Serum High Molecular Weight Form of Insulin-Like Growth Factor II from Patients with Non-Islet Cell Tumor Hypoglycemia Is O-Glycosylated1

Non-islet cell tumor hypoglycemia (NICTH) is one of major causes of fasting hypoglycemia. In some patients with NICTH, insulin-like growth factor II (IGF-II) produced by and secreted from the tumors is thought to be a hypoglycemic agent. In patients with NICTH, the major form of IGF-II is high molecular weight form of IGF-II, designated as big IGF-II. The generation of big IGF-II in the NICTH syndrome is unclear. It has been reported that in the patients with NICTH big IGF-II lacks normal E-domain O-linked glycosylation, suggesting that the patient's big IGF-II might be generated by abnormal processing of pro-IGF-II. However, we have found that the apparent size of big IGF-II varies in sera from the patients with NICTH, and that there is a possibility that slower migration pattern of IGF-II might be because of a different size of sugar moiety attached to pro-IGF-II. In the present study using the sera from 10 patients with NICTH, we investigated the effect of O-glycosidase digestion on migration of IGF-II and analyzed the results by Western immunoblot. By Western immunoblot analysis the big IGF-II was reduced in size to 9.5 kDa in the enzyme-treated sera of the 10 patients with NICTH. The migration pattern is similar to that observed in sera of normal subjects after O-glycosidase digestion. These data indicate that big IGF-II from patients with NICTH is O-glycosylated, and the sizes of the sugar moiety are larger than those from normal subjects suggesting abnormal glycosylation in NICTH.