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Effects of Growth Hormone and IGF-1 on Anabolic Signals and Stem Cell Recruitment in Human Skeletal Muscle

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ClinicalTrials.gov Identifier: NCT03878992
Recruitment Status : Not yet recruiting
First Posted : March 18, 2019
Last Update Posted : March 18, 2019
Sponsor:
Collaborator:
Aarhus University Hospital
Information provided by (Responsible Party):
University of Aarhus

Brief Summary:
12 adult hypopituitary patients with newly diagnosed Growth hormone (GH)-deficiency will be studied two times. The first examinations will be performed shortly after time of diagnose before initiation of exogenous GH treatment, where each subject will receive a single intravenous bolus of 0.5 mg GH. The examination day will be repeated after prolonged GH replacement therapy (>3 month after treatment initiation).

Condition or disease Intervention/treatment Phase
Growth Hormone Deficiency Growth Hormone Treatment Drug: Genotropin miniquick 0.5 mg, injection Not Applicable

Detailed Description:

The overarching aim of this project is to investigate the mechanisms underlying loss of muscle mass in adults (sarcopenia) and the therapeutic potential of growth hormone (GH). The underlying hypothesis is that absence of GH and subsequent reduced insulin-like growth factor I (IGF-I) will impair normal proliferation of skeletal muscle stem cells and this is associated with metabolic dysfunction.

GH is an important regulator of substrate metabolism and muscle mass. GH treatment reduces overall fat mass (FM) through lipolytic actions in adipose tissues and decreased adipose tissue triacylglycerol (TAG) synthesis. In skeletal muscle, exogenous GH administration production shifts substrate metabolism from glucose to lipid oxidation. In addition, GH mediates protein anabolic actions by production of IGF-I during sufficient nutrient supply and maintained insulin secretion. Circulating IGF-I is primarily produced in the liver, but animal studies suggest that locally produced autocrine and paracrine IGF-I is sufficient to maintain normal growth.

GH deficiency (GHD) is a rare disorder characterized by the inadequate secretion of GH from the anterior pituitary gland and requires treatment with exogenous GH administration. Cell culture studies demonstrates that GH elicits insulin-like effects in cells deprived of GH. GH exerts its biological effects through binding to site 1 and 2 on the extracellular domain of a preformed GHR dimer. GHR activation initiates auto-phosphorylation of the receptor-associated Janus Kinase 2 (JAK2), which subsequently induces GHR cross-phosphorylation. The insulin-like effects are mediated by tyrosine phosphorylation of downstream targets including insulin receptor substrate-1 (IRS-1) and IRS-2. During physiological conditions, this signaling pathway is inhibited by the actions of a class of proteins known as suppressors of cytokine signaling (SOCSs).

GHD in adults can be acquired as a result of trauma, infection, radiation therapy, or tumor growth within the brain. It is characterized by a number of variable symptoms including reduced energy levels, altered body composition and reduced muscle strength. Satellite cells (SCs), the skeletal muscle stem cells, are essential for muscle regeneration in genetic or autoimmune muscle diseases as well as after ischemic, chemical or mechanical trauma to the myofibers. Furthermore, SCs are the primary source to supply new myonuclei to growing myofibers during non-traumatic mechanical overload. In rats, GH-administration increases number of SCs in cross-sections of muscle fibres22, and fibre type composition in skeletal muscle is altered in animals with GHD. Together these findings indicate an importance of GH and IGF-I stimulation for muscle regeneration.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Intervention Model: Sequential Assignment
Intervention Model Description: All participants will be studies two times - one time before initiation of GH replacement therapy and one time following three months of GH replacement therapy. The two times are identical. The trial day includes infusion of tracers (glucose, tyrosine, phenylalanine, urea, palmitate), muscle biopsies, subcutaneous fat biopsies, an intravenous bolus of 0.5 mg GH, indirect calorimetry, plethysmography, blood samples, strength test, DXA scan and spectroscopy of liver and muscle.
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Effects of Growth Hormone and IGF-1 on Anabolic Signals and Stem Cell Recruitment in Human Skeletal Muscle
Estimated Study Start Date : March 15, 2019
Estimated Primary Completion Date : March 1, 2021
Estimated Study Completion Date : December 31, 2021


Arm Intervention/treatment
GHD
GHD patients will be studied two times - one time before initiation of GH replacement therapy and one time following three months of GH replacement therapy. The two trial days are identical
Drug: Genotropin miniquick 0.5 mg, injection
GH will be given as an injection. Muscle biopsy will be obtained from m. vests laterals of the dominant leg. Fat biopsies will be obtained from subcutaneous abdominal fat. Tracers will be given as a bolus followed by continuous infusion for 6 hours. For palmitate tracer the infusion will be for only 1,5 hours followed by a one hour break and then another 1 hour infusion. Blood tests will be drawn from a venous catheter placed on the dorsal side of the hand.
Other Names:
  • Muscle biopsy
  • fat biopsy
  • blood tests
  • pletysmography
  • Tracers of metabolism, infusion




Primary Outcome Measures :
  1. Phosphorylation of Akt in muscle biopsies [ Time Frame: Analyses will be performed through study completion, an expected average of 1.5 years ]
    Muscle biopsies will be analysed for phosphorylation of Akt


Secondary Outcome Measures :
  1. Satellite cell count [ Time Frame: Analyses will be performed through study completion, an expected average of 1.5 year ]
    The number of Satellite cells per muscle fiber will be analysed on muscle cross sections from muscle biopsies

  2. Satellite cell proliferation and differentiation in cell culture [ Time Frame: Analyses will be performed through study completion, an expected average of 1.5 year ]
    Analyses of satellite cells ability to proliferate and differentiate will be performed on cell culture following fluorescent activated cell sorting. Comparison will be between first and second visit.

  3. Strength of muscle [ Time Frame: Analyses will be performed through study completion, an expected average of 1.5 year ]
    assessed by isokinetic/dynamic measurements using a dynamometer

  4. Muscle mass [ Time Frame: Analyses will be performed through study completion, an expected average of 1.5 year ]
    Qualified by DXA scan

  5. Glucose turnover rate [ Time Frame: Analyses will be performed through study completion, an expected average of 1.5 year ]
    Evaluated through blood samples

  6. Fatty acid turn over rate [ Time Frame: Analyses will be performed through study completion, an expected average of 1.5 year ]
    evaluated through blood samples

  7. Urea turnover rate [ Time Frame: Analyses will be performed through study completion, an expected average of 1.5 year ]
    evaluated by blood samples and urin collection



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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Newly diagnosed adult onset growth hormone deficiency

Exclusion Criteria:

  • Documentation of Growth hormone deficiency for less than three months
  • Pregnancy

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03878992


Contacts
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Contact: Tine B Billeskov, PhD student +4560169141 tine@clin.au.dk
Contact: Jens Otto Jørgensen, Professor +4578462025 joj@clin.au.dk

Sponsors and Collaborators
University of Aarhus
Aarhus University Hospital
Investigators
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Study Chair: Jens Otto Jørgensen, Professor Aarhus University Hospital

Publications:

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Responsible Party: University of Aarhus
ClinicalTrials.gov Identifier: NCT03878992     History of Changes
Other Study ID Numbers: GHDSCs
First Posted: March 18, 2019    Key Record Dates
Last Update Posted: March 18, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: There is no specific plan to share IPD at the moment. If this should be of interest it will only happen after approval from the local ethics committee

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of Aarhus:
Growth hormone
Satellite cells
Metabolism
insulin-like effects
Additional relevant MeSH terms:
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Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs