Growth Hormone Signaling in Vivo in Humans
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..
|Intracellular Signaling Peptides and Proteins||Drug: Saline infusion Drug: Human Growth Hormone Drug: Pegvisomant|
|Study Design:||Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single Blind
Primary Purpose: Basic Science
|Official Title:||Growth Hormone (GH) Signaling in Vivo in Human Muscle and Adipose Tissue: Impact of Insulin, Substrate Background and gh Receptor Blockade|
- GH-receptor signaling [ Time Frame: hours ]
- Insulin sensitivity [ Time Frame: hours ]
|Study Start Date:||September 2005|
|Study Completion Date:||April 2006|
Placebo Comparator: A
I.v. saline for 8 hours
Drug: Saline infusion
0.9 % NaCl
Growth hormone (0.5 mg s.c. at t = 0 hours)
Drug: Human Growth Hormone
0.5 mg genotropin administered as a bolus at t = 0
Pegvisomant injection 30 mg 36 hours prior to the study
30 mg Somavert administered at t = - 36 hours
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00512473
|Medical Research Laboratories|
|Aarhus, Denmark, 8000|
|Principal Investigator:||Lars C Gormsen, MD||Aarhus University Hospital, Department M|