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

Growth Hormone Deficiency Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03878992
• Other study ID #: GHDSCs
• Status: Recruiting
• Phase: N/A
• Start date: April 30, 2019
• Est. completion date: December 31, 2021

Study information

• Verified date: February 2019
• Source: University of Aarhus
• Contact: Tine B Billeskov, PhD student
• Phone: +4560169141
• Email: tine[@]clin.au.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 12
• Est. completion date: December 31, 2021
• Est. primary completion date: March 1, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 100 Years

Eligibility

Inclusion Criteria:

• Newly diagnosed adult onset growth hormone deficiency

Exclusion Criteria:

• Documentation of Growth hormone deficiency for less than three months

• Pregnancy

Related Conditions & MeSH terms

• Growth Hormone Deficiency
• Growth Hormone Treatment

Intervention

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.

Locations

Country	Name	City	State
Denmark	Department of Endcrinology	Aarhus N

Sponsors (2)

Lead Sponsor	Collaborator
University of Aarhus	Aarhus University Hospital

Country where clinical trial is conducted

Denmark, 

References & Publications (12)

DeFronzo RA, Jacot E, Jequier E, Maeder E, Wahren J, Felber JP. The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes. 1981 Dec;30(12):1000-7. — View Citation

Meinhardt UJ, Ho KK. Modulation of growth hormone action by sex steroids. Clin Endocrinol (Oxf). 2006 Oct;65(4):413-22. Review. — View Citation

Nellemann B, Vendelbo MH, Nielsen TS, Bak AM, Høgild M, Pedersen SB, Biensø RS, Pilegaard H, Møller N, Jessen N, Jørgensen JO. Growth hormone-induced insulin resistance in human subjects involves reduced pyruvate dehydrogenase activity. Acta Physiol (Oxf). 2014 Feb;210(2):392-402. doi: 10.1111/apha.12183. Epub 2013 Nov 22. — View Citation

Pochini L, Oppedisano F, Indiveri C. Reconstitution into liposomes and functional characterization of the carnitine transporter from renal cell plasma membrane. Biochim Biophys Acta. 2004 Feb 10;1661(1):78-86. — View Citation

Rasmussen MH, Hvidberg A, Juul A, Main KM, Gotfredsen A, Skakkebaek NE, Hilsted J, Skakkebae NE. Massive weight loss restores 24-hour growth hormone release profiles and serum insulin-like growth factor-I levels in obese subjects. J Clin Endocrinol Metab. 1995 Apr;80(4):1407-15. Erratum in: J Clin Endocrinol Metab 1995 Aug;80(8):2446. — View Citation

Ridderstråle M. Signaling mechanism for the insulin-like effects of growth hormone--another example of a classical hormonal negative feedback loop. Curr Drug Targets Immune Endocr Metabol Disord. 2005 Mar;5(1):79-92. Review. — View Citation

Rosenbaum M, Gertner JM, Leibel RL. Effects of systemic growth hormone (GH) administration on regional adipose tissue distribution and metabolism in GH-deficient children. J Clin Endocrinol Metab. 1989 Dec;69(6):1274-81. — View Citation

Salomon F, Cuneo RC, Hesp R, Sönksen PH. The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N Engl J Med. 1989 Dec 28;321(26):1797-803. — View Citation

Ullman M, Oldfors A. Effects of growth hormone on skeletal muscle. I. Studies on normal adult rats. Acta Physiol Scand. 1989 Apr;135(4):531-6. — View Citation

Vahl N, Jørgensen JO, Jurik AG, Christiansen JS. Abdominal adiposity and physical fitness are major determinants of the age associated decline in stimulated GH secretion in healthy adults. J Clin Endocrinol Metab. 1996 Jun;81(6):2209-15. — View Citation

Vahl N, Jørgensen JO, Skjaerbaek C, Veldhuis JD, Orskov H, Christiansen JS. Abdominal adiposity rather than age and sex predicts mass and regularity of GH secretion in healthy adults. Am J Physiol. 1997 Jun;272(6 Pt 1):E1108-16. — View Citation

Zurlo F, Larson K, Bogardus C, Ravussin E. Skeletal muscle metabolism is a major determinant of resting energy expenditure. J Clin Invest. 1990 Nov;86(5):1423-7. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Phosphorylation of Akt in muscle biopsies	Muscle biopsies will be analysed for phosphorylation of Akt	Analyses will be performed through study completion, an expected average of 1.5 years
Secondary	Satellite cell count	The number of Satellite cells per muscle fiber will be analysed on muscle cross sections from muscle biopsies	Analyses will be performed through study completion, an expected average of 1.5 year
Secondary	Satellite cell proliferation and differentiation in cell culture	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.	Analyses will be performed through study completion, an expected average of 1.5 year
Secondary	Strength of muscle	assessed by isokinetic/dynamic measurements using a dynamometer	Analyses will be performed through study completion, an expected average of 1.5 year
Secondary	Muscle mass	Qualified by DXA scan	Analyses will be performed through study completion, an expected average of 1.5 year
Secondary	Glucose turnover rate	Evaluated through blood samples	Analyses will be performed through study completion, an expected average of 1.5 year
Secondary	Fatty acid turn over rate	evaluated through blood samples	Analyses will be performed through study completion, an expected average of 1.5 year
Secondary	Urea turnover rate	evaluated by blood samples and urin collection	Analyses will be performed through study completion, an expected average of 1.5 year