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Insulin‐like growth factor (IGF)‐II is considered to function as an important fetal growth factor, which is structurally and functionally related to IGF‐I and proinsulin. At least in vitro, IGF‐II actions are mediated through the IGF‐I receptor and to a lesser extent the insulin receptor. After birth, the function of IGF‐II is less clear although in adults the serum level of IGF‐II exceeds that of IGF‐I several fold. The IGF‐II gene is maternally imprinted, with exception of the liver and several parts of the brain, where it is expressed from both alleles. The regulation, organization, and translation of the IGF‐II gene is complex, with five different putative promotors leading to a range of noncoding and coding mRNAs. The 180‐amino acid pre‐pro‐IGF‐II translation product can be divided into five domains and include a N‐terminal signal peptide of 24 amino acid residues, the 67 amino acid long mature protein, and an 89 residues extension at the COOH terminus, designated as the E‐domain. After removal of the signal peptide, the processing of pro‐IGF‐II into mature IGF‐II requires various steps including glycosylation of the E‐domain followed by the action of endo‐proteases. Several of these processing intermediates can be found in the human circulation. There is increasing evidence that, besides IGF‐II, several incompletely processed precursor forms of the protein, and even a 34‐amino acid peptide (preptin) derived from the E‐domain of pro‐IGF‐II, exhibit distinct biological activities. This review will focus on the current insights regarding the specific roles of the latter proteins in cancer, glucose homeostasis, and bone physiology. To address this topic clearly in the right context, a concise overview of the biological and biochemical properties of IGF‐II and several relevant aspects of the IGF system will be provided.

The syndrome of nonislet cell tumor induced hypoglycemia (NICTH) represent extreme cases of excessive expression and production of incompletely processed high-molecular-mass pro-IGF-II forms (big IGF-II) by an often large tumor. Tumor-derived big IGF-II is responsible for enhanced insulin-like effects in the body through complicated mechanisms, leading to hypoglycemia. Case studies on NICTH usually focus on measurements of diagnostic parameters in the circulation of patients. Some studies have also reported on qualitative immunohistochemical analysis of tumor tissue, in particular with respect to the expression of IGF-II at the mRNA or protein level. However, quantitative data on the concentrations of IGFs and IGFBPs in tumor specimen causing NICTH, in relation to their corresponding plasma levels are lacking. Such an analysis would provide an estimate of the total potential of (big) IGF-II retained by the tumor and more insight in the relative levels of different IGFBPs and their origin in the circulation, that is, systemically induced by tumor related factors or directly tumor-derived. Here we investigated quantitatively the levels of IGFs and IGFBPs in a large, 1.76 kg weighing, solitary fibrous tumor from a typical case of NICTH using highly specific immunometric assays. Besides a high level of big IGF-II, patient's plasma also contained increased levels of both IGFBP-2 and -6 which declined after removal of the tumor. These IGFBPs have a higher affinity for (pro-) IGF-II than IGF-I and exhibit intrinsic IGF-independent bioactivities. Tumor tissue contained high amounts of big IGF-II and IGFBP-6, exceeding that in patient's circulation many-fold. A relatively low tumor content of IGFBP-2 was found suggesting that the preoperative high levels in plasma were attributable to systemic mechanisms. The background literature and possible implications of these findings are briefly discussed. Based on the present results we postulate that tumor tissue is not the source of the elevated levels of IGFBP-2 often seen in NICTH patients. Large tumors that cause NICTH can produce IGFBP-6 leading to enhanced levels of this IGFBP in the circulation. Hence, the measurement of IGFBP-6 in plasma may serve as an additional marker of this disease pattern. (c) 2015 BioFactors, 41(3):183-189, 2015