Delineation of the Diabetogenic Role of Extrapancreatic Glucagon in Totally Pancreatectomised Patients Using Glucagon Receptor Antagonism

Study Overview
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Brief Summary
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Patients with diabetes are characterised not only by compromised insulin secretion and action, but also by elevated plasma levels of the 29-amino acid peptide hormone glucagon, which hitherto has been considered a pancreas-derived hormone (produced in and secreted from alpha cells in the islets of Langerhans). In patients with diabetes, circulating glucagon concentrations are elevated in the fasting state and fail to decrease appropriately or even increase in response to an oral glucose tolerance test (OGTT) or after ingestion of a mixed meal. Hyperglucagonaemia is known to be a potent stimulator of hepatic glucose output, and, thus, contributes significantly to the fasting and postprandial hyperglycaemia characterising patients with diabetes. Despite intense research over the years the mechanisms behind the elevated glucagon levels in diabetes is still not clear. Recently, the investigators showed that totally pancreatectomised patients also show a hyperglucagonaemic response during OGTT, a finding that suggests that the pancreas is not the only source of glucagon production in man. In the present project, the investigators wish to evaluate the impact of gastrointestinally derived glucagon secretion observed in totally pancreatectomised patients on postprandial glucose tolerance. The investigators hypothesise that antagonisation of glucagon signalling (from gastrointestinally derived glucagon) in totally pancreatectomised patients will improve or perhaps normalise the patients glucose tolerance during a 75g-OGTT. In order to test this hypothesis, the investigators wish to apply the potent and selective oral antagonist of the human glucagon receptor LY2409021 and placebo, respectively. The study is a randomised, placebo-controlled, double-blinded, cross-over study. 10 healthy persons and 10 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 with LY2409021 and placebo, respectively, on which they will undergo an OGTT followed by a fasting period and finished off with an ad libitum meal.

Official Title
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Delineation of the Diabetogenic Role of Extrapancreatic Glucagon in Totally Pancreatectomised Patients Using Glucagon Receptor Antagonism

Conditions
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Diabetes After Total Pancreatectomy

Intervention / Treatment
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* Drug: Glucagon receptor antagonist LY2409021
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Pancreatectomised patients Caucasian above 18 years of age who have undergone total pancreatectomy Normal haemoglobin Informed consent Healthy subjects Normal fasting plasma glucose 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 Gastrointestinal resection (other than the gastro-duodenectomy performed in connection with total pancreatectomy) and/or ostomy Nephropathy (serum creatinine >150 µmol/l 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 Uncontrolled hypertension and/or significant cardiovascular disease Any condition that the investigator feels would interfere with trial participation Healthy subjects Diabetes or prediabetes (according to the WHO criteria) First-degree relatives with diabetes Inflammatory bowel disease Gastrointestinal 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

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 + LY2409021<br>During the experimental day the patient will undergo a 75gr-OGTT. On the evening before the experimental day, the patient will ingest a dose of 300mg of LY2409021. | Drug: Glucagon receptor antagonist LY2409021<br>* single oral dose of 300mg<br>|
| Placebo Comparator: Pancreatectomised + placebo<br>During the experimental day the patient will undergo a 75gr-OGTT. On the evening before the experimental day, the patient will ingest placebo tablets. | Drug: Placebo<br>* Oral dose of placebo tablets<br>|
| Active Comparator: Healthy + LLY2409021<br>During the experimental day the subject will undergo a 75gr-OGTT. On the evening before the experimental day, the subject will ingest a dose of 300mg of LY2409021. | Drug: Glucagon receptor antagonist LY2409021<br>* single oral dose of 300mg<br>|
| Placebo Comparator: Healthy + placebo<br>During the experimental day the subject will undergo a 75gr-OGTT. On the evening before the experimental day, the subject will ingest placebo tablets. | Drug: Placebo<br>* Oral dose of placebo tablets<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 | 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 | 
| glucagon pmol/l |  | -30,-15,0,5,10,15,20,25,30,40,50,60,70,80,90,105,120,135,150,180 minutes | 
| free fatty acids μmol/l |  | -30,-15,0,5,10,15,20,25,30,40,50,60,70,80,90,105,120,135,150,180 minutes | 
| p-triglyceride mmol/l |  | -30,-15,0,5,10,15,20,25,30,40,50,60,70,80,90,105,120,135,150,180 minutes | 
| Amino Acid concentration μmol/l | total and fractionated | -30,-15,0,5,10,15,20,25,30,40,50,60,70,80,90,105,120,135,150,180 minutes | 
| cholecystokinin pmol/l |  | -30,-15,0,5,10,15,20,25,30,40,50,60,70,80,90,105,120,135,150,180 minutes | 
| Gastric inhibitory peptide (GIP) and Glucagon like peptide-1 (GLP-1) pmol/l |  | -30,-15,0,5,10,15,20,25,30,40,50,60,70,80,90,105,120,135,150,180 minutes |