Central and peripheral actions of somatostatin on the growth hormone–IGF-I axis
Robert D. Murray, … , Yutaka Umehara, Shlomo Melmed
Robert D. Murray, … , Yutaka Umehara, Shlomo Melmed
Published August 1, 2004
Citation Information: J Clin Invest. 2004;114(3):349-356. https://doi.org/10.1172/JCI19933.
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Article Endocrinology

Central and peripheral actions of somatostatin on the growth hormone–IGF-I axis

Abstract

Somatostatin (SRIF) analogs provide safe and effective therapy for acromegaly. In a proportion of patients, however, SRIF analogs may lead to discordant growth hormone (GH) and IGF-I suppression, which suggests a more complex mechanism than attributable to inhibition of GH release alone. To elucidate whether SRIF acts peripherally on the GH–IGF-I axis, we showed that rat hepatocytes express somatostatin receptor subtypes-2 and -3 and that IGF-I mRNA and protein levels were suppressed in a dose-dependent manner by administration of octreotide. The inhibitory effect of SRIF was not apparent without added GH and in the presence of GH was specific for IGF-I induction and did not inhibit GH-induced c-myc or extracellular signal regulated kinase (ERK) phosphorylation. Pertussis toxin treatment of hepatocytes incubated with GH and SRIF, or with GH and octreotide, abrogated the inhibitory effect on GH-induced IGF-I, which confirms the requirement for the inhibitory G-protein. Treatment with SRIF and GH increased protein tyrosine phosphatase (PTP) activity and inhibited signal transducer and activator of transcription-5b (STAT5b) phosphorylation and nuclear localization. Octreotide also inhibited GH-stimulated IGF-I protein content of ex vivo–perfused rat livers. The results demonstrate that SRIF acts both centrally and peripherally to control the GH–IGF-I axis, providing a mechanistic explanation for SRIF analog action in treating patients with GH-secreting pituitary adenomas.

Authors

Robert D. Murray, Kiwon Kim, Song-Guang Ren, Marjorie Chelly, Yutaka Umehara, Shlomo Melmed

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SRIF suppresses GH-induced hepatocyte IGF-I. (A) Isolated rat hepatocyte...
SRIF suppresses GH-induced hepatocyte IGF-I. (A) Isolated rat hepatocytes were incubated with GH (100 or 500 ng/ml) for 24 hours with or without 1 hour preincubation with 100 nM SRIF or octreotide (OCT). RNA was quantitated by RPA analysis. Upper panel: representative blot. Lower panel: mean fold induction of IGF-I mRNA of three individual experiments after normalization for β-actin. *P < 0.05 compared with GH-treated cells. (B) Representative RPA quantitation for IGF-I and β-actin content of isolated rat hepatocytes following incubation with 100 nM SRIF or octreotide for 24 hours with no GH stimulation. Upper panel: IGF-I; lower panel: β-actin. (C) RPA analysis of IGF-I and β-actin from isolated rat hepatocytes treated with GH (500 ng/ml) for 24 hours with and without preincubation with 0.01–100 nM SRIF (upper two panels), or 0.1–500 nM octreotide for 1 hour (lower two panels).