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 (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.