The Impact of Lixisenatide on Postprandial Glucose Tolerance in Pancreatectomised Subjects

Study Overview
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Brief Summary
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Postprandial glucose (PPG) excursions are not only determined by insulin-mediated glucose disposal and endogenous glucose production (regulated by insulin and glucagon); also the rate of gastric emptying constitutes an important determinant of PPG levels 1. The short-acting glucagon-like peptide-1 (GLP-1) receptor agonist lixisenatide is used in the treatment of type 2 diabetes. It increases glucose-dependent insulin secretion, suppresses glucagon secretion and reduces gastric emptying of meals 2. These three mechanisms most likely constitute the weightiest mechanisms behind the potent impact of lixisenatide on exaggerated PPG excursions in patients with type 2 diabetes - which often are normalised during lixisenatide treatment 3. However, the separate impact of lixisenatide-induced reduction of gastric emptying (independently of the pancreatic effects) has been difficult to determine. Importantly, treatment with lixisenatide also decreases appetite and food intake and may, like native GLP-1, increase energy expenditure 4. So far an exact demarcation of the pancreatic and extrapancreatic effects of lixisenatide in humans remains to be established. The present project serves to determine whether effects of lixisenatide on gastric emptying, appetite, food intake and resting energy expenditure are dependent on the endocrine pancreas. The study is a randomised, placebo-controlled, double-blinded, cross-over study. 12 healthy persons and 12 pancreatectomized patients (i.e. patients who have had their pancreata removed due to pancreatic cancer or severe chronic pancreatitis) will be subjected to two experimental days on which they will undergo a liquid meal test followed by a fasting period and finished off with an ad libitum meal with lixisenatide and placebo, respectively.

Official Title
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The Impact of Lixisenatide on Postprandial Glucose Tolerance in Pancreatectomised Subjects -a Delineation of Extrapancreatic Effects

Conditions
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Diabetes After Total Pancreatectomy

Intervention / Treatment
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* Drug: Lixisenatide
* Drug: Lixisenatide-Placebo
* Other: Standardized liquid meal


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Pancreatectomised patients Caucasians above 18 years of age who have undergone total pancreatectomy Normal haemoglobin Informed consent Healthy subjects Normal fasting plasma glucose (FPG) and normal HbA1C (according to the World Health Organization (WHO) criteria) Normal haemoglobin Age above 18 years Informed consent Exclusion criteria Pancreatectomised patients Inflammatory bowel disease Operation within the last 3 months Ongoing chemotherapy or chemotherapy within the last 3 months Ostomy Nephropathy (serum creatinine >150 µM and/or albuminuria) Severe liver disease (serum alanine aminotransferase (ALAT) and/or serum aspartate aminotransferase (ASAT) >3×normal values) Pregnancy and/or breastfeeding Age above 80 years Any condition that the investigator feels would interfere with trial participation Healthy subjects Diabetes mellitus (DM) Prediabetes (impaired glucose tolerance and/or impaired FPG) First degree relatives with DM Inflammatory bowel disease Intestinal resection and/or ostomy Nephropathy (serum creatinine >150 µM and/or albuminuria Liver disease (ALAT and/or serum ASAT >2×normal values) Pregnancy and/or breastfeeding Age above 80 years Any condition that the investigator feels would interfere with trial participation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

