Lipolytic Effects of GH in Hypopituitary Patients in Vivo

Study Overview
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Brief Summary
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Growth hormone (GH) is essential for longitudinal bone growth and somatic development. These protein anabolic effects require sufficient nutritional supply. During fasting and caloric restriction GH predominantly promotes fat metabolism. GH counteracts the effect of insulin in many tissues, of which insulin-stimulated glucose uptake in skeletal muscle has been most extensively studied. Substrate competition between elevated free fatty acids and glucose is suggested as a mechanism, and this hypothesis can be tested mechanistically by means of acipimox, which is a nicotinic acid that suppresses the fat metabolizing effects of GH. The hypothesis is, that the suppressive effect of GH on insulin-stimulated glucose uptake in skeletal muscle is obviated by acipimox-induced inhibition of fat metabolism. In order to investigate this, eight adult hypopituitary patients with documented GH-deficiency will be studied in the presence and absence of GH and acipimox, respectively, and biopsies from skeletal muscle and subcutaneous adipose tissue will be analyzed. Knowledge of the effects of growth hormone and fat metabolism can in shot-sight as well as in long-sight have great importance for the understanding of growth disorders from overweight and type 2 diabetes to malnutrition and eating disorders.

Official Title
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Lipolytic Effects of GH in Hypopituitary Patients in Vivo: Molecular Mechanisms and Temporal Patterns.

Conditions
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Hypopituitarism, Insulin Resistance, Endocrine System Diseases, Glucose Metabolism Disorders, Metabolic Diseases, Pituitary Diseases, Brain Diseases

Intervention / Treatment
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* Drug: Acipimox
* Drug: Placebo
* Drug: GH substitution
* Other: GH pause


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: hypopituitary patients with documented GH-deficiency Exclusion Criteria: other significant disease

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Acipimox/GH substitution<br>Drug: Acipimox Tablet Acipimox 250 mg administered 4 times previous to and during the investigation day Other Name: Tablet Olbetam 250 mg Continue GH substitution as usually. | Drug: Acipimox<br>* Acipimox is administered 4 times previous to and during the investigation day. Acipimox is used to suppress the lipolytic effect of GH.<br>* Other names: Olbetam;Drug: GH substitution<br>* GH substitution as usually<br>|
| Active Comparator: Acipimox/GH pause<br>Drug: Acipimox Tablet Acipimox 250 mg administered 4 times previous to and during the investigation day Other Name: Tablet Olbetam 250 mg Pause GH substitution to days prior to the study day. | Drug: Acipimox<br>* Acipimox is administered 4 times previous to and during the investigation day. Acipimox is used to suppress the lipolytic effect of GH.<br>* Other names: Olbetam;Other: GH pause<br>* GH substitution pause two days prior to the experimental day<br>|
| Placebo Comparator: Placebo/GH substitution<br>Drug: Placebo tablets Continue GH substitution as usually. | Drug: Placebo<br>* Placebo is administered 4 times previous to and during the investigation day.<br>Drug: GH substitution<br>* GH substitution as usually<br>|
| Placebo Comparator: Placebo/GH pause<br>Drug: Placebo tablets Pause GH substitution to days prior to the study day. | Drug: Placebo<br>* Placebo is administered 4 times previous to and during the investigation day.<br>Other: GH pause<br>* GH substitution pause two days prior to the experimental day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lipolytic activity measured as area under the curve (AUC) for FFA (free fatty acid) before and during clamp-conditions. |  | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| GH signaling proteins and gene targets in adipose and skeletal muscle tissues measured by western blotting and qPCR |  | 1,5 years | 
| Insulin sensitivity as measured by M value and GIR (glucose infusion rate) |  | 6 months | 
| Substrate metabolism as measured by indirect calorimetry, tritiated glucose and circulating hormones and metabolites |  | 1 year | 
| PDH (pyruvate dehydrogenase) activity in skeletal muscle measured by an PDH activity assay |  | 1 year |