The Relationship Between Body Composition and Growth Hormone, SIRT Signaling, Protein Turnover and Insulin Sensitivity

THE RELATIONSHIP BETWEEN BODY COMPOSITION AND GROWTH HORMONE, SIRT SIGNALING, PROTEIN TURNOVER AND INSULIN SENSITIVITY. Studies of Signaling Pathways in Fat and Muscle, and Turnover of Protein, Sugar and Fat After Stimulation With Growth Hormone and During Fasting in Lean and Obese Subjects

The purpose of this study is to investigate signaling pathways in fat and muscle, as well as turnover of protein, sugar and fat after stimulation with growth hormone and during fasting in lean and obese subjects. This will help clarify differences in the human metabolism between lean and obese subject and provide us with a better understanding of the molecular mechanisms regulating the basic metabolism during prolonged fasting.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Behavioral: 72 hour fast; Behavioral: control, 12 hour fast; Drug: Growth hormone; Drug: Olbetam

Detailed Description

In an evolutionary context, it is likely that "inherited" obesity provides a survival advantage when there are shortages of food, but also increases the risk of lifestyle diseases in times of prosperity. This may explain the high incidence of obesity, diabetes and cardiovascular disease in the western world today. Obese individuals have high levels of free fatty acids (FFAs) in the blood and FFAs are both protein sparing (giving an evolutionary survival advantage) but also cause increased insulin resistance (which increases the risk of diabetes and cardiovascular disease). Obesity also leads to low growth hormone (GH)-levels, whereas fasting is accompanied by high GH- and FFA-levels and increased IGF-I mRNA in muscle. It is likely that obese individuals are more capable of fasting than lean individuals and will lose less protein during fasting, have increased activation of GH signaling and altered activation of other signaling proteins. And obese individuals are likely to be more sensitive to growth hormone than lean individuals based on FFA-responses, intracellular signaling, protein loss and insulin sensitivity.

We would like to test 3 hypotheses: (1) Obese individuals are more capable of fasting than lean individuals and will lose less protein during fasting (2) Activation of lipolysis is an important prerequisite for limiting protein loss during fasting in both slim as obese individuals. (3) Obese individuals are more sensitive to growth hormone than lean individuals based on FFA responses and activation of intracellular signals. The hypotheses are tested in 8 lean and 8 obese healthy young men, who are studied 4 times: (i) after 12 hours of fasting (ii) after 72 hours of fasting (iii) after GH-bolus (0.005 mg/kg over 20 min.) and (iv) after 72 hours of fasting with inhibition of fat metabolism (tablet acipimox 250 mg every 4 hours) during the last 12 hours of fasting and during the study period.

Each study period consists of a 4-hour basal period and a 2 hour hyperinsulinemic euglycemic clamp (30 mU/m2/min). Muscle- and fat-biopsies are taken and analyzed for enzyme expression and activation of various signaling pathways. The study subjects are given glucose-, amino acid-, urea- and palmitate-tracers and specific hormones and metabolites are measured for assessment of underlying molecular mechanisms regulating the basic human energy metabolism.

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Aarhus, Denmark, 8000
    • Department of medical endocrinology, University Hospital of Aarhus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 35 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• healthy lean (BMI19-25) and healthy obese (BMI 32-40) men
• written consent before study start

Exclusion Criteria:

• known medical conditions
• any medication

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 72 hour fast	Behavioral: 72 hour fast; The participants will be fasting 72 hours prior to the start of the study day, drinking water is allowed.
Experimental: 12 hours fast	Behavioral: control, 12 hour fast; The 12 hour fast will be used as a basic metabolic control
Experimental: 12 hour fast, growth hormone bolus	Drug: Growth hormone; Genotropin bolus(0,005 mg/kg over 20 min.) will be administered at the beginning of the study day after a 12 hour fast.
Experimental: 72 hour fast, inhibition of lipolysis	Drug: Olbetam; The participants will be fasting 72 hours prior to the start of the study day, drinking water is allowed. During the last 12 hours of fasting and the study day lipolysis will be inhibited with one tablet of olbetam 250 mg every 4 hours.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measurements of changes in metabolism	Measurements of the switch to lipid metabolism during fasting in lean and obese human subjects.	6 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Signaling pathways in muscle and fat tissue involved in regulation of metabolism	Protein and gene-exspression, phosphorylation and acetylation of specific proteins involved in lipid-, glucose and protein metabolism.	6 hours

Collaborators and Investigators

• Sponsor: University of Aarhus
• Collaborators: Aarhus University Hospital

Publications and helpful links

General Publications

• Hogild ML, Bak AM, Pedersen SB, Rungby J, Frystyk J, Moller N, Jessen N, Jorgensen JOL. Growth hormone signaling and action in obese versus lean human subjects. Am J Physiol Endocrinol Metab. 2019 Feb 1;316(2):E333-E344. doi: 10.1152/ajpendo.00431.2018. Epub 2018 Dec 21.

Study record dates

Study Major Dates

• Study Start: January 1, 2011
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: January 21, 2011
• First Submitted That Met QC Criteria: February 17, 2011
• First Posted (Estimate): February 18, 2011

Study Record Updates

• Last Update Posted (Estimate): May 26, 2014
• Last Update Submitted That Met QC Criteria: May 23, 2014
• Last Verified: May 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hyperinsulinism; Insulin Resistance; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormones
• Other Study ID Numbers: M-2010082