Journal of Clinical Endocrinology & Metabolism, Vol 73, 696-702, Copyright © 1991 by Endocrine Society

ARTICLES

Impaired formation of the ternary insulin-like growth factor-binding protein complex in patients with hypoglycemia due to nonislet cell tumors

RC Baxter and WH Daughaday
Department of Endocrinology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.

In some subjects with hypoglycemia associated with tumors of mesenchymal origin, high insulin-like growth factor-II (IGF-II) levels have been described in serum and in the tumors. Tumor IGF-II of 10-15 kDa circulates in a 60-kDa complex, in contrast to the ternary 150-kDa complex in which serum IGFs normally circulate together with the IGF- binding subunit (IGFBP-3) and the acid-labile subunit (alpha-subunit). This study examines the molecular distribution and complex-forming activity of the components of the ternary complex in the serum of subjects with mesenchymal tumor hypoglycemia. Total serum IGFBP-3 levels were 60% of normal in tumor patients and appeared at 60 kDa on gel chromatography, shifting after tumor removal to 150 kDa. Total alpha-subunit levels were 40% of normal in patients with tumors, increasing after tumor removal to 70% of normal and changing in elution profile from a peak typical of uncomplexed alpha-subunit to the normal broad peak representing both complexed and uncomplexed alpha-subunit. Although low by RIA, alpha-subunit activity in a ternary complex formation assay was normal, indicating that the ability of free alpha- subunit in the patients' circulation to combine with exogenous IGFBP-3 plus IGF-I was not impaired. In contrast, in an assay that tested the ability of IGF-IGFBP complexes in the patients' circulation to combine with pure alpha-subunit, complex formation activity was 75-85% below normal in preoperative sera, despite low normal IGFBP-3 levels. Therefore, the cause of hypoglycemia in these patients may be the inability of complexes between the abnormal tumor IGF-II and IGFBP-3 to be sequestered in the biologically inactive ternary complex.

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