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

Non-islet-cell tumour-induced hypoglycaemia (NICTH) is, in most cases, attr ibutable to tumour production of insulin-like growth factor II (IGF-II), Tu mour-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 IG F binding protein-3 (IGFBP-3) and the acid-labile subunit (ALS). Consequent ly, 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 patie nt with a disseminated haemangiopericytoma and severe hypoglycaemia. In add ition, 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 con centrations 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 filt ration 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 part ial 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 on ly 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- a nd IGF type I receptor were hardly detectable. In contrast to patient serum tumour cyst fluid strongly stimulated the insulin receptor in vitro; The p resent study suggests an important role of the simultaneous production of I GF-II and IGFBP-6 in the pathophysiology of tumour-induced hypoglycaemia.