OCTREOTIDE INHIBITS INSULIN-LIKE GROWTH FACTOR-I HEPATIC GENE-EXPRESSION IN THE HYPOPHYSECTOMIZED RAT - EVIDENCE FOR A DIRECT AND INDIRECT MECHANISM OF ACTION

Somatostatin and somatostatin analogs are known to interact with the G H-insulin-like growth factor (IGF)-I axis by inhibiting GH secretion a nd consequently hepatic IGF-I production. Indirect evidence suggests t hat octreotide, a somatostatin analog, reduces serum IGF-I levels rela tively more than expected from GH reduction, implying a GH-independent pathway of action. To study the role of octreotide in the regulation of IGF-I production, independently of endogenous GH, we used the hypop hysectomized (hypox) rat to measure hepatic IGF-I expression and also employed cultured rat hepatocytes to examine whether octreotide has an y direct effect on the production of IGF-I. Forty male hypox Sprague-D awley rats were randomized into 4 groups to receive daily injections f or 3 days of either saline, human GH (hGH) (100 g), octreotide (100 g twice), or both hGH (100 g) and octreotide (100 g twice). GH stimulate d serum IGF-I levels to 104 +/- 10-mu-g/liter as compared to saline (2 6 +/- 2-mu-g/liter). Octreotide alone had no effect, but combining oct reotide and hGH significantly reduced the hGH-induced rise in the IGF- I levels (52 +/- 6-mu-g/liter). The relative expression of hepatic IGF -I in the rats treated with hGH increased by 4-fold compared to that i n the saline-treated rats. Octreotide administered simultaneously with hGH potently blocked the hGH-induced IGF-I expression to control leve ls. In cultured hepatocytes, IGF-I mRNA levels maximally stimulated by combining bGH and glucagon were significantly inhibited in the presen ce of octreotide at low concentrations (0.3 and 3 ng/ml) by 25% and 45 %, respectively. In contrast, high concentrations of octreotide (30 an d 300 ng/ml) had no significant effect on IGF-I mRNA abundance. We con clude that: 1) octreotide inhibits IGF-I serum levels and hepatic gene expression in the hypox rat; and 2) octreotide can inhibit partially the direct effects of GH and glucagon on hepatic IGF-I production.