Gene expression and serum levels of insulin-like growth factors (IGFs) andIGF binding proteins in a case of nonlislet cell tumour hypoglycaemia

We describe a case of non-islet cell tumour hypoglycaemia (NICTH) associate d with a renal cell carcinoma. Serum insulin-like growth factors (IGFs) (in cluding IGF-II E peptide), IGF-binding proteins (IGFBPs), insulin and C-pep tide were measured before and after surgical removal of the tumour. IGFBPs were visualized by Western ligand blotting. Preoperatively 'big' IGF-II and IGFBP-2 levels were raised. IGF-I, IGFBP-1 and IGFBP-3 were low, while ins ulin, C-peptide and GH were undetectable. These changes were reversed by 2 days postoperatively. Protease assays showed little IGFBP-3 protease activi ty preoperatively. Preoperatively, neutral chromatography demonstrated most of the immunoassayable IGFBP-3 in a high molecular weight form with a smal l amount of IGF-II. Most of the IGF-II and big IGF-II eluted in lower molec ular weight forms. Postoperative samples showed a shift in IGF-II which bec ame increasingly associated with IGFBP-3 in both low and high molecular wei ght complexes. By Northern blotting, expression of all species of IGF-II mR NA in the tumour was 10-fold greater than in normal human liver. The tumour did not express IGFBP-1 or IGFBP-2. IGFBP-3 was expressed in small amounts , while the expression of IGFBP-4 was two-fold higher than in liver. In con clusion, we have confirmed high levels of big IGF-II and IGFBP-2 in NICTH, changes which are reversed postoperatively. The IGF-II is derived from the tumour which overexpresses these genes but IGFBP-2 probably arises from ext ratumour upregulation.