Dataset Information

Impact of growth hormone receptor blockade on substrate metabolism during fasting in healthy subjects.

ABSTRACT:

Context

Experimental studies in GH-deficient patients and in healthy subjects receiving somatostatin-infusion suggest that GH is an important regulator of substrate metabolism during fasting. These models may not adequately reflect the selective effects of GH, and GH receptor (GHR) blockade offers a new model to define the metabolic role of GH.

Objective

The aim of this study was to investigate the impact of GHR blockade on substrate metabolism and insulin sensitivity during fasting.

Design

We conducted a randomized, placebo-controlled, crossover study in 10 healthy young men.

Intervention

After 36 h of fasting with saline or pegvisomant (GHR blockade), the subjects were studied during a 4-h basal period and 2.5-h hyperinsulinemic euglycemic clamp.

Main outcome

We measured whole-body and forearm glucose, lipid, and protein metabolism, peripheral insulin sensitivity, and acyl and desacyl ghrelin.

Results

GHR blockade significantly suppressed circulating free fatty acids (1226 +/- 83 vs. 1074 +/- 65 micromol/liter; P = 0.03) and ketone bodies (3080 +/- 271 vs. 2015 +/- 235 micromol/liter; P ConclusionGHR blockade, without changes in circulating or tissue IGF-I levels, selectively suppresses lipid mobilization and oxidation after short-term fasting. This supports the notion that stimulation of lipolysis is a primary and important effect of GH.

SUBMITTER: Moller L

PROVIDER: S-EPMC2775657 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Publications

Impact of growth hormone receptor blockade on substrate metabolism during fasting in healthy subjects.

Moller Louise L Norrelund Helene H Jessen Niels N Flyvbjerg Allan A Pedersen Steen B SB Gaylinn Bruce D BD Liu Jianhua J Thorner Michael O MO Moller Niels N Lunde Jorgensen Jens Otto JO

The Journal of clinical endocrinology and metabolism 20091009 11

<h4>Context</h4>Experimental studies in GH-deficient patients and in healthy subjects receiving somatostatin-infusion suggest that GH is an important regulator of substrate metabolism during fasting. These models may not adequately reflect the selective effects of GH, and GH receptor (GHR) blockade offers a new model to define the metabolic role of GH.<h4>Objective</h4>The aim of this study was to investigate the impact of GHR blockade on substrate metabolism and insulin sensitivity during fasti ...[more]

PMID: 19820031

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Project description:Hepatocellular carcinoma (HCC) is an aggressive neoplasm with poor clinical outcome because most patients present at an advanced stage, at which point curative surgical options, such as tumor excision or liver transplantation, are not feasible. Therefore, the majority of HCC patients require systemic therapy. Nonetheless, the currently approved systemic therapies have limited effects, particularly in patients with advanced and resistant disease. Hence, there is a critical need to identify new molecular targets and effective systemic therapies to improve HCC outcome. The liver is a major target of the growth hormone receptor (GHR) signaling, and accumulating evidence suggests that GHR signaling plays an important role in HCC pathogenesis. We tested the hypothesis that GHR could represent a potential therapeutic target in this aggressive neoplasm. We measured GH levels in 767 HCC patients and 200 healthy controls, and then carried out clinicopathological correlation analyses. Moreover, specific inhibition of GHR was performed in vitro using siRNA and pegvisomant (a small peptide that blocks GHR signaling and is currently approved by the FDA to treat acromegaly) and in vivo, also using pegvisomant. GH was significantly elevated in 49.5% of HCC patients, and these patients had a more aggressive disease and poorer clinical outcome (P<0.0001). Blockade of GHR signaling with siRNA or pegvisomant induced substantial inhibitory cellular effects in vitro. In addition, pegvisomant potentiated the effects of sorafenib (P<0.01) and overcame sorafenib resistance (P<0.0001) in vivo. Mechanistically, pegvisomant decreased the phosphorylation of GHR downstream survival proteins including JAK2, STAT3, STAT5, IRS-1, AKT, ERK, and IGF-IR. In two patients with advanced-stage HCC and high GH who developed sorafenib resistance, pegvisomant caused tumor stability. Our data show that GHR signaling represents a novel "druggable" target, and pegvisomant may function as an effective systemic therapy in HCC. Our findings could also lead to testing GHR inhibition in other aggressive cancers.

Dataset Information

Impact of growth hormone receptor blockade on substrate metabolism during fasting in healthy subjects.

Context

Objective

Design

Intervention

Main outcome

Results

Publications

Impact of growth hormone receptor blockade on substrate metabolism during fasting in healthy subjects.

Similar Datasets

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