Growth Hormone Signaling in Vivo in Humans

This study has been completed.
Sponsor:
Information provided by:
University of Aarhus
ClinicalTrials.gov Identifier:
NCT00512473
First received: August 6, 2007
Last updated: NA
Last verified: August 2007
History: No changes posted

August 6, 2007
August 6, 2007
September 2005
Not Provided
GH-receptor signaling [ Time Frame: hours ]
Same as current
No Changes Posted
Insulin sensitivity [ Time Frame: hours ]
Same as current
Not Provided
Not Provided
 
Growth Hormone Signaling in Vivo in Humans
Growth Hormone (GH) Signaling in Vivo in Human Muscle and Adipose Tissue: Impact of Insulin, Substrate Background and gh Receptor Blockade

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..

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.

Interventional
Not Provided
Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Crossover Assignment
Masking: Single Blind
Primary Purpose: Basic Science
Intracellular Signaling Peptides and Proteins
  • Drug: Saline infusion
    0.9 % NaCl
  • Drug: Human Growth Hormone
    0.5 mg genotropin administered as a bolus at t = 0
  • Drug: Pegvisomant
    30 mg Somavert administered at t = - 36 hours
  • Placebo Comparator: A
    I.v. saline for 8 hours
    Intervention: Drug: Saline infusion
  • Experimental: GH
    Growth hormone (0.5 mg s.c. at t = 0 hours)
    Intervention: Drug: Human Growth Hormone
  • Experimental: Pegvisomant
    Pegvisomant injection 30 mg 36 hours prior to the study
    Intervention: Drug: Pegvisomant

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
8
April 2006
Not Provided

Inclusion Criteria:

  • Male
  • Healthy
  • Not taking medication

Exclusion Criteria:

  • Insulin resistance
Male
20 Years to 40 Years
Yes
Contact information is only displayed when the study is recruiting subjects
Denmark
 
NCT00512473
20050113
No
Not Provided
University of Aarhus
Not Provided
Principal Investigator: Lars C Gormsen, MD Aarhus University Hospital, Department M
University of Aarhus
August 2007

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP