Growth Hormone Signaling in Vivo in Humans
Condition: Intracellular Signaling Peptides and Proteins
Study type: Interventional

Summary: 
      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..
    

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.
    

Intervention name(s): Saline infusion; Human Growth Hormone; Pegvisomant
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 0.9 % NaCl; 0.5 mg genotropin administered as a bolus at t = 0; 30 mg Somavert administered at t = - 36 hours
Intervention MeSH terms: Hormones
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single
Primary purpose: Basic Science
Keywords: GH, GH receptor blockade, GH signaling, insulin resistance