THE EFFECT OF GROWTH-HORMONE TREATMENT ON THE INSULIN-LIKE GROWTH-FACTOR AXIS IN A CHILD WITH NONISLET CELL TUMOR HYPOGLYCEMIA

We have previously described a case of tumor-associated hypoglycemia s econdary to the production of high molecular weight insulinlike growth factor (IGF)-II in a child with congenital neuroblastoma. The child's hypoglycemia resolved with GH therapy and has continued to be well co ntrolled for 1 yr. This represents one of the first cases of nonislet cell tumor hypoglycemia (NICTH) treated successfully with long-term ex ogenous GH. We now present an in-depth analysis of the IGF axis in thi s patient, before and after GH treatment. Although IGF-II levels at pr esentation were in the normal range, they were inappropriate for the p atient's low GH state. Furthermore, the percentage of ''big'' IGF-II w as elevated, as was the level of the IGF-IIE peptide, which is normall y cleaved in the processing of the mature peptide. On the initial eval uation, GH levels failed to rise in response to hypoglycemia, IGF-I le vels were low, IGF binding protein-3 (IG-FBP-3) levels were suppressed , and IGFBP-2 levels were elevated. We have shown that baseline IGFBP- 3 levels were low by RIA and immunoblotting and have demonstrated that this decrease was not associated with IGFBP protease activity. We hav e also demonstrated the baseline suppression of the acid labile subuni t (ALS) of the 150K ternary complex by a novel immunoblot assay. The r atio of IGFs to IGFBP-3 was dramatically elevated, presumably leading to hypoglycemia. Furthermore, the percentage of serum IGF-I and IGF-II present as part of a binary (50K) complex with IGFBPs was also increa sed. GH therapy resulted in a normalization of the levels of blood sug ars, IGFBP-3, ALS, IGFBP-2, and IGF-I, as well as the IGF/IGFBP-3 rati o. In summary, we have presented evidence that the hypoglycemia in thi s patient resulted from tumor production of high molecular weight IGF- II, which suppressed GH secretion, leading to the described derangemen ts in the IGF binding proteins. We speculate that as a result of the d ecreased IGFBP-3 and ALS levels, the IGF population was shifted from t he stable 150K complex to lower molecular weight complexes with IGF bi nding proteins, increasing IGF availability to tissues due to rapid tu rnover of these low molecular weight complexes. We demonstrated the re versal of the abnormalities in the IGFBP levels with GH treatment, cor responding to the clinical response of euglycemia.