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

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.

• Controlled on LA-SMSA
  Patients with controlled acromegaly on long-acting somatostatin analogs
• Controlled on LA-SMSA and pegvisomant
  Patients with controlled acromegaly on long-acting somatostatin analogs and pegvisomant
• Controlled after surgery
  Controlled acromegaly patients without need for medical therapy after surgery
• Healhy controls
  Healthy volunteers
• Uncontrolled on LA-SMSA
  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

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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