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The insulin-like growth factor (IGF) system comprises two ligands, IGF-I and IGF-II, that regulate multiple physiological processes, including mammalian development, metabolism and growth, through the type 1 IGF receptor (IGF-1R). The growth hormone (GH)-IGF-I axis is the major regulator of longitudinal growth. IGF-II is expressed in many tissues, notably the placenta, to regulate human pre- and post-natal growth and development. This review provides a brief introduction to the IGF system and summarizes findings from reports arising from recent larger genomic sequencing studies of human genetic mutations in IGF1 and IGF2 and genes of proteins regulating IGF action, namely the IGF-1R, IGF-1R signaling pathway components and the IGF binding proteins (IGFBPs). A perspective on the effect of homozygous mutations on structure and function of the IGFs and IGF-1R is also given and this is related to the effects on growth., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Insects encode multiple ILPs but only one homolog of the vertebrate IR that activates the insulin-signaling pathway. However, it remains unclear whether all insect ILPs are high affinity ligands for the IR or have similar biological functions. The yellow fever mosquito, Aedes aegypti, encodes eight ILPs with prior studies strongly implicating ILPs from the brain in regulating metabolism and the maturation of eggs following blood feeding. Here we addressed whether two ILP family members expressed in the brain, ILP4 and ILP3, have overlapping functional and receptor binding activities. Our results indicated that ILP3 exhibits strong insulin-like activity by elevating carbohydrate and lipid storage in sugar-fed adult females, whereas ILP4 does not. In contrast, both ILPs exhibited dose-dependent gonadotropic activity in blood-fed females as measured by the stimulation of ovaries to produce ecdysteroids and the uptake of yolk by primary oocytes. Binding studies using ovary membranes indicated that ILP4 and ILP3 do not cross compete; a finding further corroborated by cross-linking and immunoblotting experiments showing that ILP3 binds the MIR while ILP4 binds an unknown 55kDa membrane protein. In contrast, each ILP activated the insulin-signaling pathway in ovaries as measured by enhanced phosphorylation of Akt. RNAi and inhibitor studies further indicated that the gonadotropic activity of ILP4 and ILP3 requires the MIR and a functional insulin-signaling pathway. Taken together, our results indicate that two members of the Ae. aegypti ILP family exhibit partially overlapping biological activity and different binding interactions with the MIR., (Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.)

White adipose tissue is a mesenchymal tissue that begins developing in the fetus. Classically known for storing the body's fuel reserves, adipose tissue is now recognized as an endocrine organ. As such, the secretions from adipose tissue are known to affect several systems such as the vascular and immune systems and play major roles in metabolism. Numerous studies have shown nutrient or hormonal manipulations can greatly influence adipose tissue development. In addition, the associations between various disease states, such as insulin resistance and cardiovascular disease, and disregulation of adipose tissue seen in epidemiological and intervention studies are great. Evaluation of known adipokines suggests these factors secreted from adipose tissue play roles in several pathologies. As the identification of more adipokines and determination of their role in biological systems, and the interactions between adipocytes and other cells types continues, there is little doubt that we will gain a greater appreciation for a tissue once thought to simply store excess energy.

Hormonal signals can modulate lifespan and reproductive capacity across the animal kingdom. The use of model organisms such as worms, flies and mice has been fundamentally important for aging research in the discovery of genetic alterations that can extend healthy lifespan. The effects of mutations in the insulin and insulin-like growth factor-like signaling (IIS) pathways are evolutionarily conserved in that they can increase lifespan in all three animal models. Additionally, steroids and other lipophilic signaling molecules modulate lifespan in diverse organisms. Here we shall review how major hormonal pathways in the fruit fly Drosophila melanogaster interact to influence reproductive capacity and aging.

Longevity in yeast, nematodes, fruit flies and mice is affected by mutations in the insulin/IGF-1 or homologous pathways. Studies on long-living people revealed some associations between genetic variants of the insulin/IGF-1 pathway and longevity. Here, we review such investigations, and we will report human longevity association studies regarding the variability of genes which modulate lifespan in model organisms by interacting with the insulin/IGF-1 pathway. These studies will be presented in three groups: (1) insulin/IGF-1 pathway transcriptional target, superoxide dismutase 2, heat shock protein, cytochrome p450 isoenzymes, glutathione transferases; (2) insulin/IGF-1 pathway accessory transduction proteins H-Ras, p66Shc; and (3) longevity pathways that converge on the insulin/IGF-1 pathway (Klotho, p53, Sirtuins, TGF-beta). The data reported support the notion that the insulin/IGF-1 pathway drives an evolutionarily conserved network that regulates lifespan and affects longevity across species.

