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

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.