Impaired formation of the ternary insulin-like growth factor-binding protein complex in patients with hypoglycemia due to nonislet cell tumors.
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.
Baxter
R C
RC
Department of Endocrinology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
Daughaday
W H
WH
D000368:Aged; D002352:Carrier Proteins / Q000097:blood / Q000378:metabolism*; D002845:Chromatography / Q000379:methods; D005260:Female; D005354:Fibrosarcoma / Q000150:complications; D006801:Humans; D007003:Hypoglycemia / Q000209:etiology / Q000378:metabolism*; D018969:Insulin-Like Growth Factor Binding Proteins; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D007680:Kidney Neoplasms / Q000150:complications; D007890:Leiomyosarcoma / Q000150:complications; D008113:Liver Neoplasms / Q000150:complications; D008297:Male; D008654:Mesothelioma / Q000150:complications; D008875:Middle Aged; D009369:Neoplasms / Q000150:complications*; D010386:Pelvic Neoplasms / Q000150:complications; D013899:Thoracic Neoplasms / Q000150:complications; D009396:Wilms Tumor / Q000150:complications
D002352:Carrier Proteins; D018969:Insulin-Like Growth Factor Binding Proteins; D007335:Insulin-Like Growth Factor II