Regulation of the insulin-like growth factors and their binding proteins by glucocorticoid and growth hormone in nonislet cell tumor hypoglycemia.
Hypoglycemia in patients with nonislet cell tumors is often secondary to overexpression of tumor insulin-like growth factor (IGF) II. In these patients the formation of serum complexes between IGFs, IGF binding protein-3 (IGFBP-3), and the acid-labile subunit (ALS) is impaired. An 87-yr-old woman with nonislet cell tumor hypoglycemia resulting from a localized fibrous tumor of the pleura was treated for 97 days with graded doses of prednisolone (30, 10, and 5 mg/day) followed by GH (1, 4, 8, 4, and 2 U/day). Both prednisolone and GH alleviated the hypoglycemia, concomitantly with increases in IGF-I, IGFBP-3, and ALS levels. Pretreatment serum IGFBP-2 and IGFBP-6 levels were greatly elevated, but as glucose normalized with treatment, only IGFBP-2 decreased, showing an inverse correlation with glucose (r = 0.716). IGFBP-1 gave a variable pattern not clearly related to blood glucose. Both treatments caused a redistribution of serum IGFBP-3 from binary- to ternary-complexed forms. However, only prednisolone improved the ability of IGFBP-3 to bind ALS in vitro. Prednisolone also suppressed IGF-II, the effect being confined to pro-IGF-II forms. Compared with normal IGF-II, pro-IGF-II inhibited ALS binding to IGFBP-3 in vitro. Although prednisolone and GH reverse hypoglycemia by different mechanisms, with only prednisolone suppressing tumor IGF-II secretion, both increase the formation of ternary IGF-IGFBP-3 complexes. We conclude that the failure of serum IGFBP-3 and tumor IGF-II to complex with ALS is a primary cause of hypoglycemia in nonislet cell tumor hypoglycemia.
Baxter
R C
RC
Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, New South Wales, Australia.
Holman
S R
SR
Corbould
A
A
Stranks
S
S
Ho
P J
PJ
Braund
W
W
D000368:Aged; D000369:Aged, 80 and over; D002352:Carrier Proteins / Q000378:metabolism*; D005260:Female; D005350:Fibroma / Q000150:complications; D013006:Growth Hormone / Q000627:therapeutic use*; D006801:Humans; D007003:Hypoglycemia / Q000209:etiology* / Q000378:metabolism; D018969:Insulin-Like Growth Factor Binding Proteins; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D010997:Pleural Neoplasms / Q000150:complications*; D011241:Prednisone / Q000627:therapeutic use*; D013002:Somatomedins / Q000378:metabolism*
D002352:Carrier Proteins; D018969:Insulin-Like Growth Factor Binding Proteins; D013002:Somatomedins; D007335:Insulin-Like Growth Factor II; D013006:Growth Hormone; D011241:Prednisone