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

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.


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