Dissection of the Gastrointestinal-mediated Glucose Disposal and Incretin Defect in Patients With Type 2 Diabetes

Dissection of the Gastrointestinal-mediated Glucose Disposal and Incretin Defect in Patients With Type 2 Diabetes - the Role of Glucagon

In patients with type 2 diabetes, the incretin effect is markedly reduced contributing to the relative insulin deficiency that characterizes these patients. This defect is believed to be due to a decreased effect of GLP-1 and an almost ceased effect of GIP. Nevertheless, the impact of the defect on glucose tolerance is not fully understood. The so-called gastrointestinal-mediated glucose disposal (GIGD) is a measure of glucose handling, which includes the incretin effect, but also other factors affecting glucose disposal (e.g. glucagon secretion). Interestingly, patients with type 2 diabetes exhibit elevated plasma glucagon levels in the fasting state, and glucagon concentrations fail to decrease appropriately and may even increase in response to ingestion of glucose and show exaggerated increases after a mixed meal. With the current project the investigators wish to elucidate how this paradoxical glucagon response observed in patients with type 2 diabetes affects the GIGD, the incretin effect and postprandial glucose excursions.

Ten patients with type 2 diabetes and 10 healthy matched control subjects will be enrolled in this randomised, placebo-controlled, double-blinded study. The aim is to examine the effect of a glucagon receptor antagonist (GRA) on gastrointestinal-mediated glucose disposal (GIGD), incretin effect and postprandial glucose excursions in patients with type 2 diabetes and healthy controls. Participants will attend two oral glucose tolerance tests (OGTT), two isoglycaemic iv glucose infusion (IIGI) and two standardised liquid meals.

Inclusion Criteria:

Patients with type 2 diabetes

• Caucasians above 35 years of age with diet or metformin treated type 2 diabetes for at least 3 month (diagnosed according to the criteria of the World Health Organization (WHO)
• Normal haemoglobin
• Informed consent

Healthy subjects

• Normal fasting plasma glucose (FPG) <6.1 mmol/l and HbA1c <42 mmol/mol (6.0%)
• Normal haemoglobin
• Age above 35 years
• Informed consent

Exclusion Criteria:

Patients with type 2 diabetes

• Inflammatory bowel disease
• Intestinal resections
• Nephropathy (serum creatinine above normal range and/or albuminuria)
• Liver disease (serum alanine aminotransferase (ALAT) and/or serum aspartate aminotransferase (ASAT) >2×normal values)
• Treatment with medicine that cannot be paused for 12 hours
• Pregnancy and/or breastfeeding
• Family history of pancreatic islet tumours
• Age above 80 years

Healthy subjects

• Diabetes or prediabetes with reduced glucose tolerance: FPG >6.0 mmol/l and/or HbA1c >42 mmol/mol
• First degree relatives with type 2 diabetes
• Inflammatory bowel disease
• Intestinal resections
• Treatment with medicine that cannot be paused for 12 hours
• Pregnancy and/or breastfeeding
• Age above 80 years