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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Control | No Intervention | 12 hours of fasting | |
| Fasting and saline | Experimental | 72 hours of fasting and concomitant saline |
|
| Fasting and GHR blockade | Experimental | 72 hours of fasting and concomitant Growth hormone receptor (GHR) blockade with Pegvisomant (Somavert) for inhibition of the fasting-induced GH secretion |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Fasting | Other | 72 hours of fasting |
| |
| 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) |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jens Otto L. Jørgensen, Professor | Aarhus University / Aarhus University Hospital | Principal Investigator |
| Jens Otto L. Jørgensen, Professor | Aarhus University / Aarhus University Hospital | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Aarhus University Hospital | Aarhus | 8000 | Denmark |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 31724339 | Derived | 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. |
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| ID | Term |
|---|---|
| C407088 | Angptl4 protein, mouse |
| D012965 | Sodium Chloride |
| C406545 | pegvisomant |
| ID | Term |
|---|---|
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
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| Saline |
| Drug |
Concomitant saline during fasting |
|
| Pegvisomant | Drug | Concomitant Growth hormone receptor blockade with Pegvisomant during fasting |
|
| 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) |
| D017670 |
| Sodium Compounds |