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

University of Aarhus

Status: Completed

Conditions: Healthy

Treatments: Drug: Growth hormone; Behavioral: control, 12 hour fast; Drug: Olbetam; Behavioral: 72 hour fast

Study type: Interventional

Funder types: Other

Identifiers

NCT01299831

M-2010082

Details and patient eligibility

About

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.

Full 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.

Enrollment: 19 patients

Sex: Male

Ages: 20 to 35 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

---

19 participants in 4 patient groups

72 hour fast

Experimental group

Treatment:

Behavioral: 72 hour fast

12 hours fast

Experimental group

Treatment:

Behavioral: control, 12 hour fast

12 hour fast, growth hormone bolus

Experimental group

Treatment:

Drug: Growth hormone

72 hour fast, inhibition of lipolysis

Experimental group

Treatment:

Drug: Olbetam