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Growth hormone (GH) plays a pivotal role in the regulation of body composition including ectopic lipid deposition in insulin sensitive organs like liver and skeletal muscle. Recent evidence indicates that the GH-IGF1 axis affects body composition via regulating mitochondrial oxidation capacity.
Thus, excessive GH secretion by a pituitary adenoma (Acromegaly) might be accompanied by increased mitochondrial activity leading to inappropriately low intracellular lipid depots, especially in metabolically active tissue like liver and skeletal muscle.
This study aims to assess metabolic activity and intracellular lipid content in skeletal muscle and liver in patients suffering from acromegaly compared to controls by 31P/1H Magnetic resonance spectroscopy before and in follow up examinations 3, 6 and 12 months after initiation of GH lowering treatments including surgery, somatostatinanalogs or pegvisomant, as well as oral glucose tolerance tests at each examination to assess treatment responses and calculate validated parameters for insulin sensitivity and resistance.
Background: Growth hormone (GH) plays a pivotal role in the regulation of body composition including ectopic lipid deposition in insulin sensitive organs like liver and skeletal muscle. Direct inhibition of growth hormone action by a receptor antagonist has been shown to induce hepatic steatosis and growth hormone replacement decreases liver fat content in obese humans. Of note, recent evidence indicates that the GH-IGF1 axis affects body composition via regulating mitochondrial oxidation capacity.
Hypothesis: Direct and/or indirect effects of GH on mitochondrial function might mediate the changes in body composition and lipid deposition. Thus, excessive GH secretion by a pituitary adenoma (Acromegaly) might be accompanied by increased mitochondrial activity leading to inappropriately low intracellular lipid depots, especially in metabolically active tissue like liver and skeletal muscle.
Aim: Assessment of metabolic activity and intracellular lipid content in skeletal muscle and liver in patients suffering from acromegaly compared to controls.
Methods: Non-interventional study:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Acromegalic patients | Acromegalic patients before and after initiation of individual therapy will be investigated by 1H/31P magnetic resonance spectroscopy, thyroid sonography and oral glucose tolerance testing |
| |
| Healthy control subjects | Age and Body mass index matched control subjects will be investigated by 1H/31P magnetic resonance spectroscopy and oral glucose tolerance testing |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 1H/31P Magnetic Resonance Spectroscopy | Other | The 31P-MRS examinations will be performed in a 7 T MR system (Siemens Healthcare, Erlangen, Germany) using a double-tuned (31P/1H) surface coil (Rapid Biomedical Ltd, Rimpar, Germany), with a diameter of 10 cm. Participants will be investigated lying in lateral position with the right lobe of the liver positioned over the coil. |
| Measure | Description | Time Frame |
|---|---|---|
| Changes in hepatic energy metabolism | The 31P-MRS examinations will be performed in a 7 T MR system (Siemens Healthcare, Erlangen, Germany) using a double-tuned (31P/1H) surface coil (Rapid Biomedical Ltd, Rimpar, Germany), with a diameter of 10 cm. | before & 3,6,9, and 12 months after initiation of therapy |
| Measure | Description | Time Frame |
|---|---|---|
| Changes in hepatic lipid content | Hepatic lipid content will be assessed using localized single voxel 1H MRS as published by our study group. STEAM sequence (VOI= 3×3×3 cm3; TE= 30, 50, 70, 120 ms; NA= 4 for each TE) data acquisition will be performed during repetitive single breath holds. Hepatocellular lipid (HCL) content will be calculated from ration of summed area of methylene and methyl resonance to that of water following the individual spin-spin relaxation correction as per cent of total tissue MRS signal (water + methylene + methyl). |
| Measure | Description | Time Frame |
|---|---|---|
