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Assessment of Changes in Metabolic Activity in Liver & Skeletal Muscle in Patients Suffering From Acromegaly

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ClinicalTrials.gov Identifier: NCT02115906
Recruitment Status : Unknown
Verified September 2016 by Prof. Dr. Michael Krebs, Medical University of Vienna.
Recruitment status was:  Recruiting
First Posted : April 16, 2014
Last Update Posted : September 27, 2016
Sponsor:
Information provided by (Responsible Party):
Prof. Dr. Michael Krebs, Medical University of Vienna

Brief Summary:

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.


Condition or disease Intervention/treatment
Acromegaly Other: 1H/31P Magnetic Resonance Spectroscopy Other: oral glucose tolerance testing Other: Thyroid sonography

Detailed Description:

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:

  • 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.
  • oral glucose tolerance tests at each examination to assess treatment responses and calculate validated parameters for insulin sensitivity and resistance.

Study Type : Observational
Estimated Enrollment : 24 participants
Observational Model: Case Control
Time Perspective: Prospective
Official Title: Assessment of Changes in Metabolic Activity in Liver & Skeletal Muscle in Patients Suffering From Acromegaly - a 31P/1H Magnetic Resonance Spectroscopy Pilot Study
Study Start Date : August 2014
Estimated Primary Completion Date : May 2017
Estimated Study Completion Date : May 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Health Checkup

Group/Cohort Intervention/treatment
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
Other: 1H/31P Magnetic Resonance Spectroscopy
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.

Other: oral glucose tolerance testing

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.


Other: Thyroid sonography
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.

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
Other: 1H/31P Magnetic Resonance Spectroscopy
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.

Other: oral glucose tolerance testing

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.





Primary Outcome Measures :
  1. Changes in hepatic energy metabolism [ Time Frame: before & 3,6,9, and 12 months after initiation of therapy ]
    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.


Secondary Outcome Measures :
  1. Changes in hepatic lipid content [ Time Frame: before, as well as 3,6,9 &12 months after initiation of therapy ]
    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).


Other Outcome Measures:
  1. Changes in skeletal muscle energy metabolism [ Time Frame: before, as well as 3,6,9 and 12 months after initiation of therapy ]
    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.

  2. Changes in skeletal muscle lipid content [ Time Frame: before, as well as 3,6,9 and 12 months after initiation of therapy ]
    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.

  3. Changes in thyroid morphology [ Time Frame: before and 12 months after initiation of individual therapy ]
    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.



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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
acromegalic patients and healthy controls matched for sex, age and body mass index
Criteria

Inclusion Criteria:

  • age between 18-75 years

Exclusion Criteria:

  • (known) overt diabetes mellitus
  • known coronary artery disease (history of myocardial infarction or angina pectoris)
  • acute or chronic (inflammatory, metabolic [hyperlipidemia, arterial hypertension, thyroid disorder]) disease (healthy controls)
  • intake of medication potentially affecting glucose or lipid metabolism
  • metal devices or other magnetic material in or on the subjects body which will be hazardous for NMR investigation [heart pacemaker, brain (aneurysm) clip, nerve stimulators, electrodes, ear implants, post coronary by-pass graft (epicardial pace wires), penile implants, colored contact lenses, patch to deliver medications through the skin, coiled spring intrauterine device, vascular filter for blood clots, orthodontic braces, shunt- spinal or ventricular, any metal implants (rods, joints, plates, pins, screws, nails, or clips without MR-authorization), embolization coil, or any metal fragments or shrapnel in the body].
  • tendency toward claustrophobia
  • severe liver disorders (plasma transaminases elevated > 3fold)
  • any acute inflammatory disease within 2 weeks prior the study
  • pregnancy
  • nursing
  • clinically relevant anemia

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02115906


Contacts
Contact: Peter Wolf, MD 00431404004311 peter.wolf@meduniwien.ac.at

Locations
Austria
Medical University Of Vienna, Department of Internal Medicine III Recruiting
Vienna, Austria, 1090
Contact: Peter Wolf, MD    00431404004311    peter.wolf@meduniwien.ac.at   
Principal Investigator: Michael Krebs, MD, Prof         
Sponsors and Collaborators
Medical University of Vienna
Investigators
Principal Investigator: Michael Krebs, MD, Prof. Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria

Publications:
Responsible Party: Prof. Dr. Michael Krebs, ao. Univ. Prof. Dr. med. univ., Medical University of Vienna
ClinicalTrials.gov Identifier: NCT02115906     History of Changes
Other Study ID Numbers: THIGHT_2
First Posted: April 16, 2014    Key Record Dates
Last Update Posted: September 27, 2016
Last Verified: September 2016

Additional relevant MeSH terms:
Acromegaly
Bone Diseases, Endocrine
Bone Diseases
Musculoskeletal Diseases
Hyperpituitarism
Pituitary Diseases
Hypothalamic Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Endocrine System Diseases