LEAP2 on Postprandial Glucose Metabolism and Food Intake n Obese Males

Study Overview
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Brief Summary
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The study aims to delineate the effects of the naturally occurring peptide liver-enriched antimicrobial peptide 2 (LEAP-2) on postprandial glucose metabolism and food intake in obese volunteers. The overall objective is to investigate the physiological importance of LEAP-2 in obese subjects.

Detailed Description
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In a recent study, the molecular phenotype of enteroendocrine cells in the small intestine before and after Roux-en-Y Gastric Bypass (RYGB) surgery in obese individuals was examined. Enteroendocrine cells were identified and isolated from intestinal biopsies and analysed for differentially expressed genes by Illumina High Throughput RNA-sequencing. It was discovered that the gene encoding liver-enriched antimicrobial peptide 2 (LEAP-2), a naturally occurring peptide in humans, was significantly upregulated compared to baseline expression. Interestingly, LEAP-2 was recently shown to antagonize ghrelin function in response to feeding in mice. Moreover, the mature murine LEAP-2 peptide is identical in mice and humans. Thus, LEAP-2 has been identified as an endogenous peptide that may be able to alter feeding behaviour and maintenance of glucose levels during calorie restriction. Our group recently found a 12 % relative reduction in ad libitum food intake and reduced postprandial glucose excursions. The present study hypothesis is that LEAP-2 alters postprandial glucose metabolism and decreases appetite as well as food intake in relation to a liquid mixed meal and a standardised ad libitum meal compared with saline (placebo) in obese subjects.

Official Title
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LEAP2 on Postprandial Glucose Metabolism and Food Intake in Obese Males

Conditions
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Obesity

Intervention / Treatment
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* Drug: LEAP-2 Protein, Human


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Caucasian men Age between 18 and 25 years Body mass index between 30-50 kg/m2 Informed consent Exclusion Criteria: Anaemia (haemoglobin below normal range) Alanine aminotransferase (ALAT) and/or aspartate aminotransferase (ASAT) >2 times normal values) or history of hepatobiliary and/or gastrointestinal disorder(s) Nephropathy (serum creatinine above normal range and/or albuminuria) Allergy or intolerance to ingredients included in the standardised meals First-degree relatives with diabetes and/or glycated haemoglobin (HbA1c) >48 mmol/mol Regular tobacco smoking or use of other nicotine-containing products Any ongoing medication that the investigator evaluates would interfere with trial participation. Any physical or psychological condition that the investigator evaluates would interfere with trial participation including any acute or chronic illnesses

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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 |
| --- | --- |
| Placebo Comparator: Placebo<br>IV infusion of saline, approximately 5.5 hours | Drug: LEAP-2 Protein, Human<br>* Intravenous infusion, mixed meal test, ad libitum meal test<br>|
| Experimental: Liver-enriched antimicrobial peptide 2<br>IV infusion of LEAP2, approximately 5.5 hours | Drug: LEAP-2 Protein, Human<br>* Intravenous infusion, mixed meal test, ad libitum meal test<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Food intake, kilojoules | Difference in food intake during an ad libitum meal. Food intake is examined as kilojoules of food eaten during the ad libitum meal. | 290 to 320 minutes | 
| Food intake, kilojoules per kilogram body weight | Difference in food intake during an ad libitum meal. Food intake is examined as kilojoules per kilogram body weight of food eaten during the ad libitum meal. | 290 to 320 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| VAS, appetite | Visual analogue scales (VASs) assessing appetite (from 0 to 9,5 cm on a scale = from minimum to maximum sensation) | -35 to 320 minutes | 
| VAS, satiety | Visual analogue scales (VASs) assessing satiety sensations (from 0 to 9,5 cm on a scale = from minimum to maximum sensation) | -35 to 320 minutes | 
| VAS, hunger | Visual analogue scales (VASs) assessing hunger sensations (from 0 to 9,5 cm on a scale = from minimum to maximum sensation) | -35 to 320 minutes | 
| VAS, thirst | Visual analogue scales (VASs) assessing thirst (from 0 to 9,5 cm on a scale = from minimum to maximum sensation) | -35 to 320 minutes | 
| Alterations in gastric emptying | Paracetamol concentration in plasma after intake of 1.5 g paracetamol | -35 to 320 minutes | 
| Plasma insulin levels and beta cell secretion assessed by plasma C-peptide concentration relative to plasma glucose concentration | Plasma insulin levels and beta cell secretion assessed by plasma C-peptide concentration relative to plasma glucose concentration | -35 to 320 minutes | 
| Plasma/serum concentrations of LEAP-2, acyl-ghrelin as well as other glucose- and appetite-regulating gut hormones | Plasma/serum concentrations of LEAP-2, acyl-ghrelin as well as other glucose- and appetite-regulating gut hormones | -35 to 320 minutes | 
| Changes in resting energy expenditure (REE) | Changes in resting energy expenditure (REE) measured by indirect calorimetry | -35 to 320 minutes | 
| Triglyceride responses | Plasma triglyceride | -35 to 320 minutes | 
| Cholesterol responses | Plasma Cholesterol | -35 to 320 minutes | 
| Free fatty acid responses | Plasma Free fatty acid | -35 to 320 minutes |