Hypoglycaemia associated with the production of insulin‐like growth factor II and insulin‐like growth factor binding protein 6 by a haemangiopericytoma

Abstract

Non-islet-cell tumour-induced hypoglycaemia (NICTH) is, in most cases, attributable to tumour production of insulin-like growth factor II (IGF-II). Tumour-derived IGF-II has a higher than normal molecular weight (big 'IGF-II') and an impaired ability to form the normal ternary 150 kD complex with IGF binding protein-3 (IGFBP-3) and the acid-labile subunit (ALS). Consequently, tumoral IGF-II circulates mainly in smaller binary complexes which have a higher bioavailability than the ternary complex. We had the opportunity to analyze IGFs and IGF-related factors in both pre- and post-operative blood, tumour tissue and tumour cyst fluid from a patient with a disseminated haemangiopericytoma and severe hypoglycaemia. In addition, the effect of serum and tumour cyst fluid on autophosphorylation of the insulin receptor was examined. Patient serum contained low levels of IGF-I, IGFBP-3 and ALS, while the concentrations of IGFBP-2 and IGFBP-6 were markedly elevated. The total level of circulating IGF-II was within the normal range, but Biogel P-60 gel filtration of patient serum revealed that 77% of the IGF-II was present in high molecular weight forms (normal: 10-15%), which decreased to 53% after partial removal of the tumour. Most of the IGF-II immunoreactivity in pre- and post-operative patient serum was associated with 50-60 kD complexes with only a minimal contribution (<10%) from the 150 kD complex. Tumour cyst fluid contained excessive amounts of both big IGF-II and IGFBP-6. Northern blot analysis of total mRNA isolated from the tumour demonstrated high expression of the IGF-II gene and abundant 1.1 kb IGFBP-6 transcript, while the genes encoding IGFBP-3, -4 and -5 were only weakly expressed and mRNA of IGFBP-1, -2 and IGF-I could not be detected. mRNAs for the IGF type II receptor could be easily demonstrated, whereas those for the insulin- and IGF type I receptor were hardly detectable. In contrast to patient serum tumour cyst fluid strongly stimulated the insulin receptor in vitro. The present study suggests an important role of the simultaneous production of IGF-II and IGFBP-6 in the pathophysiology of tumour-induced hypoglycaemia.

Pro- and mature IGF-II during diet-induced weight loss in obese subjects

“…Major drawbacks are the multiple IGF-II determinations required per patient sample and the time-consuming methodology. In addition, it has been speculated that the use of an antibody directed against mature IGF-II due to a lower affinity for pro-IGF-II may result in an underestimation of pro-IGF-II levels (13).…”

“…In serum from healthy subjects the concentration of pro-IGF-II constitutes roughly 10 -15% of circulating IGF-II (13,14). The regulation and biological role of pro-IGF-II is unknown, but its insulin-like bioactivity has been shown to be 3-fold increased in the rat fatcell bioassay as compared with mature IGF-II (14).…”

Recurrent Hypoglycaemia in a Case of Phyllodes Tumour of the Breast: A Rare Case Report

“…Plasma concentrations of IGF-1and IGF-2 can be 1000 times greater than insulin in NICTH permitting them to cause hypoglycemia [19]. More than 95% of IGF-2 in the circulation is bound to insulin like growth factor binding proteins (IGFBP) [20]. At the cellular level, IGF-2 binds with IGF-2 receptor which mediates functions like endocytosis, intracellular hormone transport and metabolism of circulating IGF-2 [21].…”

Hypoglycaemia secondary to the secretion of pro-insulin like growth factor ii by a metastatic neuroendocrine tumour with sarcomatous differentiation

“…Prednisolone, at daily doses of 30mg or more, alleviates hypoglycaemia by direct stimulation of gluconeogenesis and glycogenolysis and may also suppress tumour production and clearance of pro-IG.-II 2 . A significant fall in circulating pro-IG.-II is accompanied by a rise in serum ALS and redistribution of IG.BP-3 from binary to ternary forms 8 . It is therefore probable that although both treatments are similarly effective in relieving hypoglycaemia, glucocorticoid therapy may be of greater long-term benefit through pro-IG.-II suppression and the postulated mechanisms may explain the occasional failures of GH therapy when administered alone 2,6 .…”

“…Tumour-derived IG.-II molecules represent truncated forms of pro-IG.-II with molecular weights ranging from 10-20kD, instead of the fully processed 7.4 kD peptide 8 . In normal human serum, 70-80% of IG.-II is associated with a ternary 150kD IG.BP complex, consisting of IG.-II, IG.BP-3 and an acid labile subunit (ALS), while 20-30% is bound to a binary complex of less than 60kD consisting of IG.-II and IG.BP-3, and less than 2% is present in the free form 1,7,8 . In NICTH, IG.BP-3 and ALS production is decreased and the ability of the binary complex to form the more stable ternary complex is impaired and thus tumour derived IG.-II appears as binary IG.-IG.BP complexes which has a greatly increased turnover compared with the ternary 150-kDa .…”