Growth Hormone Signaling in Vivo in Humans

Intracellular Signaling Peptides and Proteins Clinical Trial

Official title:

Growth Hormone (GH) Signaling in Vivo in Human Muscle and Adipose Tissue: Impact of Insulin, Substrate Background and gh Receptor Blockade

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00512473
• Other study ID #: 20050113
• Status: Completed
• Phase: N/A
• First received: August 6, 2007
• Last updated: August 6, 2007
• Start date: September 2005
• Est. completion date: April 2006

Study information

• Verified date: August 2007
• Source: University of Aarhus
• Contact: n/a
• Is FDA regulated: No
• Health authority: Denmark: The Danish National Committee on Biomedical Research Ethics
• Study type: Interventional

Clinical Trial Summary

Objective: GH induces insulin resistance in muscle and fat and in vitro data indicate that this may involve crosstalk between the signaling pathways of the two hormones.

Aim: To investigate GH and insulin signaling in vivo in human muscle and fat tissue in response to GH, GH receptor blockade and insulin stimulation..

Description:

The molecular mechanisms by which GH promotes insulin antagonism are still unclear. Stimulation of lipolysis could be of importance since high plasma FFA levels have been shown to interfere with insulin receptor signaling via inhibition of insulin-stimulated insulin receptor substrate (IRS)-1 associated phosphatidylinositol (PI) 3-kinase activity in human skeletal muscle, resulting in a decreased GLUT4 translocation and glucose transport (6). A recent study, however, was unable to document a suppression in the insulin-stimulated activity of either IRS-1 associated PI 3-kinase or the serin/threonin kinase Akt after GH administration to healthy humans, despite induction of lipolysis and insulin resistance (7). Other studies have shown that acute GH exposure induces insulin resistance in skeletal muscle rapidly and before the subsequent rise in plasma FFA (1;7;8). These observations indicate that GH may cause insulin resistance via a non-FFA mediated mechanism.

The predominant GH signal transduction cascade comprises activation of the GHR dimer, phosphorylation of JAK2 and subsequently activation of Stat5. The intact JAK2/Stat5 pathway is necessary for normal statural growth (9). There is animal and in vitro evidence to suggest that insulin and GH share post-receptor signaling pathways (10). Convergence has been reported at the levels of Stat5 and SOCS3 as well as on protein kinases comprising the major IR signaling pathway; IRS 1/2, PI 3-kinase, Akt and ERK 1/2 (11-14).

Pegvisomant is a GH analog and a competitive reversible GH receptor antagonist, which blocks peripheral GH signal transduction (15). Pegvisomant has been shown to inhibit the necessary conformational change of the GHR dimer and thus constitutes an optimal negative control in GH signaling studies.

The aim of this work was to further study GH signal transduction pathways in vivo in muscle and adipose tissue from healthy subjects in response to acute and more prolonged GH exposure as well as during hyperinsulinemia. The design also included administration of pegvisomant in an attempt to correct for spontaneous GH secretion.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 8
• Est. completion date: April 2006
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 20 Years to 40 Years

Eligibility

Inclusion Criteria:

• Male

• Healthy

• Not taking medication

Exclusion Criteria:

• Insulin resistance

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Crossover Assignment, Masking: Single Blind, Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Intracellular Signaling Peptides and Proteins

Intervention

Drug:
• Saline infusion
0.9 % NaCl
• Human Growth Hormone
0.5 mg genotropin administered as a bolus at t = 0
• Pegvisomant
30 mg Somavert administered at t = - 36 hours

Locations

Country	Name	City	State
Denmark	Medical Research Laboratories	Aarhus

Sponsors (1)

Lead Sponsor	Collaborator
University of Aarhus

Country where clinical trial is conducted

Denmark, 

References & Publications (1)

Gormsen LC, Nielsen C, Gjedsted J, Gjedde S, Vestergaard ET, Christiansen JS, Jørgensen JO, Møller N. Effects of free fatty acids, growth hormone and growth hormone receptor blockade on serum ghrelin levels in humans. Clin Endocrinol (Oxf). 2007 May;66(5) — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	GH-receptor signaling		hours
Secondary	Insulin sensitivity		hours