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

Diabetes After Total Pancreatectomy Clinical Trial

— PX-GRA  

Official title:

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

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT02944110
• Other study ID #: H-15009763
• Status: Enrolling by invitation
• Phase: N/A
• Start date: April 2016
• Est. completion date: July 2021

Study information

• Verified date: May 2021
• Source: University Hospital, Gentofte, Copenhagen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 20
• Est. completion date: July 2021
• Est. primary completion date: November 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetes After Total Pancreatectomy

Intervention

Drug:
• Glucagon receptor antagonist LY2409021
single oral dose of 300mg
• Placebo
Oral dose of placebo tablets

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital, Gentofte, Copenhagen	Eli Lilly and Company

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	food intake and appetite	assessed by a visual analogue scale	at time 0,30,60,90,120,150,180 minutes
Secondary	resting energy expenditure (REE)	measured by calorimetry	-90,30,150 minutes
Secondary	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
Secondary	glucagon pmol/l		-30,-15,0,5,10,15,20,25,30,40,50,60,70,80,90,105,120,135,150,180 minutes
Secondary	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
Secondary	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
Secondary	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
Secondary	cholecystokinin pmol/l		-30,-15,0,5,10,15,20,25,30,40,50,60,70,80,90,105,120,135,150,180 minutes
Secondary	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