OCTREOTIDE STIMULATES INSULIN-LIKE GROWTH FACTOR-BINDING PROTEIN-1 - A POTENTIAL PITUITARY-INDEPENDENT MECHANISM FOR DRUG-ACTION

As the long-acting somatostatin analog octreotide attenuates polypeptide hormone hypersecretion, has recently been used to effectively treat acromegaly and gastrointestinal carcinoid tumors. Most growth-promoting actions of GH are mediated by insulin-like growth factor-I (IGF-I), which circulates complexed with multiple binding proteins (IGFBPs). IGFBP-1, a nonglycosylated peptide, competes with the IGF-I receptor for ligand binding and also regulates IGF action. To examine GH-independent mechanisms for octreotide regulation of the GH axis, circulating levels of IGFBP-1 were measured hourly after sc octreotide or saline administration in normal and GH-deficient adults. As IGFBP-1 is inhibited by insulin and GH, the dynamic pattern of alterations in GH and insulin levels was also assessed. After octreotide (100 mug) administration to 10 normal subjects, mean IGFBP-1 concentrations were stimulated from 23 +/- 4 to 72 +/- 18 mug/L (P < 0.007 us. saline) after 2 h. Maximal induction of IGFBP-1 levels occurred after 3 h (325 +/- 115 mug/L; P < 0.02 vs. saline) and remained elevated (P < 0.005) for 6 h. IGFBP-1 was induced by octreotide in all subjects and was confirmed by Western ligand blotting. Insulin and GH levels preceding the rise in IGFBP-I were unaltered by octreotide. Octreotide stimulated IGFBP-I 5-fold during a sustained fast in 4 normal subjects, despite equally suppressed insulin levels in both saline- and octreotide-treated groups. In 4 GH-deficient adults, IGFBP-1 levels were stimulated by octreotide from 16 +/- 3 to 146 +/- 36 and 154 +/- 28 mug/L after 3 and 4 h, respectively. In conclusion, the somatostatin analog octreotide induces IGFBP-1 independently of GH and insulin. As IGFBP-1 regulates the action of IGF-I, octreotide stimulation of IGFBPs may represent an additional pharmacological mechanism for attenuating the GH-IGF-I axis.