Transient neural injuries, such as asphyxia, can trigger considerable delayed neuronal death. Inappropriate induction of apoptosis is thought to play an important role in this process. Our studies have shown marked changes in the IGF system in the brain in response to these injuries with an induction of insulin growth factor (IGF)-1 and insulin growth factor binding protein (IGFBP)-2 and IGFBP-3 in glial cells in the region of injury. This suggests that the IGF-1 system may be an endogenous neuroprotective system. Earlier administration of IGF-1 - 2 h after injury reduced the phase of secondary neuronal loss suggesting that IGF-1 may well have therapeutic potential as a neuronal rescue agent. The action of IGF-1 appears to involve binding proteins, transport to the site of injury and the IGF-1 receptor and inhibition of apoptosis, but might also involve generation of GPE which itself appears to be neuroprotective. Together these results indicate considerable potential of these agents to treat stroke, perinatal asphyxia and other forms of acute brain injury.

Insulin-like growth factors (IGF-I and -II) promote cellular mitosis and differentiation and have been implicated in fetal and placental growth. Together with the IGF receptors and IGF binding proteins (IGFBPs) they form a complex network, with tissue specific activity. This review will discuss the data generated to elucidate the functions of the IGF system during mouse development.

The present study shows that pretreatment of BAC cells with insulin or insulin-like growth factor-I (IGF-I) enhances the cAMP response to maximal concentrations of ACTH and cholera toxin. However, the effects of IGF-I at a nanomolar concentration (50 ng/ml) were higher than for insulin at the same concentration but similar for insulin at a micromolar concentration (10 micrograms/ml). We have investigated whether the effects of the two peptides can be related to some modifications of the guanine nucleotide regulatory binding protein Gs. Insulin enhanced Gs as observed by ADP ribosylation and immunoblotting but the effects were approximately the same at nanomolar and micromolar concentrations; again, the effects of IGF-I (50 ng/ml) were higher. These results indicate that both IGF-I and insulin increase the Gs complex of adenylate cyclase, but IGF-I is more potent than insulin at physiological concentrations.

By using immature porcine Sertoli cells cultured in serum-free defined medium, we report that Sertoli cell-conditioned medium (SCCM) contains immunoreactive somatomedin C/insulin-like growth factor 1 (ir-SmC/IGF 1) which dilutes in parallel with purified human SmC/IGF 1. The release of ir-SmC/IGF 1 in the culture medium was dependent on the exposure time to Sertoli cells: no measurable ir-SmC/IGF 1 at 8 h, 12.1 +/- 1.2 ng/10(6) cells at 24 h and 33.9 +/- 5.3 ng/10(6) cells at 48 h of incubation. Moreover, ir-SmC/IGF 1 was also evidenced in SCCM following high performance liquid chromatography using a muC18 Bondapak column; ir-SmC/IGF 1 Sertoli cell-conditioned medium co-eluted with pure human SmC/IGF, suggesting a high homology between the two peptides. The effects of SmC/IGF 1 on testicular steroidogenesis were studied by incubating immature porcine Leydig cells with a biosynthetic human SmC/IGF 1. SmC/IGF 1 exerted a dose- and time-dependent stimulating effect on Leydig cell function with a maximal response at 50 ng/ml after 48 h of treatment. SmC/IGF 1 increased both LH/hCG binding (4.3-fold), basal testosterone (4-fold) and DHAS- and hCG-stimulated testosterone and DHAS (dehydroepiandrosterone sulfate) production (15.5- and 6.4-fold respectively). The slight effect of SmC/IGF 1 (100 ng for 48 h) on cell number (1.3-fold) and incorporation of [3H]thymidine into DNA (1.5-fold) in comparison with the high steroidogenic effect, supports the concept that SmC/IGF 1 acts as a cytodifferentiative factor rather than as a growth factor.(ABSTRACT TRUNCATED AT 250 WORDS)

