Separate and Combined Extrapancreatic Effects of the Incretin Hormones

Study Overview
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Brief Summary
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The two gut-derived hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) is secreted from intestinal cells in relation to a meal and increase insulin secretion from the pancreas. The hormones also exert effects outside the pancreas, but especially for GIP, these are poorly investigated. Because of this, only GLP-1 based drugs (GLP-1 receptor agonists) are on the market for the treatment of type 2 diabetes and obesity. Nonetheless, a new drug is in clinical development: a combined GIP-GLP-1-receptor agonist (tirzepatide), which has shown better results than GLP-1 alone. The mechanism behind these impressive effects are unknown and in this study, the investigators will look into the exptrapancreatic effects of GIP and GLP-1, separate and combined and thus elucidate the mechanisms of action of this new drug class.

Official Title
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Separate and Combined Extrapancreatic Effects of Glucose-dependent Insulinotropic Polypeptide and Glucagon-like Peptide 1

Conditions
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Pancreatectomy; Hyperglycemia

Intervention / Treatment
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* Other: Intravenous infusion
* Other: Intravenous infusion
* Other: Intravenous infusion
* Other: Intravenous infusion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Total pancreatectomy Caucasians Blood haemoglobin >7 mmol/l for males and >6.5 mmol/l for females Exclusion Criteria: Pancreatectomy within the last 3 months Ongoing chemotherapy or chemotherapy within the last 3 months Treatment with GLP-1R agonists within the last 3 months Renal impairment (estimated by eGFR <60 ml/min/1.73 m2) and/or albuminuria Calcium related disease, hypo-/hyperthyroidism Known significant liver disease, ALT or AST >3 times normal value or INR outside normal range Severe arteriosclerotic heart disease or heart failure (NYHA group III or IV) Pregnancy and/or breastfeeding Use of more than 14 units of alcohol per week or abuse of narcotics Any condition that the investigator feels would interfere with trial participation

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

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: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GIPRA<br> | Other: Intravenous infusion<br>* GIP receptor antagonist (GIP(3-30)NH2)<br>|
| Experimental: GLP-1RA<br> | Other: Intravenous infusion<br>* GLP-1 receptor antagonist (exendin(9-39)NH2)<br>|
| Experimental: GIPRA + GLP-1RA<br> | Other: Intravenous infusion<br>* GIP(3-30)NH2 and exendin(9-39)NH2<br>|
| Placebo Comparator: Saline<br> | Other: Intravenous infusion<br>* Saline<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in plasma levels of glucose between interventions assessed through frequently blood sampling during the experimental days | mmol/l | Up to two months | 
| Changes in plasma levels of glucagon (gut-derived) between interventions assessed through frequently blood sampling during the experimental days | pmol/l | Up to two months | 
| Changes in plasma levels of insulin/C-peptide between interventions assessed through frequently blood sampling during the experimental days | pmol/l | Up to two months | 
| Changes in plasma triglycerides between interventions assessed through frequently blood sampling during the experimental days. | mmol/l lipoproteins, neutral and complex lipids. | Up to two months | 
| Changes in plasma lipoproteins between interventions assessed through frequently blood sampling during the experimental days. | mg/dl | Up to two months | 
| Changes in brown adipose tissue activity between interventions, assessed by thermographic camera |  | Up to two months | 
| Changes in adiponectin in plasma between interventions, assessed through frequently blood sampling during the experimental days. | μg/mL | Up to two months | 
| Changes in CTX between interventions assessed through frequently blood sampling during the experimental days | ng/ml | Up to two months | 
| Changes in plasma P1NP between interventions assessed through frequently blood sampling during the experimental days | ng/ml | Up to two months |