Glucagon-like Peptide 2 - a Glucose Dependent Glucagonotropic Hormone?

Study Overview
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Brief Summary
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Infusion of glucagon-like peptide 2 (GLP-2) during euglycaemia, hypoglycaemia and hyperglycaemia and evaluation of the effect on glucagon secretion in healthy subjects.

Detailed Description
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This is a cross-over, randomized, double-blinded study in which 10 participants will undergo 6 experimental days each. The participants will have their plasma glucose clamped at either euglycaemia (fasting level), hypoglycemia (2,5 mmol/l) or hyperglycemia (10 mmol/l) during infusion of GLP-2 or saline (placebo) The six days will be as follows: Euglycaemia + Placebo Euglycaemia + GLP-2 Hyperglycaemia + Placebo Hyperglycaemia + GLP-2 Hypoglycaemia + Placebo Hypoglycaemia + GLP-2 The primary endpoint will be levels of plasma glucagon. Secondary endpoint will be levels of GLP-1, GLP-2, Insulin/C-peptide, OXM, Amino acids, CCK, Gastrin, norepinephrine, bile acids, FGF-19/FGF-21. Secondary endpoints will also include ultrasound scan of the gallbladder.

Official Title
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Glucagon-like Peptide 2 - a Glucose Dependent Glucagonotropic Hormone?

Conditions
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Glucose Metabolism Disorders, Endocrine or Metabolic Disease

Intervention / Treatment
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* Other: Glucagon-like peptide 2
* Other: Saline
* Other: Glucose
* Other: Insulin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Caucasian ethnicity Body mass index (BMI): 18.5-27 kg/m2 Glycated haemoglobin (HbA1c) < 42 mmol/mol Normal haemoglobin (8.3-10.5 mmol/l) Informed and oral and written consent Exclusion Criteria: Prediabetes, type 1 diabetes or type 2 diabetes or first-degree relatives with type 1 or type 2 diabetes Nephropathy (eGFR < 60 and/or albuminuria) Known liver disease and/or alanine transaminase (ALAT) or aspartate transaminase (ASAT) > 2 × upper normal limit Bilirubin > 25 μmol/l Known intestinal disease or previous surgery of the intestines Active or recent malignant disease Treatment with medicine that cannot be paused for 12 hours Any condition considered incompatible with participation by the investigators

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Male

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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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hyperglycaemia + GLP-2<br>Glucose + GLP-2 | Other: Glucagon-like peptide 2<br>* Human glucagon-like peptide 2<br>Other: Glucose<br>* 20% (w/v) glucose infusion for regulating plasma glucose<br>|
| Active Comparator: Hyperglycaemia + Placebo<br>Glucose + saline | Other: Saline<br>* Placebo<br>Other: Glucose<br>* 20% (w/v) glucose infusion for regulating plasma glucose<br>|
| Experimental: Hypoglycaemia + GLP-2<br>Insulin + glucose + GLP-2 | Other: Glucagon-like peptide 2<br>* Human glucagon-like peptide 2<br>Other: Glucose<br>* 20% (w/v) glucose infusion for regulating plasma glucose<br>Other: Insulin<br>* Actrapid (insulin) for lowering plasma glucose<br>|
| Active Comparator: Hypoglycaemia + Saline<br>Insulin + glucose | Other: Saline<br>* Placebo<br>Other: Glucose<br>* 20% (w/v) glucose infusion for regulating plasma glucose<br>Other: Insulin<br>* Actrapid (insulin) for lowering plasma glucose<br>|
| Experimental: Euglycaemia + GLP-2<br>GLP-2 | Other: Glucagon-like peptide 2<br>* Human glucagon-like peptide 2<br>|
| Active Comparator: Euglycaemia + Placebo<br> | Other: Saline<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glucagon secretion | Assessed by difference in absolute plasma glucagon concentrations (measured in pmol/liter) and incremental (baseline-subtracted) area under curve (AUC) for plasma glucagon | 110 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma glucose | Measured in mmol/liter | 110 minutes | 
| GLP-1 | Glucagon-like peptide 1, Measured in pmol/liter | 110 minutes | 
| GLP-2 | Glucagon-like peptide 2, Measured in pmol/liter | 110 minutes | 
| Insulin | Measured in pmol/liter | 110 minutes | 
| GIP | Glucose dependent insulinotropic hormone, Measured in pmol/liter | 110 minutes | 
| OXM | Oxytomodulin, Measured in pmol/liter | 110 minutes | 
| Amino acids | Measured in pmol/liter | 110 minutes | 
| CCK | Cholecystokinin, Measured in pmol/liter | 110 minutes | 
| Gastrin | Measured in pmol/liter | 110 minutes | 
| FGF-19 | Fibroblast Growth factor 19, Measured in ng/mL | 110 minutes | 
| FGF-21 | Fibroblast Growth factor 21, Measured in ng/mL | 110 minutes | 
| Bile acids | Measured in nmol/ml | 110 minutes | 
| Norepinephrine | Measured in pmol/liter | 110 minutes | 
| GH | Growth hormone, Measured in nmol/ml | 110 minutes | 
| P1NP | Procollagen type I N-terminal propeptide (Bonemarker), Measured in nmol/ml | 110 minutes | 
| CTX | C-terminal telopeptide (Bonemarker), Measured in nmol/ml | 110 minutes | 
| Gallbladder ultrasound | Measuring of gallbladder size in respons to GLP-2 | 110 minutes | 
| Glucose infusion | Amount of glucose infusion (20% v/w) in milliliters needed to clamp at isoglycemic levels (hyperglycemia and hypoglycemia) in respons to GLP-2 | 90 minutes | 
| Blood pressure | Systolic (mmHg) and diastolic (mmHg) blood pressure in respons to GLP-2 | 110 minutes | 
| Heart rate | Heart rate (beats/minutes) in respons to GLP-2 | 110 minutes | 
| C-peptide | Measured in pmol/liter | 110 minutes | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GLP-2, Glucagon