The potential regulatory action of Sertoli cells on Leydig cell functions has been investigated by using a coculture system of Leydig and Sertoli cells obtained from immature pig or by culturing Leydig cells with Sertoli cell-conditioned medium (SCCM). Coculture of Leydig and Sertoli cells for 48 h in the absence of insulin or somatomedin-C (Sm-C), produced a small but significant increase in both hCG receptors and hCG-induced testosterone production. Addition to the medium of pFSH (100 ng/ml), insulin (5 micrograms/ml) or somatomedin-C (50 ng/ml) produced a marked increase in these two parameters of Leydig cell function. A further significant increase was observed when pFSH was associated with insulin or Sm-C. In contrast, coculture of Leydig cells with aortic endothelial cells decreased both the hCG receptor number and the hCG responsiveness. SCCM stimulated Leydig cell testosterone production following a 4 h incubation. The stimulation depended upon the amount of SCCM used and the conditions in which Sertoli cells were cultured. The most active was the medium from cells cultured in the presence of pFSH and insulin at high concentrations. Since pig Sertoli cells have specific somatomedin-C receptors, but not insulin receptors, it is likely that the effect of micromolar concentrations of insulin are exerted through Sm-C receptors. In addition, SCCM produced a long-term effect after 48 h incubation. SCCM from cells cultured in the absence of insulin and pFSH inhibited both the hCG receptor number and hCG responsiveness. A similar inhibition was observed with SCCM medium from cells cultured without insulin but with pFSH.(ABSTRACT TRUNCATED AT 250 WORDS)

The somatomedins, such as the insulin-like growth factors I and II, somatomedins A and C, and multiplication-stimulating activity, are small, growth hormone dependent polypeptides which are the assumed mediators of growth hormone action on extraskeletal tissues. The somatomedins are unique among polypeptide hormones in that they exist in serum as two high molecular weight complexes of approximately 150 000 and 60 000 molecular weight. Little, if any, free hormone is present in plasma or serum. These circulating complexes appear to represent the reservoir for these hormones since none is stored in any other tissue and the circulating concentration (approx. 1 microgram/ml) exceeds the biologically active concentration of the free hormone by many fold. Many recent investigations regarding the subunit composition of the two serum carrier protein complexes and their effect on the biological activity of the somatomedins have revealed an elaborate system of intense physiological control ultimately aimed at delivering somatomedin to its specific receptor on the surface of the target cell.

Defined factors regulating or influencing mammalian ventricular myocyte (cardiomyocyte) development are not known at this time. During early neonatal ventricular growth, cardiomyocytes begin a 'transition phase' of development toward cellular maturation (hypertrophy) that entails terminal proliferation and cellular binucleation. Insulin-like growth factor-I and -II (IGFs) are believed to play a major role in mammalian postnatal and fetal growth, possibly functioning in local environments which facilitate autocrine or paracrine tissue growth characteristics. Therefore, we examined the expression of the IGF genes and their corresponding membrane receptors in ventricles of normotensive and spontaneously hypertensive (SHR) rat pups during the first 7-14 days of age. We have determined: (1) by receptor crosslinking that neonatal ventricular membranes possess type 1 and type 2 IGF receptors; (2) by receptor binding analysis that type 1 IGF receptor concentration is elevated between days 1-7 in the SHR and shows an age-related decline in concentration and an increase in affinity in both strains; (3) by Northern blot analysis that neonatal rat ventricular tissue expresses primarily IGF-II RNA transcripts of 3.6, 2.3 and 1.7 kilobases (kb) in size, with low levels of IGF-I transcripts detected; (4) by slot-blot hybridization that SHR ventricles contain higher levels of IGF-II transcripts at 3 days of age; and (5) localized the IGF transcripts to ventricular myocytes by tissue in situ hybridization. These observations support a role for cardiomyocyte-produced IGFs that may be locally produced and act in an autocrine or paracrine fashion to modulate cardiomyocyte growth and maturation in the developing rat heart. Because both IGF receptor and IGF RNA transcript parameters differed in SHR hearts, genetically predisposed to hypertrophy, a potentially important biochemical alteration may be associated with the fetal/neonatal growth abnormalities of the developing heart in this rat strain.