- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00512473
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..
Study Overview
Status
Intervention / Treatment
Detailed 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.
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
-
-
-
Aarhus, Denmark, 8000
- Medical Research Laboratories
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Male
- Healthy
- Not taking medication
Exclusion Criteria:
- Insulin resistance
Study Plan
How is the study designed?
Design Details
- Primary Purpose: BASIC_SCIENCE
- Allocation: RANDOMIZED
- Interventional Model: CROSSOVER
- Masking: SINGLE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
PLACEBO_COMPARATOR: A
I.v. saline for 8 hours
|
0.9 % NaCl
|
EXPERIMENTAL: GH
Growth hormone (0.5 mg s.c. at t = 0 hours)
|
0.5 mg genotropin administered as a bolus at t = 0
|
EXPERIMENTAL: Pegvisomant
Pegvisomant injection 30 mg 36 hours prior to the study
|
30 mg Somavert administered at t = - 36 hours
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
GH-receptor signaling
Time Frame: hours
|
hours
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Insulin sensitivity
Time Frame: hours
|
hours
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Lars C Gormsen, MD, Aarhus University Hospital, Department M
Publications and helpful links
General Publications
- Gormsen LC, Nielsen C, Gjedsted J, Gjedde S, Vestergaard ET, Christiansen JS, Jorgensen JO, Moller 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):641-5. doi: 10.1111/j.1365-2265.2007.02786.x.
- Gormsen LC, Nielsen C, Jessen N, Jorgensen JO, Moller N. Time-course effects of physiological free fatty acid surges on insulin sensitivity in humans. Acta Physiol (Oxf). 2011 Mar;201(3):349-56. doi: 10.1111/j.1748-1716.2010.02181.x. Epub 2010 Oct 11.
- Nielsen C, Gormsen LC, Jessen N, Pedersen SB, Moller N, Lund S, Jorgensen JO. Growth hormone signaling in vivo in human muscle and adipose tissue: impact of insulin, substrate background, and growth hormone receptor blockade. J Clin Endocrinol Metab. 2008 Jul;93(7):2842-50. doi: 10.1210/jc.2007-2414. Epub 2008 May 6.
Study record dates
Study Major Dates
Study Start
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ESTIMATE)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 20050113
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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