Delineation of the Diabetogenic Role of Extrapancreatic Glucagon in Totally Pancreatectomised Patients Using Glucagon Receptor Antagonism (PX-GRA)

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.

Study Overview

• Status: Enrolling by invitation
• Conditions: Diabetes After Total Pancreatectomy
• Intervention / Treatment: Drug: Glucagon receptor antagonist LY2409021; Drug: Placebo

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: DOUBLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Pancreatectomised + LY2409021; 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; single oral dose of 300mg
Placebo Comparator: Pancreatectomised + placebo; 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; Oral dose of placebo tablets
Active Comparator: Healthy + LLY2409021; 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; single oral dose of 300mg
Placebo Comparator: Healthy + placebo; 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; Oral dose of placebo tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: University Hospital, Gentofte, Copenhagen
• Collaborators: Eli Lilly and Company
• Investigators: Principal Investigator: Filip K Knop, Professor, Head of department at Center for Diabetes Research, Gentofte Hospital, Kildegaardsvej 28, 2900 Hellerup, Denmark

Publications and helpful links

General Publications

• Juel CTB, Dejgaard TF, Hansen CP, Storkholm JH, Vilsboll T, Lund A, Knop FK. Glycemic Control and Variability of Diabetes Secondary to Total Pancreatectomy Assessed by Continuous Glucose Monitoring. J Clin Endocrinol Metab. 2021 Jan 1;106(1):168-173. doi: 10.1210/clinem/dgaa731. Erratum In: J Clin Endocrinol Metab. 2021 Jun 16;106(7):e2854.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2016
• Primary Completion (Actual): November 1, 2019
• Study Completion (Anticipated): July 1, 2021

Study Registration Dates

• First Submitted: October 24, 2016
• First Submitted That Met QC Criteria: October 24, 2016
• First Posted (Estimate): October 25, 2016

Study Record Updates

• Last Update Posted (Actual): May 5, 2021
• Last Update Submitted That Met QC Criteria: May 3, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Gastrointestinal Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Glucagon
• Other Study ID Numbers: H-15009763

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO