IGF-I Bioactivity in Aging, Health and Disease

The existence of insulin-like growth factors (IGFs) in blood was fi rst recognized by Wiliam D. Salmon Jr. and Wiliam H. Daughaday in 1956. Examining the role of pituitary-regulated growth-stimulating substances, these authors demonstrated that a growth hormone (GH) dependent factor in serum could stimulate labeled sulfate (35SO4) incorporation into chondroitin sulfate (cartilage) in vitro. In line with their fi ndings, Salmon and Daughaday initially designated this factor as ‘sulfation factor’. Comparative studies were also performed in vivo. Hypophysectomy of rats markedly reduced labeled sulfate incorporation into chondroitin sulfate of epiphyseal cartilage, whereas injections of pituitary extracts and purifi ed bovine GH effectively restored 35SO4 incorporation. The observations that the direct effect of bovine GH on costal cartilage was minimal, whereas serum from hypophysectomized rats treated with bovine GH stimulated 3H-thymidine incorporation into cartilage led to the postulation that GH utilized the intermediary substance sulfation factor

The insulin-like growth factor-I receptor stimulating activity (IRSA) in health and disease

Determination of true IGF-I bioactivity in serum and other biological fluids is still a substantial challenge. The IGF-IR Kinase Receptor Activation assay (IGF-IR KIRA assay) is a novel tool to asses IGF-IR stimulating activity (IRSA) and has opened a new era in studying the IGF system. In this paper we discuss many studies showing that measuring IRSA by the IGF-IR KIRA assay often provides fundamentally different information about the IGF system than the commonly used total IGF-I immunoassays. With the IGF-IR KIRA assay phosphorylation of tyrosine residues of the IGF-IR is used as read out to quantify IRSA in unknown (serum) samples. The IGF-IR KIRA assay gives information about net overall effects of circulating IGF-I, IGF-II, IGFBPs and IGFBP-proteases on IGF-IR activation and seems especially superior to immunoreactive total IGF-I in monitoring therapeutic interventions. Although the IRSA as measured by the IGF-IR KIRA assay probably more closely reflects true bioactive IGF-I than measurements of total IGF-I in serum, the IGF-IR KIRA assay in its current form does not give information about all the post-receptor intracellular events mediated by the IGF-IR. Interestingly, in several conditions in health and disease IRSA measured by the IGF-IR KIRA assay is considerably higher in interstitial fluid and ascites than in serum. This suggests that both the paracrine (local) and endocrine (circulating) IRSA should be measured to get a complete picture about the role of the IGF system in health and disease

Effects of Somatostatin Analogs and Dopamine Agonists on Insulin-Like Growth Factor 2-Induced Insulin Receptor Isoform-A Activation by Gastroenteropancreatic Neuroendocrine Tumor Cells

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Revisiting the role of insulin-like growth factor-I receptor stimulating activity and the apolipoprotein E in Alzheimer's disease

__Background:__ Alterations in insulin-like growth factor I (IGF-I) signaling have been associated with dementia and Alzheimer's disease (AD). Studies on the association between IGF-I levels and dementia risk have been inconclusive. We reported earlier that higher levels of IGF-I receptor stimulating activity are associated with a higher prevalence and incidence of dementia. __Objective:__ In the present study, we test the robustness of the association between IGF-I receptor stimulating activity and dementia by extending the follow-up period to 16 years and investigate possible effect modification by apolipoprotein E (ApoE). __Methods:__ At baseline, circulating IGF-I receptor stimulating activity was determined by the IGF-I kinase receptor activation (KIRA) assay in 1,014 elderly from the Rotterdam Study. Dementia was assessed from baseline (1997-1999) to follow-up in January 2015. Associations of IGF-I receptor stimulating activity and incident dementia were assessed with Cox proportional hazards models. __Results:__ During 10,752 person-years of follow-up, 174 people developed dementia. In the extended follow-up we no longer observed a dose-response relationship between IGF-I receptor stimulating activity and risk of dementia [adjusted odd

High IGFBP2 levels are not only associated with a better metabolic risk profile but also with increased mortality in elderly men

Objective: Serum IGF-binding protein 2 (IGFBP2) concentrations are reduced in obese humans and increase after a prolonged period of fasting. We investigated the association between IGFBP2 levels and mortality together with other factors that are related to IGFBP2, including the metabolic syndrome and physical function. Design: A prospective observational study at a clinical research center of 403 independently living elderly men (aged 73-94 years). Methods: Mortality was registered during 8.6 years of follow-up. Physical performance score (PPS), grip strength (GS), and bone minera

Heterophilic antibodies may be a cause of falsely low total IGF1 levels

Background: A low serum total IGF1 is considered as a diagnostic indicator of GH deficiency (GHD) in the presence of hypopituitarism. Introduction of IRMA and chemiluminescent immunometric assay (CLIA) IGF1 immunoassays has introduced endogenous antibodies as a new source of interference. In general, this goes unnoticed and might lead to unnecessary diagnostic and therapeutic interventions. Case: A 56-year-old man was referred with a decline in physical performance, unexplained osteopenia, and weight loss of 3 kg over the past 8 months. Although clinical signs and symptoms were unremarkable, laboratory results pointed to secondary hypothyroidism and secondary hypogonadism. In addition, the serum total IGF1 level (CLIA; Siemens Medical Solutions Diagnostics) was in the low normal range. Two GH stimulation tests were performed, but these te