Growth Hormone, IGF-1 and Medical Treatment in Acromegaly: Are There Effects on Gut Hormone Physiology and Postprandial Substrate Metabolism?

Study Overview
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Brief Summary
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Acromegaly is a rare hormonal disorder leading to increased morbidity and mortality. In the vast majority of cases, a pituitary somatotroph cell adenoma causes excess growth hormone (GH) secretion, leading to hepatic insulin-like-growth factor 1 (IGF-1) hypersecretion. Both the disease as well as its treatment with long-acting somatostatin analogs (LA-SMSA) and/or pegvisomant affect glucose and lipid metabolism, possibly contributing to increased cardiovascular risk. In this pilot study, the investigators want to explore insulin sensitivity, postprandial gut hormone response, lipid handling and adipocytokine profile in the following 4 groups: controlled acromegalic patients on LA-SMSA (group 1) controlled acromegalic patients on combination treatment of LA-SMSA and pegvisomant (group 2) acromegalic patients without need for medical therapy after surgery (group 3) healthy control subjects (group 4) Furthermore, a longitudinal exploration will be performed in uncontrolled acromegalic patients (i.e. patients with serum IGF-1 levels above age-specific thresholds and/or symptoms due to active acromegaly (excessive sweating , arthralgia)) on LA-SMSA monotherapy (group 5). In this group, insulin sensitivity, postprandial gut hormone response, lipid handling and adipocytokine profile will be explored before introducing pegvisomant and three months after normalisation of IGF-1 levels. The investigators hypothesize that lipid and glucose handling will be less efficient in the controlled acromegalic patients on LA-SMSA than in controlled patients on combination therapy or after surgery, and that there will be no difference in substrate metabolism between healthy controls and controlled acromegalic patients on combination treatment or after surgery. Further, they hypothesize that introducing pegvisomant in uncontrolled acromegalic patients will improve their postprandial lipid and glucose handling.

Official Title
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Growth Hormone, IGF-1 and Medical Treatment in Acromegaly: Are There Effects on Gut Hormone Physiology and Postprandial Substrate Metabolism?

Conditions
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Acromegaly

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of acromegaly over 1 year ago, no changes in treatment schedule since at least 6 months (groups 1-3 and 5) OR healthy volunteer without diagnosis of acromegaly (group 4) Patient is willing to participate and has signed the informed consent Age > 18 years and < 80 years Body Mass Index 18-40 kg/m² Exclusion Criteria: Biochemistry: liver function tests > 3x ULN; HbA1C > 58 mmol/mol All untreated endocrine disorders including uncontrolled diabetes mellitus type 2 (i.e. HbA1C > 58 mmol/mol) Bariatric surgery; malabsorptive syndromes; hepatic or renal failure Current medication use: insulin, metformin, sulfonylurea, fibrates, incretin mimetics, dopamine agonists (for all but insulin, participation is allowed after a 2- week wash-out period) Abuse of alcohol or drugs Weight changes > 10% of body weight during preceding 12 months

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Controlled on LA-SMSA<br>Patients with controlled acromegaly on long-acting somatostatin analogs | |
| Controlled on LA-SMSA and pegvisomant<br>Patients with controlled acromegaly on long-acting somatostatin analogs and pegvisomant | |
| Controlled after surgery<br>Controlled acromegaly patients without need for medical therapy after surgery | |
| Healhy controls<br>Healthy volunteers | |
| Uncontrolled on LA-SMSA<br>Patients with uncontrolled acromegaly (i.e. with serum IGF-1 levels above age-specific thresholds and/or symptoms due to active acromegaly (e.g. excessive sweating, arthralgia)) on LA-SMSA monotherapy in maximal dosage | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| change in insulin sensitivity | Glucose disposal rate during last half hour of hyperinsulinemic-euglycemic clamp procedure, corrected for lean body mass (in µmol/min/kgLBM) | before start of pegvisomant and 3 months after normalisation of IGF-1 after start of pegvisomant in group 5 | 
| insulin sensitivity | Glucose disposal rate during last half hour of hyperinsulinemic-euglycemic clamp procedure, corrected for lean body mass (in µmol/min/kgLBM) | At enrollment in groups 1-4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| fasting and postprandial glucose | Serum glucose levels during mixed-meal test (before and 10, 30, 60, 120, 180, 240, 300 minutes after ingestion of standard mixed-meal (bread, margarine, cheese and milk) providing a caloric content of 1000 kCal whereby 45% of the energy comes from fat, 36% from carbohydrates and 19% from proteins) | At enrollment in groups 1-4 | 
| fasting and postprandial insulin | Insulin levels during standard mixed-meal test (cfr.supra) | At enrollment in groups 1-4 | 
| fasting and postprandial gut hormone levels | Serum levels of gastric inhibitory polypeptide (GIP), ghrelin, peptide YY, pancreatic polypeptide, glucagon-like peptide 1 (GLP-1), oxyntomodulin and cholecystokinin before start during standard mixed-meal test (cfr.supra) | At enrollment in groups 1-4 | 
| fasting adipokine levels | Fasting serum levels of leptin, adiponectin and interleukin 6 (IL-6) | At enrollment in group 1-4 | 
| fasting lipid levels | Fasting serum levels of triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol | At enrollment in groups 1-4 | 
| change in fasting and postprandial glucose | Serum glucose levels during mixed-meal test (before and 10, 30, 60, 120, 180, 240, 300 minutes after ingestion of standard mixed-meal (bread, margarine, cheese and milk) providing a caloric content of 1000 kCal whereby 45% of the energy comes from fat, 36% from carbohydrates and 19% from proteins) | before start of pegvisomant and 3 months after normalisation of IGF-1 levels after start of pegvisomant in group 5 | 
| change in fasting and postprandial insulin levels | Insulin levels during standard mixed-meal test (cfr.supra) | before start of pegvisomant and 3 months after normalisation of IGF-1 levels after start of pegvisomant in group 5 | 
| change in fasting and postprandial gut hormone levels | Serum levels of gastric inhibitory polypeptide (GIP), ghrelin, peptide YY, pancreatic polypeptide, glucagon-like peptide 1 (GLP-1), oxyntomodulin and cholecystokinin before start during standard mixed-meal test (cfr.supra) | before start of pegvisomant and 3 months after normalisation of IGF-1 levels after start of pegvisomant in group 5 | 
| change in fasting adipokine levels | Fasting serum levels of leptin, adiponectin and interleukin 6 (IL-6) | before start of pegvisomant and 3 months after normalisation of IGF-1 levels after start of pegvisomant in group 5 | 
| change in fasting lipid levels | Fasting serum levels of triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol | before start of pegvisomant and 3 months after normalisation of IGF-1 levels after start of pegvisomant in group 5 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acromegaly, Acromegaly treatment, Long-acting somatostatin analogs, Pegvisomant, Insulin sensitivity, Gut hormones, Lipid metabolism, Adipokines