Lipolytic Effects of GH in Hypopituitary Patients in Vivo

NCT02782208 | Completed

• 1 other identifier: GHD01
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• Lipolytic activity measured as area under the curve (AUC) for FFA (free fatty acid) before and during clamp-conditions.

  1 year

Secondary Outcomes (4)

• 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

Study Arms (4)

Acipimox/GH substitution

ACTIVE COMPARATOR

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; Drug: GH substitution

Acipimox/GH pause

ACTIVE COMPARATOR

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; Other: GH pause

Placebo/GH substitution

PLACEBO COMPARATOR

Drug: Placebo tablets Continue GH substitution as usually.

Drug: Placebo; Drug: GH substitution

Placebo/GH pause

PLACEBO COMPARATOR

Drug: Placebo tablets Pause GH substitution to days prior to the study day.

Drug: Placebo; Other: GH pause

Interventions

Acipimox DRUG

Acipimox is administered 4 times previous to and during the investigation day. Acipimox is used to suppress the lipolytic effect of GH.

Also known as: Olbetam

Acipimox/GH pause; Acipimox/GH substitution

Placebo DRUG

Placebo is administered 4 times previous to and during the investigation day.

Placebo/GH pause; Placebo/GH substitution

GH substitution DRUG

GH substitution as usually

Acipimox/GH substitution; Placebo/GH substitution

GH pause OTHER

GH substitution pause two days prior to the experimental day

Acipimox/GH pause; Placebo/GH pause

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• hypopituitary patients with documented GH-deficiency

You may not qualify if:

• other significant disease

Sponsors & Collaborators

• University of Aarhus: lead

Study Sites (1)

University Hospital of Aarhus

Aarhus, 8000, Denmark

Location

Related Publications (8)

• 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.

  PMID: 12563315 BACKGROUND

• 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.

  PMID: 24148194 BACKGROUND

• 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.

  PMID: 25050904 BACKGROUND

• 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.

  PMID: 21613350 BACKGROUND

• 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.

  PMID: 24577718 BACKGROUND

• 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.

  PMID: 19240267 BACKGROUND

• 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.

  PMID: 11574412 BACKGROUND

• 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.

  PMID: 32945898 DERIVED

MeSH Terms

Conditions

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

Interventions

acipimox

Condition Hierarchy (Ancestors)

Hypothalamic Diseases; Central Nervous System Diseases; Nervous System Diseases; Hyperinsulinism; Nutritional and Metabolic Diseases

Study Officials

• Jens Otto L Jørgensen, Professor

  University Hospital of Aarhus

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 18, 2016
• First Posted: May 25, 2016
• Study Start: February 10, 2016
• Primary Completion: December 22, 2016
• Study Completion: December 22, 2016
• Last Updated: March 26, 2020

Record last verified: 2017-10

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)