Growth Hormone Signaling in Vivo in Humans

University of Aarhus

Status: Completed

Conditions: Intracellular Signaling Peptides and Proteins

Treatments: Drug: Saline infusion; Drug: Pegvisomant; Drug: Human Growth Hormone

Study type: Interventional

Funder types: Other

Identifiers

NCT00512473

20050113

Details and patient eligibility

About

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..

Full 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.

Enrollment: 8 patients

Sex: Male

Ages: 20 to 40 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

• Male
• Healthy
• Not taking medication

Exclusion criteria

• Insulin resistance

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Single Blind

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8 participants in 3 patient groups, including a placebo group

A

Placebo Comparator group

Description:

I.v. saline for 8 hours

Treatment:

Drug: Saline infusion

GH

Experimental group

Description:

Growth hormone (0.5 mg s.c. at t = 0 hours)

Treatment:

Drug: Human Growth Hormone

Pegvisomant

Experimental group

Description:

Pegvisomant injection 30 mg 36 hours prior to the study

Treatment:

Drug: Pegvisomant