Lipolytic Effects of GH in Hypopituitary Patients in Vivo

Insulin Resistance Clinical Trial

Official title:

Lipolytic Effects of GH in Hypopituitary Patients in Vivo: Molecular Mechanisms and Temporal Patterns.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02782208
• Other study ID #: GHD01
• Status: Completed
• Phase: N/A
• Start date: February 10, 2016
• Est. completion date: December 22, 2016

Study information

• Verified date: October 2017
• Source: University of Aarhus
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Growth hormone (GH) is essential for longitudinal bone growth and somatic development. These protein anabolic effects require sufficient nutritional supply. During fasting and caloric restriction GH predominantly promotes fat metabolism.

GH counteracts the effect of insulin in many tissues, of which insulin-stimulated glucose uptake in skeletal muscle has been most extensively studied. Substrate competition between elevated free fatty acids and glucose is suggested as a mechanism, and this hypothesis can be tested mechanistically by means of acipimox, which is a nicotinic acid that suppresses the fat metabolizing effects of GH.

The hypothesis is, that the suppressive effect of GH on insulin-stimulated glucose uptake in skeletal muscle is obviated by acipimox-induced inhibition of fat metabolism.

In order to investigate this, eight adult hypopituitary patients with documented GH-deficiency will be studied in the presence and absence of GH and acipimox, respectively, and biopsies from skeletal muscle and subcutaneous adipose tissue will be analyzed.

Knowledge of the effects of growth hormone and fat metabolism can in shot-sight as well as in long-sight have great importance for the understanding of growth disorders from overweight and type 2 diabetes to malnutrition and eating disorders.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 9
• Est. completion date: December 22, 2016
• Est. primary completion date: December 22, 2016
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• hypopituitary patients with documented GH-deficiency

Exclusion Criteria:

• other significant disease

Related Conditions & MeSH terms

• Brain Diseases
• Endocrine System Diseases
• Glucose Metabolism Disorders
• Hypopituitarism
• Insulin Resistance
• Metabolic Diseases
• Pituitary Diseases

Intervention

Drug:
• Acipimox
Acipimox is administered 4 times previous to and during the investigation day. Acipimox is used to suppress the lipolytic effect of GH.
• Placebo
Placebo is administered 4 times previous to and during the investigation day.
• GH substitution
GH substitution as usually

Other:
• GH pause
GH substitution pause two days prior to the experimental day

Locations

Country	Name	City	State
Denmark	University Hospital of Aarhus	Aarhus

Sponsors (1)

Lead Sponsor	Collaborator
University of Aarhus

Country where clinical trial is conducted

Denmark, 

References & Publications (7)

Clasen BF, Poulsen MM, Escande C, Pedersen SB, Møller N, Chini EN, Jessen N, Jørgensen JO. Growth hormone signaling in muscle and adipose tissue of obese human subjects: associations with measures of body composition and interaction with resveratrol treatment. J Clin Endocrinol Metab. 2014 Dec;99(12):E2565-73. doi: 10.1210/jc.2014-2215. — View Citation

Krusenstjerna-Hafstrøm T, Clasen BF, Møller N, Jessen N, Pedersen SB, Christiansen JS, Jørgensen JO. Growth hormone (GH)-induced insulin resistance is rapidly reversible: an experimental study in GH-deficient adults. J Clin Endocrinol Metab. 2011 Aug;96(8):2548-57. doi: 10.1210/jc.2011-0273. Epub 2011 May 25. — View Citation

Møller N, Jørgensen JO. Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects. Endocr Rev. 2009 Apr;30(2):152-77. doi: 10.1210/er.2008-0027. Epub 2009 Feb 24. 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

Nielsen S, Møller N, Christiansen JS, Jørgensen JO. Pharmacological antilipolysis restores insulin sensitivity during growth hormone exposure. Diabetes. 2001 Oct;50(10):2301-8. — View Citation

Nielsen TS, Jessen N, Jørgensen JO, Møller N, Lund S. Dissecting adipose tissue lipolysis: molecular regulation and implications for metabolic disease. J Mol Endocrinol. 2014 Jun;52(3):R199-222. doi: 10.1530/JME-13-0277. Epub 2014 Feb 27. Review. — View Citation

Tunaru S, Kero J, Schaub A, Wufka C, Blaukat A, Pfeffer K, Offermanns S. PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect. Nat Med. 2003 Mar;9(3):352-5. Epub 2003 Feb 3. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Lipolytic activity measured as area under the curve (AUC) for FFA (free fatty acid) before and during clamp-conditions.		1 year
Secondary	GH signaling proteins and gene targets in adipose and skeletal muscle tissues measured by western blotting and qPCR		1,5 years
Secondary	Insulin sensitivity as measured by M value and GIR (glucose infusion rate)		6 months
Secondary	Substrate metabolism as measured by indirect calorimetry, tritiated glucose and circulating hormones and metabolites		1 year
Secondary	PDH (pyruvate dehydrogenase) activity in skeletal muscle measured by an PDH activity assay		1 year