Clinical trial NCT02782208: Lipolytic Effects of GH in Hypopituitary Patients in Vivo
Official title: Lipolytic Effects of GH in Hypopituitary Patients in Vivo: Molecular Mechanisms and Temporal Patterns.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Hypopituitarism
Insulin Resistance
Endocrine System Diseases
Glucose Metabolism Disorders
Metabolic Diseases
Pituitary Diseases
Brain Diseases
Lead sponsor: University of Aarhus
Sponsor class: OTHER
First posted: 2016-05-25
Enrollment: 9
Sex: MALE
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: BASIC_SCIENCE

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.


Eligibility criteria: Inclusion Criteria:

* hypopituitary patients with documented GH-deficiency

Exclusion Criteria:

* other significant disease

Primary outcomes:
measure: Lipolytic activity measured as area under the curve (AUC) for FFA (free fatty acid) before and during clamp-conditions.
timeFrame: 1 year
Secondary outcomes:
measure: GH signaling proteins and gene targets in adipose and skeletal muscle tissues measured by western blotting and qPCR
timeFrame: 1,5 years
measure: Insulin sensitivity as measured by M value and GIR (glucose infusion rate)
timeFrame: 6 months
measure: Substrate metabolism as measured by indirect calorimetry, tritiated glucose and circulating hormones and metabolites
timeFrame: 1 year
measure: PDH (pyruvate dehydrogenase) activity in skeletal muscle measured by an PDH activity assay
timeFrame: 1 year
Other outcomes:
Locations:
city: Aarhus
country: Denmark
facility: University Hospital of Aarhus
Study officials:
affiliation: University Hospital of Aarhus
name: Jens Otto L Jørgensen, Professor
role: PRINCIPAL_INVESTIGATOR
References:
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. doi: 10.1038/nm824. Epub 2003 Feb 3.
citation: Nellemann B, Vendelbo MH, Nielsen TS, Bak AM, Hogild M, Pedersen SB, Bienso RS, Pilegaard H, Moller N, Jessen N, Jorgensen 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.
citation: Clasen BF, Poulsen MM, Escande C, Pedersen SB, Moller N, Chini EN, Jessen N, Jorgensen 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.
citation: Krusenstjerna-Hafstrom T, Clasen BF, Moller N, Jessen N, Pedersen SB, Christiansen JS, Jorgensen 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.
citation: Nielsen TS, Jessen N, Jorgensen JO, Moller 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.
citation: Moller N, Jorgensen 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.
citation: Nielsen S, Moller N, Christiansen JS, Jorgensen JO. Pharmacological antilipolysis restores insulin sensitivity during growth hormone exposure. Diabetes. 2001 Oct;50(10):2301-8. doi: 10.2337/diabetes.50.10.2301.
citation: Hjelholt AJ, Charidemou E, Griffin JL, Pedersen SB, Gudiksen A, Pilegaard H, Jessen N, Moller N, Jorgensen JOL. Insulin resistance induced by growth hormone is linked to lipolysis and associated with suppressed pyruvate dehydrogenase activity in skeletal muscle: a 2 x 2 factorial, randomised, crossover study in human individuals. Diabetologia. 2020 Dec;63(12):2641-2653. doi: 10.1007/s00125-020-05262-w. Epub 2020 Sep 18.