within the body is very different from that of the traditional peptide hormone. The IGF-binding proteins bind the IGFs with greater affinity than the cell surface receptors, enabling them to tightly control tissue activity. In addition to their role in fetal and childhood growth, IGFs play an important role in metabolic regulation. This article describes the basic underlying human physiology of IGFs, how this differs from that of experimental models, and why some information can only be learned from human clinical studies., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Insulin-like growth factors (IGFs) play an integral role in development, growth, and survival. This article details the current understanding of the effects of IGFs in the peripheral nervous system (PNS) during health and disease, and introduces how the IGF system regulates PNS development and impacts growth and survival of PNS cells. Also discussed are implications of IGF signaling in neurodegeneration and the status and prospects of IGF therapies for PNS conditions. There is substantial support for the application of IGF therapies in the treatment of PNS injury and disease., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Recognition of molecular pathways relevant to cancer biology have led to advances in prevention and treatment. Numerous laboratory and clinical investigations have implicated the insulin-like growth factors (IGFs) in tumourigenesis. In this review, the evidence for the involvement of IGFs in cancer is discussed. While these data are persuasive, it is clear that additional methods to regulate IGF action in cancer patients are needed to substantiate the role of this growth factor family in cancer biology., (Copyright 2001 Elsevier Science Ltd.)

IGFs are important positive modulators of overall body and muscle growth in different species. Genetic variation in IGF-I gene expression exists as shown by the possibility of genetic selection for high or low circulating IGF-I concentrations in mice and the associated variations in growth potential. Targeted over-expression of IGF-I in transgenic mice results in muscle hypertrophy, but it is yet unknown whether genetic variability in muscle IGF-I gene expression exists. Much less data are available in birds. This review is focussed on the potential role of IGFs on chicken muscle development. Apart from the absence of a type 2 IGF receptor (IGF-II receptor), the general characteristics of the chicken IGF system seem to be similar to mammalian species. In different genetic models with altered growth rates or body composition, differences in the IGF system are observed suggesting its importance in regulating body growth in those species. The components for a paracrine action of IGF are also present in chicken muscle but it has not yet been demonstrated if they contribute to differences in muscle development.

Insulin-like growth factors, their receptors, binding proteins, and binding protein proteases are important in normal and abnormal ovarian follicle development. IGFs stimulate ovarian cellular mitosis and steroidogenesis and inhibit apoptosis. Patterns of expression of IGF family members are characteristic of whether follicles are estrogen- or androgen-dominant. The PCOS follicle is androgen-dominant but does not appear to be atretic and has characteristic IGF family expression. Available data strongly support an intraovarian, as opposed to endocrine, role for this growth factor family in ovarian follicle growth, steroidogenesis, and atresia.

A large amount of research, primarily in mammals, has defined to a great extent the pleiotropic effects of the IGF system on growth, development, and intermediary metabolism. Similar elucidations in poultry were hindered to some extent by the absence of native peptides (IGF-I and IGF-II) until their purification, followed by the production of recombinant chicken IGFs. In many ways IGF physiology in birds is similar to that in other species, including but not limited to the fact that IGF-I synthesis is both GH- and GH-independent, and that autocrine-paracrine IGF action is evident. However, it is clear that several unique differences in IGF physiology exist between birds and mammals. For example, more IGF is present in the free form in chickens, and the biological responses to the IGFs is different in several metabolic pathways in birds compared to mammals. To date, no unique IGF-II receptor has been identified in birds. Despite an increasing understanding of the IGFs in aves, several important questions remain to be answered. What is the role of IGF-II in embryo development and posthatch growth? Does an IGF-II receptor entity exist in nonmammalian species? How does nutrition affect IGF-I and IGF-II gene expression, and can this information be used to enhance poultry production? What is the biochemical composition of the IGFBPs, and what are their roles in birds? Can the genetic variation present in poultry be used to positively modify IGF gene expression and physiology? How do the IGFs regulate intermediary metabolism? What is the role of the IGFs in the etiology of several disease states associated with rapid growth in poultry, including tibial dyschondroplasia, obesity, ascites, and spiking mortality syndrome? Answers to these questions are relevant to our understanding of the basic mechanisms of IGF physiology as well as possibly assisting in the amelioration of problems found in modern poultry production.

The main source of insulin-like growth factor I (IGF-I) postnatally is the liver, under growth hormone stimulation, although IGF-I is already present in embryonic tissues and in fetal serum, when its expression is independent of growth hormone. The extracellular alpha-subunit of the IGF-I receptor (IGF-IR) contains an IGF-I binding domain, and the beta-subunit possesses tyrosine kinase activity, which is greatly enhanced when IGF-I binds to the alpha-subunit and leads to its autophosphorylation. Insulin receptor substrate 1 (IRS-1) is the most well characterized cellular substrate for IGF-I, containing at least 20 potential tyrosine phosphorylation sites. The tyrosine phosphorylated form of IRS-1 acts as a docking protein by associating SH2-containing proteins including the p85 regulatory subunit of phosphatidylinositol-3-kinase (P13-kinase), the protein tyrosine phosphatase SH-PTP2, the SH2- and SH3-containing adaptor protein Nck and the growth factor receptor-bound protein-2 (Grb2/Sem5) protein. Grb2 is found associated with mSOS, a GTP/GDP exchange factor involved in converting the inactive Ras-GDP to the active Ras-GTP. The p85 regulatory subunit of PI3-kinase can be also a direct in vitro substrate of the IGF-IR. Although IRS-1 is the major substrate of the IGF-IR, there is another early phosphotyrosine substrate termed SHC, which also activates Ras via Grb2-mSos complex. Activation of p21-Ras induces a serine/threonine kinase cascade leading to the activation of MAP-kinases. The importance of IGF-I as a mitogen throughout development has been clearly demonstrated in IGF-I and IGF-IR knockout mouse studies and also in transgenic mice over-expressing IGF-I. IGF-I is a mitogen in many cell types in culture such as T lymphocytes, chondrocytes or osteoblasts and it is considered to be a progression factor in mouse fibroblasts. IGF-I is also involved in muscle, neurons and adipogenic differentiation of mesenchymal cells. However, IGF-I induces proliferation and differentiation in fetal brown adipocytes, suggesting that both cellular processes are not necessarily mutually exclusive in fetal cells.