THE INSULIN-LIKE GROWTH-FACTORS AND THEIR BINDING-PROTEINS IN A CASE OF NON-ISLET-CELL TUMOR-ASSOCIATED HYPOGLYCEMIA

Non-islet-cell tumours which induce hypoglycaemia are rare. Insulin-like growth factor-II (IGF-II) produced by some tumours is thought to be responsible for the hypoglycaemia and other systemic effects, despite normal or even low serum IGF-II levels. We studied a 44-year-old woman presenting with symptomatic hypoglycaemia associated with a large intraabdominal haemangiopericytoma. The serum IGF-II level was 455-mu-g/l when measured after acid-ethanol extraction (normal range (NR) 450-750-mu-g/l) and 1063-mu-g/l after acid chromatography (normal human serum pool 1068-mu-g/l). Levels of fasting plasma insulin, C-peptide, glucose and serum IGF-I levels were low before the operation (< 2 mU/l (NR < 2-14), 0.23 nmol/l (NR 0.4-1.2), 3.1 mmol/l, (NR 3.7-5.9) and 0.02 U/ml respectively). After tumour removal, the symptoms resolved rapidly and the patient made a full recovery. Secretion of both insulin and growth hormone was suppressed before the operation in response to a 75 g glucose meal and to an infusion of 100-mu-g GH-releasing hormone (GHRH) respectively in comparison with studies after the operation. Serum IGF-II levels 6 weeks and 12 weeks after the operation fell to 385-mu-g/l (777-mu-g/l; acid chromatography) and 280-mu-g/l (647-mu-g/l; acid chromatography) and serum IGF-I levels increased to 0.35 U/ml and 0.26 U/ml. Serum before the operation and tumour extract contained chiefly a large molecular weight precursor IGF-II (molecular weight 15 000-20 000) which disappeared from the serum after the operation. The IGF-binding proteins (IGFBP-1, IGFBP-2, IGFBP-3 and IGFBP-4) were examined. The preoperation fasting serum IGFBP-1 level was lower than expected (31-mu-g/l (NR 20-70-mu-g/l)) and similar to levels at 6 weeks after the operation (33-mu-g/l). This was surprising given the differences in plasma insulin levels before and after the operation (< 2 mU/l versus 13 mU/l). Using Western ligand blotting techniques, serum IGFBP-3 levels were found to be low and IGFBP-2 appeared to be the dominant IGFBP before the operation. Serum IGFBP-3 levels after the operation fell further. This further decrease appeared, in part, to be due to the presence of a cation-dependent IGFBP-3-specific protease which has previously only been described in late pregnancy. We conclude that in this subject, despite normal serum IGF-II levels, the hypoglycaemia and systemic effects on insulin and GH secretion were due to increased bioavailability of a circulating tumour-produced precursor form of IGF-II. This increased bioavailability appears to be due to alterations in the circulating levels and perhaps affinities of the IGFBPs.