The Role of GIP and GLP-2 in Postprandial Splanchnic Blood Flow Distribution and Metabolism

Study Overview
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Brief Summary
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This project will describe the mechanisms of action and the relative contributions of GIP and GLP-2 to changes in gastrointestinal blood flow induced by oral glucose, exogenous GIP and GLP-2 infusions, and endogenous GIP and GLP-2 with the use of two novel receptor antagonists GIP(3-30)NH2 and GLP-2(3-33) in healthy individuals.

Detailed Description
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Each participant will attend eight independent randomised experimental days in the MRI-scanner with intravenous infusion (hormone/placebo), subcutaneous injection (hormon/placebo) and oral ingestion (glucose/water). On experimental day A-C, an intravenous infusion of saline, GIP(3-30)NH2, or GLP-2(3-33), respectively, starts at time point -20 minutes. On experimental day D-F, the same infusions are combined with an oral glucose tolerance test (75 gram of glucose dissolved in 250 ml water ingested orally) at time point 0 minutes. On experimental days G-H, a subcutaneous injection of either GIP or GLP-2 at time point 0 minutes is performed (positive control) during saline infusion and oral water ingestion. MRI measurements are repeatedly performed and blood samples are drawn to be analysed for endocrine responses from the intestines, pancreas, and bones.

Official Title
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The Role of the Intestinal Hormones Glucose-dependent Insulinotropic Polypeptide (GIP) and Glucagon-like Peptide 2 (GLP-2) in Postprandial Splanchnic Blood Flow Distribution and Metabolism in Humans

Conditions
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Blood Flow

Intervention / Treatment
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* Other: GIPR antagonist / study tool
* Other: GLP-2R antagonist / study tool
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: No first degree relatives with diabetes BMI 20-27 kg/m2 Exclusion Criteria: Not MRI-compatible implants Claustrophobia Diabetes Abnormal kidney or liver function Anemia Planned weight loss or change in diet Hypertension Other conditions that could be expected to affect the primary or secondary outcomes

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 70 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
Interventional Model Description: Single blind, placebo controlled, randomized, crossover study
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: SAL-WAT<br>Saline infusion, saline injection, water ingestion | Other: Placebo<br>* Saline<br>|
| Active Comparator: SAL-GLU<br>Saline infusion, saline injection, glucose ingestion | Other: Placebo<br>* Saline<br>|
| Active Comparator: SAL-GIP<br>Saline infusion, GIP injection, water ingestion | Other: Placebo<br>* Saline<br>|
| Active Comparator: SAL-GLP-2<br>Saline infusion, GLP-2 injection, water ingestion | Other: Placebo<br>* Saline<br>|
| Experimental: GIA-WAT<br>GIPR antagonist infusion, saline injection, water ingestion | Other: GIPR antagonist / study tool<br>* Selective antagonist of the GIPR, GIP(3-30)NH2<br>Other: Placebo<br>* Saline<br>|
| Experimental: GIA-GLU<br>GIPR antagonist infusion, saline injection, glucose ingestion | Other: GIPR antagonist / study tool<br>* Selective antagonist of the GIPR, GIP(3-30)NH2<br>|
| Experimental: GLA-WAT<br>GLP-2R antagonist infusion, saline injection, water ingestion | Other: GLP-2R antagonist / study tool<br>* Selective antagonist of the GLP-2R, GLP-2(3-33)<br>Other: Placebo<br>* Saline<br>|
| Experimental: GLA-GLU<br>GLP-2R antagonist infusion, saline injection, glucose ingestion | Other: GLP-2R antagonist / study tool<br>* Selective antagonist of the GLP-2R, GLP-2(3-33)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Redistribution of splanchnic blood flow (functional MRI) | Flow in mesenteric superior artery | 90 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| GIP levels | Blood sample (pmol/L) | 90 minutes | 
| GLP-2 levels | Blood sample (pmol/L) | 90 minutes | 
| GIP(3-30)NH2 levels | Blood sample (nmol/L) | 90 minutes | 
| GLP-2(1-33) levels | Blood sample (nmol/L) | 90 minutes | 
| CTX (bone resorption marker) | Blood sample | 90 minutes | 
| P1NP (bone formation marker) | Blood sample | 90 minutes | 
| Glucose | Blood sample (mmol/L) | 90 minutes | 
| C-peptide | Blood sample (pmol/L) | 90 minutes | 
| Insulin | Blood sample (pmol/L) | 90 minutes | 
| Glucagon | Blood sample (pmol/L) | 90 minutes | 
| Heart rate | Beats/minute | 90 minutes | 
| Flow in coeliac trunk | Functional MRI estimated blood flow | 90 minutes | 
| Flow in hepatic artery | Functional MRI estimated blood flow | 90 minutes | 
| Flow in portal vein | Functional MRI estimated blood flow | 90 minutes | 
| Liver oxygen content | Functional MRI estimated oxygenation | 90 minutes | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GIP, Gut hormones, GLP-2, Physiology