The Relationship Between Body Composition and Growth Hormone, SIRT Signaling, Protein Turnover and Insulin Sensitivity
Condition: Healthy
MeSH terms: Insulin Resistance
Study type: Interventional

Summary: 
      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.
    

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.
    

Intervention name(s): 72 hour fast; control, 12 hour fast; Growth hormone; Olbetam
Intervention type(s): Behavioral; Behavioral; Drug; Drug
Intervention description(s): The participants will be fasting 72 hours prior to the start of the study day, drinking water is allowed.; The 12 hour fast will be used as a basic metabolic control; Genotropin bolus(0,005 mg/kg over 20 min.) will be administered at the beginning of the study day after a 12 hour fast.; 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.
Intervention MeSH terms: Hormones
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Basic Science