Non-islet cell tumour-induced hypoglycaemia: a review of the literature including two new cases

  1. Winette T A van der Graaf4
  1. 1Department of Internal Medicine,, Isala Klinieken, Dr van Heesweg 2, 8025 AB Zwolle, The Netherlands 2Department of Metabolic and Endocrine Diseases,, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht, The Netherlands 3Department of Internal Medicine,, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands 4Department of Medical Oncology,, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  1. (Correspondence should be addressed to J W B de Groot; Email:{at}
  1. Figure 1

    Structure of the insulin-like growth factor (IGF)-II gene and the precursor-IGF-II-protein. The IGF-II gene has four promoters (P1–P4). Only exons 7, 8 and a part of 9 (depicted in grey) encode for the pre-pro-IGF-II protein. The N-terminal signalling peptide (SP) is enzymatically cleaved leading to the formation of pro-IGF-II. The E-domain is degraded through several steps into the mature 7.5 kDa IGF-II. Pro-IGF-II (68–88) is a relatively stable intermediary in this process.

  2. Figure 2

    In situ hybridisation of insulin-like growth factor (IGF)-II mRNA in a solitary fibrous tumour of the right kidney from patient 1, demonstrating high expression of the IGF-II gene (A). IGF-I is not expressed (B).

  3. Figure 3

    Analysis of complex formation in patient 2 using S200 column chromatography. An aliquot of patient's serum (250 μl) or normal control serum was incubated with 50 μl 125I-labelled purified human insulin-like growth factor (IGF)-I (100 000 c.p.m.) and the different complexes were subsequently separated. In patient's serum, 150 kDa complex formation is reduced and, instead, relatively higher proportions of [125I]-IGF-I are associated with the smaller 40–50 kDa binary complexes and remain unbound.

  4. Figure 4

    Proposed mechanism of the development of non-islet cell tumour hypoglycaemia (NICTH). It is likely that tumour cells cannot process the augmented amounts of pro-insulin-like growth factor-II (pro-IGF-II) synthesised, resulting in a substantial release of ‘big’-IGF-II into the circulation. ‘Big’-IGF-II competes with the mature IGF-II and IGF-I for binding to IGF-binding proteins (IGFBPs). However, the formation of the ternary complex between ‘big’-IGF-II, IGFBP-3 and the acid-labile subunit (ALS) in the circulation is hampered. As a consequence, primarily 40–50 kDa binary complexes are formed. In addition, both free fractions of IGF-I and total IGF-II are increased. Since the binary complexes and free IGFs can pass the capillary membrane relatively easily when compared with the 150 kDa ternary complex, the concentrations of IGFs, presumably especially ‘big’-IGF-II, at the tissue level will rise inducing a strong insulin-like effect via the insulin receptors, causing hypoglycaemia. Moreover, because of an increasing negative feedback on growth hormone (GH) production by the anterior pituitary gland the synthesis of GH-dependent peptides such as IGF-I, IGFBP-3, IGFBP-5 and acid-labile subunit (ALS) are decreased. This leads to even further declined formation of ternary complexes. Abbreviations: FFA, free fatty acids.

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