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 |
| --- | --- |
| Active Comparator: Pancreatectomised + Lixisenatide<br>During the experimental day the patient will ingest a standardized liquid meal (200 ml containing 1,650 kJ (394 kcal): carbohydrate 50%, protein 15%, fat 35%, consisting of glucose (48.4 g + 1.6 g [U-13C6]-glucose), rapeseed oil (14.1 g), whey protein (15.2 g) and 1.5 g paracetamol). Before the meal a Lixisenatide-injection will be given subcutaneously | Drug: Lixisenatide<br>* single injection of 20 µg lixisenatide subcutaneously<br>* Other names: Lyxumia;Other: Standardized liquid meal<br>* standardized liquid meal (200 ml containing 1,650 kJ (394 kcal): carbohydrate 50%, protein 15%, fat 35%, consisting of glucose (48.4 g + 1.6 g [U-13C6]-glucose), rapeseed oil (14.1 g), whey protein (15.2 g) and 1.5 g paracetamol).<br>|
| Placebo Comparator: Pancreatectomized + lixisenatide-placebo<br>During the experimental day the patient will ingest a standardized liquid meal (200 ml containing 1,650 kJ (394 kcal): carbohydrate 50%, protein 15%, fat 35%, consisting of glucose (48.4 g + 1.6 g [U-13C6]-glucose), rapeseed oil (14.1 g), whey protein (15.2 g) and 1.5 g paracetamol). Before the meal a placebo-injection will be given subcutaneously. | Drug: Lixisenatide-Placebo<br> <br> Other: Standardized liquid meal<br>* standardized liquid meal (200 ml containing 1,650 kJ (394 kcal): carbohydrate 50%, protein 15%, fat 35%, consisting of glucose (48.4 g + 1.6 g [U-13C6]-glucose), rapeseed oil (14.1 g), whey protein (15.2 g) and 1.5 g paracetamol).<br>|
| Active Comparator: Healthy + Lixisenatide<br>During the experimental day the subject will ingest a standardized liquid meal (200 ml containing 1,650 kJ (394 kcal): carbohydrate 50%, protein 15%, fat 35%, consisting of glucose (48.4 g + 1.6 g [U-13C6]-glucose), rapeseed oil (14.1 g), whey protein (15.2 g) and 1.5 g paracetamol). Before the meal a Lixisenatide-injection will be given subcutaneously | Drug: Lixisenatide<br>* single injection of 20 µg lixisenatide subcutaneously<br>* Other names: Lyxumia;Other: Standardized liquid meal<br>* standardized liquid meal (200 ml containing 1,650 kJ (394 kcal): carbohydrate 50%, protein 15%, fat 35%, consisting of glucose (48.4 g + 1.6 g [U-13C6]-glucose), rapeseed oil (14.1 g), whey protein (15.2 g) and 1.5 g paracetamol).<br>|
| Placebo Comparator: Healthy + lixisenatide-placebo<br>During the experimental day the subject will ingest a standardized liquid meal (200 ml containing 1,650 kJ (394 kcal): carbohydrate 50%, protein 15%, fat 35%, consisting of glucose (48.4 g + 1.6 g [U-13C6]-glucose), rapeseed oil (14.1 g), whey protein (15.2 g) and 1.5 g paracetamol). Before the meal a placebo-injection will be given subcutaneously | Drug: Lixisenatide-Placebo<br> <br> Other: Standardized liquid meal<br>* standardized liquid meal (200 ml containing 1,650 kJ (394 kcal): carbohydrate 50%, protein 15%, fat 35%, consisting of glucose (48.4 g + 1.6 g [U-13C6]-glucose), rapeseed oil (14.1 g), whey protein (15.2 g) and 1.5 g paracetamol).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PPG excursions measured as incremental area under curve (iAUC) |  | -120,-45,-30,-15,0,5,10,15,20,25,30,40,50,60,70,80,90,105,120,135,150,180 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| differences in gastric emptying, measurement of s-paracetamol | measurement of time to peak and incremental area under the curve (iAUC) | -30,-15,0,5,10,15,20,25,30,40,50,60,70,80,90,105,120,135,150,180 minutes | 
| food intake and appetite | assessed by a visual analogue scale (VAS) | at time 0,30,60,90,120,150,180 minutes | 
| resting energy expenditure (REE) | measured by calorimetry | -90,30,150 minutes | 
| p-glucose mmol/L |  | -30,-15,0,5,10,15,20,25,30,40,50,60,70,80,90,105,120,135,150,180 minutes | 
| p-C-peptide pmol/l |  | -30,-15,0,5,10,15,20,25,30,40,50,60,70,80,90,105,120,135,150,180 minutes | 
| glucagon, gastrin, cholecystokinin, GIP, GLP-1, oxyntomodulin |  | -30,-15,0,5,10,15,20,25,30,40,50,60,70,80,90,105,120,135,150,180 minutes |