Substrate Metabolism, Growth Hormone Signaling, and Insulin Sensitivity During Fasting

Substrate Metabolism, Growth Hormone Signaling, and Insulin Sensitivity During Fasting in Overweight and Obese Human Subjects and the Impact of Growth Hormone Receptor Blockade

Background: Calorie restriction increases longevity in many species and attenuate the development of chronic disorders including type 2 diabetes, cardiovascular diseases and cancer. In mice reduced activity of insulin-like growth factor I (IGF-I) and/or insulin is associated with extended longevity. Growth hormone (GH) is the main regulator of IGF-I production, but the molecular mechanism whereby GH switches from IGF-I stimulation (protein anabolism) to fatty acid oxidation (fatty acid catabolism) as well as induction of insulin resistance during fasting remains enigmatic.

Hypotheses: The changes of the global set of metabolites, induction of insulin resistance, and the shift in metabolism from protein anabolism to lipolysis together with the potentially favorable effect of calorie restriction during fasting depend on preserved fasting-induced GH secretion.

Aim: The investigators wish to provide knowledge on changes in metabolites and shift in signaling pathways that take place at the transition to the fasting state among healthy overweight and obese subjects. Furthermore the investigators wish to determine the effect of GH on the adaption of the metabolism to a fasting state.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Other: Fasting; Drug: Saline; Drug: Pegvisomant

• Study Type: Interventional
• Enrollment (Anticipated): 10
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Aarhus, Denmark, 8000
    • Aarhus University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• healthy men
• written consent
• body mass index (BMI) 25-40
• age 20-60 years

Exclusion Criteria:

• any kind of disease
• regular medication

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control; 12 hours of fasting
Experimental: Fasting and saline; 72 hours of fasting and concomitant saline	Other: Fasting; 72 hours of fasting; Drug: Saline; Concomitant saline during fasting
Experimental: Fasting and GHR blockade; 72 hours of fasting and concomitant Growth hormone receptor (GHR) blockade with Pegvisomant (Somavert) for inhibition of the fasting-induced GH secretion	Other: Fasting; 72 hours of fasting; Drug: Pegvisomant; Concomitant Growth hormone receptor blockade with Pegvisomant during fasting

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin and growth hormone signaling, expressed as CHANGE in phosphorylation of intracellular target proteins and CHANGE in messenger ribonucleic acid (mRNA) expression of target genes in muscle- and fat-tissue.	Change in phosphorylation of target proteins and mRNA expression of target genes	Muscle and fat biopsies obtained at t1= 9.00 am (60 min) and t2=12.30 am (270 min) on each study day after 0, 4 and 8 weeks (interval of 4 weeks between each of the three study days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glucose metabolism	Change in glucose metabolism assessed by tracer kinetics on every study day and by indirect calorimetry.	Change in glucose metabolism using glucose tracer from t=0 min - 360 min on each study day after 0, 4 and 8 weeks (interval of 4 weeks between each of the three study days)
Magnetic resonance (MR) spectroscopy		During fasting: t= 12 hours and t= 48 hours of fasting
Change in concentrations of metabolites in the insulin and growth hormone signaling pathways using metabolomics	Method: Metabolomics	Muscle-tissue obtained at t1= 9.00 am (60 min) and t2=12.30 am (270min) on each study day after 0, 4 and 8 weeks (interval of 4 weeks between each of the three study days)
Fat metabolism	Change in fat metabolism assessed by tracer kinetics on every study day and by indirect calorimetry.	Change in fat metabolism using palmitic acid tracer from t1=180 min - 240 min and t2=300 min - 360 min on each study day after 0, 4 and 8 weeks (interval of 4 weeks between each of the three study days)
Protein metabolism	Change in protein metabolism assessed by tracer kinetics on every study day and by indirect calorimetry.	Change in protein metabolism using urea tracer from t=0 min - 240 min on each study day after 0, 4 and 8 weeks (interval of 4 weeks between each of the three study days)

Collaborators and Investigators

• Sponsor: University of Aarhus
• Investigators: Principal Investigator: Jens Otto L. Jørgensen, Professor, Aarhus University / Aarhus University Hospital; Study Chair: Jens Otto L. Jørgensen, Professor, Aarhus University / Aarhus University Hospital

Publications and helpful links

General Publications

• Hogild ML, Gudiksen A, Pilegaard H, Stodkilde-Jorgensen H, Pedersen SB, Moller N, Jorgensen JOL, Jessen N. Redundancy in regulation of lipid accumulation in skeletal muscle during prolonged fasting in obese men. Physiol Rep. 2019 Nov;7(21):e14285. doi: 10.14814/phy2.14285.

Study record dates

Study Major Dates

• Study Start: July 1, 2015
• Primary Completion (Actual): November 1, 2016
• Study Completion (Actual): November 1, 2016

Study Registration Dates

• First Submitted: July 10, 2015
• First Submitted That Met QC Criteria: July 14, 2015
• First Posted (Estimate): July 16, 2015

Study Record Updates

• Last Update Posted (Estimate): November 23, 2016
• Last Update Submitted That Met QC Criteria: November 22, 2016
• Last Verified: November 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hyperinsulinism; Insulin Resistance
• Other Study ID Numbers: fasting8000