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