| Changes in skeletal muscle energy metabolism | Resting-state ATP turnover will be measured using a ST experiment. The subjects will be lying in a supine position with the surface coil fixed underneath the right calf muscle. Baseline intramyocellular concentrations of phosphorous metabolites will be assessed based on T1 corrected partially relaxed baseline spectra (TR, 15 s; 16 averages). The exchange between γ-ATP and PCr (i.e., CK reaction), and between γ-ATP and Pi (i.e., ATP- synthesis) will be investigated. |
Inclusion Criteria:
Exclusion Criteria:
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acromegalic patients and healthy controls matched for sex, age and body mass index
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Peter Wolf, MD | Contact | 00431404004311 | peter.wolf@meduniwien.ac.at |
| Name | Affiliation | Role |
|---|---|---|
| Michael Krebs, MD, Prof. | Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Medical University Of Vienna, Department of Internal Medicine III | Recruiting | Vienna | State of Vienna | 1090 | Austria |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24647824 | Background | Valkovic L, Gajdosik M, Traussnigg S, Wolf P, Chmelik M, Kienbacher C, Bogner W, Krebs M, Trauner M, Trattnig S, Krssak M. Application of localized (3)(1)P MRS saturation transfer at 7 T for measurement of ATP metabolism in the liver: reproducibility and initial clinical application in patients with non-alcoholic fatty liver disease. Eur Radiol. 2014 Jul;24(7):1602-9. doi: 10.1007/s00330-014-3141-x. Epub 2014 Mar 20. |
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| ID | Term |
|---|---|
| D000172 | Acromegaly |
| ID | Term |
|---|---|
| D001849 | Bone Diseases, Endocrine |
| D001847 | Bone Diseases |
| D009140 | Musculoskeletal Diseases |
| D006964 | Hyperpituitarism |
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| oral glucose tolerance testing | Other | In patients without overt diabetes, glucose tolerance will be assessed by an oral glucose tolerance test, routinely performed at the outpatients clinic. The test will be performed in the morning after an overnight fast of at least 8 hours. Blood will be drawn via a catheter placed in an antecubital vein of one arm. Blood samples for the assessment of glucose, insulin, C-peptide, free fatty acids and growth hormone will be drawn at baseline as well as 30, 60, 90 and 120 minutes after ingestion of 75g glucose in a solution. Concentrations of glucose, insulin and C-peptide will be used to derive parameters of insulin secretion and insulin sensitivity by mathematical modelling. |
|
| Thyroid sonography | Other | In acromegalic patients thyroid morphology will be assessed at the outpatient clinic of the Division of Endocrinology and Metabolism, using standard ultrasound technique. Measurements will be performed by a well- experienced physician at baseline and at each follow up examination in an out-patient care setting. |
|
| before, as well as 3,6,9 &12 months after initiation of therapy |
| before, as well as 3,6,9 and 12 months after initiation of therapy |
| Changes in skeletal muscle lipid content | Intramyocellular lipid content will be assessed using localized single voxel 1H MRS as published by our studygroup[34]. STEAM sequence (VOI= 12x12x12 mm3; TE= 20 ms; TR= 4 sec, NA= 16) data acquisition will be performed in two volumes of interest positioned in soleus and tibialis anterior muscle. Separate spectra without water signal suppression (NA= 4) will be obtained from both muscle groups. Intramyocellular lipid content (IMCL) content will be calculated from ratio of area of methylene (1.25 ppm) to that of water following the individual spin-spin relaxation correction as per cent of tissue water MRS signal. | before, as well as 3,6,9 and 12 months after initiation of therapy |
| Changes in thyroid morphology | In acromegalic patients thyroid morphology will be assessed at the outpatient clinic of the Division of Endocrinology and Metabolism, using standard ultrasound technique. Measurements will be performed by a well- experienced physician at baseline and at each follow up examination in an out-patient care setting. | before and 12 months after initiation of individual therapy |
| D010900 |
| Pituitary Diseases |
| D007027 | Hypothalamic Diseases |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D004700 | Endocrine System Diseases |