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

NCT ID: NCT02944110

Last Updated: 2021-05-05

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: NA
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-04-30
• Study Completion Date: 2021-07-31

Brief Summary

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.

Conditions

Diabetes After Total Pancreatectomy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: DOUBLE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

Glucagon receptor antagonist LY2409021

Intervention Type: DRUG

single oral dose of 300mg

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Oral dose of placebo tablets

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.

Group Type: ACTIVE_COMPARATOR

Glucagon receptor antagonist LY2409021

Intervention Type: DRUG

single oral dose of 300mg

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Oral dose of placebo tablets

Interventions

Glucagon receptor antagonist LY2409021

single oral dose of 300mg

Intervention Type: DRUG

Placebo

Oral dose of placebo tablets

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Eli Lilly and Company

INDUSTRY

Sponsor Role: collaborator

University Hospital, Gentofte, Copenhagen

OTHER

Sponsor Role: lead

Responsible Party

Filip Krag Knop

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Filip K Knop, Professor

Role: PRINCIPAL_INVESTIGATOR

Head of department at Center for Diabetes Research, Gentofte Hospital, Kildegaardsvej 28, 2900 Hellerup, Denmark

References

Juel CT, Lund AB, Haedersdal S, Andersen MM, Hansen CP, Storkholm JH, van Hall G, Hartmann B, Rosenkilde MM, Kibsgaard CJ, Dela F, Albrechtsen NJW, Holst JJ, Vilsboll T, Knop FK. Using glucagon receptor antagonism to evaluate the physiological effects of extrapancreatic glucagon in totally pancreatectomised individuals: a randomised controlled trial. Diabetologia. 2025 Sep 18. doi: 10.1007/s00125-025-06534-z. Online ahead of print.

Reference Type: DERIVED

PMID: 40968190 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33053154 (View on PubMed)

Other Identifiers

H-15009763

Identifier Type: -

Identifier Source: org_study_id