Serum "Big Insulin-Like Growth Factor II" from Patients with Tumor Hypoglycemia Lacks Normal E-Domain O-Linked Glycosylation, a Possible Determinant of Normal Propeptide Processing

The insulin-like growth factor II (IGF-II) gene is overexpressed in many mesenchymal tumors and can lead to non-islet-cell tumor hypoglycemia (NICTH). ProIGF-II consists of the 67 aa of IGF-II with a carboxyl 89-aa extension, the E domain. A derivative of proIGF-II containing only the first 21 aa of the E domain [proIGF-II-(E1-21)] has been isolated by others from normal serum and has O-linked glycosylation. We found that the "big IGF-II" of normal serum, as detected by an RIA directed against residues 1-21 of the E domain of proIGF-II, was reduced in size by treatment with neuraminidase and O-glycosidase. The big IGF-II, which is greatly increased in NICTH sera, was unaffected by neuraminidase and O-glycosidase treatment. We have also shown that big IGF-II from normal serum is retained by jacalin lectin columns and that big IGF-II from NICTH serum was not retained, indicating that it lacked O-glycosylation. Normal O-linked glycosylation may be required for proper peptidase processing of proIGF-II. The lack of normal O-linked glycosylation by tumors may explain the predominance of big IGF-II in NICTH sera. In normal serum, most of the IGF-II is present in a 150-kDa ternary complex with IGF-II binding protein (IGFBP) 3 and α subunit. In NICTH serum, however, the complexes carrying big IGF-II are