Lipolytic Effects of GH in Hypopituitary Patients in Vivo
Study Details
Study Description
Brief 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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
N/A |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: Acipimox/GH substitution Drug: Acipimox Tablet Acipimox 250 mg administered 4 times previous to and during the investigation day Other Name: Tablet Olbetam 250 mg Continue GH substitution as usually. |
Drug: Acipimox
Acipimox is administered 4 times previous to and during the investigation day. Acipimox is used to suppress the lipolytic effect of GH.
Other Names:
Drug: GH substitution
GH substitution as usually
|
| Active Comparator: Acipimox/GH pause Drug: Acipimox Tablet Acipimox 250 mg administered 4 times previous to and during the investigation day Other Name: Tablet Olbetam 250 mg Pause GH substitution to days prior to the study day. |
Drug: Acipimox
Acipimox is administered 4 times previous to and during the investigation day. Acipimox is used to suppress the lipolytic effect of GH.
Other Names:
Other: GH pause
GH substitution pause two days prior to the experimental day
|
| Placebo Comparator: Placebo/GH substitution Drug: Placebo tablets Continue GH substitution as usually. |
Drug: Placebo
Placebo is administered 4 times previous to and during the investigation day.
Drug: GH substitution
GH substitution as usually
|
| Placebo Comparator: Placebo/GH pause Drug: Placebo tablets Pause GH substitution to days prior to the study day. |
Drug: Placebo
Placebo is administered 4 times previous to and during the investigation day.
Other: GH pause
GH substitution pause two days prior to the experimental day
|
Outcome Measures
Primary Outcome Measures
- Lipolytic activity measured as area under the curve (AUC) for FFA (free fatty acid) before and during clamp-conditions. [1 year]
Secondary Outcome Measures
- GH signaling proteins and gene targets in adipose and skeletal muscle tissues measured by western blotting and qPCR [1,5 years]
- Insulin sensitivity as measured by M value and GIR (glucose infusion rate) [6 months]
- Substrate metabolism as measured by indirect calorimetry, tritiated glucose and circulating hormones and metabolites [1 year]
- PDH (pyruvate dehydrogenase) activity in skeletal muscle measured by an PDH activity assay [1 year]
Eligibility Criteria
Criteria
Inclusion Criteria:
- hypopituitary patients with documented GH-deficiency
Exclusion Criteria:
- other significant disease
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University Hospital of Aarhus | Aarhus | Denmark | 8000 |
Sponsors and Collaborators
- University of Aarhus
Investigators
- Principal Investigator: Jens Otto L Jørgensen, Professor, University Hospital of Aarhus
Study Documents (Full-Text)
None provided.More Information
Publications
- 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.
- 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.
- 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.
- 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.
- Nielsen S, Møller N, Christiansen JS, Jørgensen JO. Pharmacological antilipolysis restores insulin sensitivity during growth hormone exposure. Diabetes. 2001 Oct;50(10):2301-8.
- 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.
- 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.
- GHD01